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96 results on '"Memeo L"'

1. Quantitative predictions of neoadjuvant chemotherapy effects in breast cancer by individual patient data assimililation

Author

Castorina, P., Carco', D., Colarossi, C., Mare, M., Memeo, L., Pace, M., Puliafito, I., and Giuffrida, D.

Subjects
Quantitative Biology - Quantitative Methods
Abstract

Neoadjuvant chemotherapy has been used for breast cancer aiming at downgrading before surgery. In this article we propose a new quantitative analysis of the effects of the neoadjuvant therapy to obtain numerical, personalized, predictions on the shrinkage of the tumor size after the drug doses, by data assimilation of the individual patient. The algorithm has been validated by a sample of 37 patients with histological diagnosis of locally advanced primary breast carcinoma. The biopsy specimen, the initial tumor size and its reduction after each treatment were known for all patients. We find that: a) the measure of tumor size at the diagnosis and after the first dose permits to predict the size reduction for the follow up; b) the results are in agreement with our data sample, within 10-20 %, for about 90% of the patients. The quantitative indications suggest the best time for surgery. The analysis is patient oriented, weakly model dependent and can be applied to other cancer phenotypes., Comment: In press on Annals of Hematology and Oncology

Published
2021

2. Adipose stem cell niche reprograms the colorectal cancer stem cell metastatic machinery

Author

Di Franco, Silvia, Bianca, P., Sardina, D. S., Turdo, A., Gaggianesi, M., Veschi, V., Nicotra, A., Mangiapane, L. R., Lo Iacono, M., Pillitteri, I., van Hooff, S., Martorana, F., Motta, G., Gulotta, E., Lentini, V. L., Martorana, Giuseppe Ettore, Fiori, Micol Eleonora, Vieni, S., Bongiorno, M. R., Giannone, G., Giuffrida, D., Memeo, Lorenzo, Colarossi, L., Mare, M., Vigneri, P., Todaro, M., De Maria Marchiano, Ruggero, Medema, J. P., Stassi, G., Di Franco S., Martorana E., Fiori M. E., Memeo L., De Maria R. (ORCID:0000-0003-2255-0583), Di Franco, Silvia, Bianca, P., Sardina, D. S., Turdo, A., Gaggianesi, M., Veschi, V., Nicotra, A., Mangiapane, L. R., Lo Iacono, M., Pillitteri, I., van Hooff, S., Martorana, F., Motta, G., Gulotta, E., Lentini, V. L., Martorana, Giuseppe Ettore, Fiori, Micol Eleonora, Vieni, S., Bongiorno, M. R., Giannone, G., Giuffrida, D., Memeo, Lorenzo, Colarossi, L., Mare, M., Vigneri, P., Todaro, M., De Maria Marchiano, Ruggero, Medema, J. P., Stassi, G., Di Franco S., Martorana E., Fiori M. E., Memeo L., and De Maria R. (ORCID:0000-0003-2255-0583)

Abstract

Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored. Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 +), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease.

Published
2021

10. The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling

Author

Engström, W. Darbre, P. Eriksson, S. Gulliver, L. Hultman, T. Karamouzis, M.V. Klaunig, J.E. Mehta, R. Moorwood, K. Sanderson, T. Sone, H. Vadgama, P. Wagemaker, G. Ward, A. Singh, N. Al-Mulla, F. Al-Temaimi, R. Amedei, A. Colacci, A.M. Vaccari, M. Mondello, C. Ivana Scovassi, A. Raju, J. Hamid, R.A. Memeo, L. Forte, S. Roy, R. Woodrick, J. Salem, H.K. Ryan, E. Brown, D.G. Bisson, W.H.

Abstract

The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span. © The Author 2015.

Published
2015

11. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: The challenge ahead

Author

Goodson, W.H., III Lowe, L. Carpenter, D.O. Gilbertson, M. Ali, A.M. de Cerain Salsamendi, A.L. Lasfar, A. Carnero, A. Azqueta, A. Amedei, A. Charles, A.K. Collins, A.R. Ward, A. Salzberg, A.C. Colacci, A. Olsen, A.-K. Berg, A. Barclay, B.J. Zhou, B.P. Blanco-Aparicio, C. Baglole, C.J. Dong, C. Mondello, C. Hsu, C.-W. Naus, C.C. Yedjou, C. Curran, C.S. Laird, D.W. Koch, D.C. Carlin, D.J. Felsher, D.W. Roy, D. Brown, D.G. Ratovitski, E. Ryan, E.P. Corsini, E. Rojas, E. Moon, E.-Y. Laconi, E. Marongiu, F. Al-Mulla, F. Chiaradonna, F. Darroudi, F. Martin, F.L. Van Schooten, F.J. Goldberg, G.S. Wagemaker, G. Nangami, G. Calaf, G.M. Williams, G. Wolf, G.T. Koppen, G. Brunborg, G. Kim Lyerly, H. Krishnan, H. Hamid, H.A. Yasaei, H. Sone, H. Kondoh, H. Salem, H.K. Hsu, H.-Y. Park, H.H. Koturbash, I. Miousse, I.R. Ivana Scovassi, A. Klaunig, J.E. Vondráček, J. Raju, J. Roman, J. Wise, J.P., Sr. Whitfield, J.R. Woodrick, J. Christopher, J.A. Ochieng, J. Martinez-Leal, J.F. Weisz, J. Kravchenko, J. Sun, J. Prudhomme, K.R. Narayanan, K.B. Cohen-Solal, K.A. Moorwood, K. Gonzalez, L. Soucek, L. Jian, L. D'Abronzo, L.S. Lin, L.-T. Li, L. Gulliver, L. McCawley, L.J. Memeo, L. Vermeulen, L. Leyns, L. Zhang, L. Valverde, M. Khatami, M. Romano, M.F. Chapellier, M. Williams, M.A. Wade, M. Manjili, M.H. Lleonart, M. Xia, M. Gonzalez, M.J. Karamouzis, M.V. Kirsch-Volders, M. Vaccari, M. Kuemmerle, N.B. Singh, N. Cruickshanks, N. Kleinstreuer, N. Van Larebeke, N. Ahmed, N. Ogunkua, O. Krishnakumar, P.K. Vadgama, P. Marignani, P.A. Ghosh, P.M. Ostrosky-Wegman, P. Thompson, P. Dent, P. Heneberg, P. Darbre, P. Leung, P.S. Nangia-Makker, P. Cheng, Q.S. Brooks Robey, R. Al-Temaimi, R. Roy, R. Andrade-Vieira, R. Sinha, R.K. Mehta, R. Vento, R. Di Fiore, R. Ponce-Cusi, R. Dornetshuber-Fleiss, R. Nahta, R. Castellino, R.C. Palorini, R. Hamid, R.A. Langie, S.A.S. Eltom, S. Brooks, S.A. Ryeom, S. Wise, S.S. Bay, S.N. Harris, S.A. Papagerakis, S. Romano, S. Pavanello, S. Eriksson, S. Forte, S. Casey, S.C. Luanpitpong, S. Lee, T.-J. Otsuki, T. Chen, T. Massfelder, T. Sanderson, T. Guarnieri, T. Hultman, T. Dormoy, V. Odero-Marah, V. Sabbisetti, V. Maguer-Satta, V. Kimryn Rathmell, W. Engström, W. Decker, W.K. Bisson, W.H. Rojanasakul, Y. Luqmani, Y. Chen, Z. Hu, Z.

Abstract

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology. © The Author 2015.

Published
2015

12. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Author

Goodson, WH, Lowe, L, Carpenter, DO, Gilbertson, M, Ali, AM, de Cerain Salsamendi, AL, Lasfar, A, Carnero, A, Azqueta, A, Amedei, A, Charles, AK, Collins, AR, Ward, A, Salzberg, AC, Colacci, A, Olsen, A-K, Berg, A, Barclay, BJ, Zhou, BP, Blanco-Aparicio, C, Baglole, CJ, Dong, C, Mondello, C, Hsu, C-W, Naus, CC, Yedjou, C, Curran, CS, Laird, DW, Koch, DC, Carlin, DJ, Felsher, DW, Roy, D, Brown, DG, Ratovitski, E, Ryan, EP, Corsini, E, Rojas, E, Moon, E-Y, Laconi, E, Marongiu, F, Al-Mulla, F, Chiaradonna, F, Darroudi, F, Martin, FL, Van Schooten, FJ, Goldberg, GS, Wagemaker, G, Nangami, G, Calaf, GM, Williams, G, Wolf, GT, Koppen, G, Brunborg, G, Lyerly, HK, Krishnan, H, Ab Hamid, H, Yasaei, H, Sone, H, Kondoh, H, Salem, HK, Hsu, H-Y, Park, HH, Koturbash, I, Miousse, IR, Scovassi, AI, Klaunig, JE, Vondracek, J, Raju, J, Roman, J, Wise, JP, Whitfield, JR, Woodrick, J, Christopher, JA, Ochieng, J, Fernando Martinez-Leal, J, Weisz, J, Kravchenko, J, Sun, J, Prudhomme, KR, Narayanan, KB, Cohen-Solal, KA, Moorwood, K, Gonzalez, L, Soucek, L, Jian, L, D'Abronzo, LS, Lin, L-T, Li, L, Gulliver, L, McCawley, LJ, Memeo, L, Vermeulen, L, Leyns, L, Zhang, L, Valverde, M, Khatami, M, Romano, MF, Chapellier, M, Williams, MA, Wade, M, Manjili, MH, Lleonart, M, Xia, M, Gonzalez, MJ, Karamouzis, MV, Kirsch-Volders, M, Vaccari, M, Kuemmerle, NB, Singh, N, Cruickshanks, N, Kleinstreuer, N, van Larebeke, N, Ahmed, N, Ogunkua, O, Krishnakumar, PK, Vadgama, P, Marignani, PA, Ghosh, PM, Ostrosky-Wegman, P, Thompson, P, Dent, P, Heneberg, P, Darbre, P, Leung, PS, Nangia-Makker, P, Cheng, QS, Robey, RB, Al-Temaimi, R, Roy, R, Andrade-Vieira, R, Sinha, RK, Mehta, R, Vento, R, Di Fiore, R, Ponce-Cusi, R, Dornetshuber-Fleiss, R, Nahta, R, Castellino, RC, Palorini, R, Abd Hamid, R, Langie, SAS, Eltom, S, Brooks, SA, Ryeom, S, Wise, SS, Bay, SN, Harris, SA, Papagerakis, S, Romano, S, Pavanello, S, Eriksson, S, Forte, S, Casey, SC, Luanpitpong, S, Lee, T-J, Otsuki, T, Chen, T, Massfelder, T, Sanderson, T, Guarnieri, T, Hultman, T, Dormoy, V, Odero-Marah, V, Sabbisetti, V, Maguer-Satta, V, Rathmell, WK, Engstrom, W, Decker, WK, Bisson, WH, Rojanasakul, Y, Luqmani, Y, Chen, Z, Hu, Z, Goodson, WH, Lowe, L, Carpenter, DO, Gilbertson, M, Ali, AM, de Cerain Salsamendi, AL, Lasfar, A, Carnero, A, Azqueta, A, Amedei, A, Charles, AK, Collins, AR, Ward, A, Salzberg, AC, Colacci, A, Olsen, A-K, Berg, A, Barclay, BJ, Zhou, BP, Blanco-Aparicio, C, Baglole, CJ, Dong, C, Mondello, C, Hsu, C-W, Naus, CC, Yedjou, C, Curran, CS, Laird, DW, Koch, DC, Carlin, DJ, Felsher, DW, Roy, D, Brown, DG, Ratovitski, E, Ryan, EP, Corsini, E, Rojas, E, Moon, E-Y, Laconi, E, Marongiu, F, Al-Mulla, F, Chiaradonna, F, Darroudi, F, Martin, FL, Van Schooten, FJ, Goldberg, GS, Wagemaker, G, Nangami, G, Calaf, GM, Williams, G, Wolf, GT, Koppen, G, Brunborg, G, Lyerly, HK, Krishnan, H, Ab Hamid, H, Yasaei, H, Sone, H, Kondoh, H, Salem, HK, Hsu, H-Y, Park, HH, Koturbash, I, Miousse, IR, Scovassi, AI, Klaunig, JE, Vondracek, J, Raju, J, Roman, J, Wise, JP, Whitfield, JR, Woodrick, J, Christopher, JA, Ochieng, J, Fernando Martinez-Leal, J, Weisz, J, Kravchenko, J, Sun, J, Prudhomme, KR, Narayanan, KB, Cohen-Solal, KA, Moorwood, K, Gonzalez, L, Soucek, L, Jian, L, D'Abronzo, LS, Lin, L-T, Li, L, Gulliver, L, McCawley, LJ, Memeo, L, Vermeulen, L, Leyns, L, Zhang, L, Valverde, M, Khatami, M, Romano, MF, Chapellier, M, Williams, MA, Wade, M, Manjili, MH, Lleonart, M, Xia, M, Gonzalez, MJ, Karamouzis, MV, Kirsch-Volders, M, Vaccari, M, Kuemmerle, NB, Singh, N, Cruickshanks, N, Kleinstreuer, N, van Larebeke, N, Ahmed, N, Ogunkua, O, Krishnakumar, PK, Vadgama, P, Marignani, PA, Ghosh, PM, Ostrosky-Wegman, P, Thompson, P, Dent, P, Heneberg, P, Darbre, P, Leung, PS, Nangia-Makker, P, Cheng, QS, Robey, RB, Al-Temaimi, R, Roy, R, Andrade-Vieira, R, Sinha, RK, Mehta, R, Vento, R, Di Fiore, R, Ponce-Cusi, R, Dornetshuber-Fleiss, R, Nahta, R, Castellino, RC, Palorini, R, Abd Hamid, R, Langie, SAS, Eltom, S, Brooks, SA, Ryeom, S, Wise, SS, Bay, SN, Harris, SA, Papagerakis, S, Romano, S, Pavanello, S, Eriksson, S, Forte, S, Casey, SC, Luanpitpong, S, Lee, T-J, Otsuki, T, Chen, T, Massfelder, T, Sanderson, T, Guarnieri, T, Hultman, T, Dormoy, V, Odero-Marah, V, Sabbisetti, V, Maguer-Satta, V, Rathmell, WK, Engstrom, W, Decker, WK, Bisson, WH, Rojanasakul, Y, Luqmani, Y, Chen, Z, and Hu, Z

Abstract

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

Published
2015

13. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: The challenge ahead

Author

Goodson, W, Lowe, L, Carpenter, D, Gilbertson, M, Ali, A, de Cerain Salsamendi, A, Lasfar, A, Carnero, A, Azqueta, A, Amedei, A, Charles, A, Collins, A, Ward, A, Salzberg, A, Colacci, A, Olsen, A, Berg, A, Barclay, B, Zhou, B, Blanco Aparicio, C, Baglole, C, Dong, C, Mondello, C, Hsu, C, Naus, C, Yedjou, C, Curran, C, Laird, D, Koch, D, Carlin, D, Felsher, D, Roy, D, Brown, D, Ratovitski, E, Ryan, E, Corsini, E, Rojas, E, Moon, E, Laconi, E, Marongiu, F, Al Mulla, F, Chiaradonna, F, Darroudi, F, Martin, F, Van Schooten, F, Goldberg, G, Wagemaker, G, Nangami, G, Calaf, G, Williams, G, Wolf, G, Koppen, G, Brunborg, G, Kim Lyerly, H, Krishnan, H, Hamid, H, Yasaei, H, Sone, H, Kondoh, H, Salem, H, Hsu, H, Park, H, Koturbash, I, Miousse, I, Ivana Scovassi, A, Klaunig, J, Vondráček, J, Raju, J, Roman, J, Wise, J, Whitfield, J, Woodrick, J, Christopher, J, Ochieng, J, Martinez Leal, J, Weisz, J, Kravchenko, J, Sun, J, Prudhomme, K, Narayanan, K, Cohen Solal, K, Moorwood, K, Gonzalez, L, Soucek, L, Jian, L, D'Abronzo, L, Lin, L, Li, L, Gulliver, L, Mccawley, L, Memeo, L, Vermeulen, L, Leyns, L, Zhang, L, Valverde, M, Khatami, M, Romano, M, Chapellier, M, Williams, M, Wade, M, Manjili, M, Lleonart, M, Xia, M, Gonzalez, M, Karamouzis, M, Kirsch Volders, M, Vaccari, M, Kuemmerle, N, Singh, N, Cruickshanks, N, Kleinstreuer, N, Van Larebeke, N, Ahmed, N, Ogunkua, O, Krishnakumar, P, Vadgama, P, Marignani, P, Ghosh, P, Ostrosky Wegman, P, Thompson, P, Dent, P, Heneberg, P, Darbre, P, Leung, P, Nangia Makker, P, Cheng, Q, Brooks Robey, R, Al Temaimi, R, Roy, R, Andrade Vieira, R, Sinha, R, Mehta, R, Vento, R, Di Fiore, R, Ponce Cusi, R, Dornetshuber Fleiss, R, Nahta, R, Castellino, R, Palorini, R, Hamid, R, Langie, S, Eltom, S, Brooks, S, Ryeom, S, Wise, S, Bay, S, Harris, S, Papagerakis, S, Romano, S, Pavanello, S, Eriksson, S, Forte, S, Casey, S, Luanpitpong, S, Lee, T, Otsuki, T, Chen, T, Massfelder, T, Sanderson, T, Guarnieri, T, Hultman, T, Dormoy, V, Odero Marah, V, Sabbisetti, V, Maguer Satta, V, Kimryn Rathmell, W, Engström, W, Decker, W, Bisson, W, Rojanasakul, Y, Luqmani, Y, Chen, Z, Hu, Z, CHIARADONNA, FERDINANDO, PALORINI, ROBERTA, Hu, Z., Goodson, W, Lowe, L, Carpenter, D, Gilbertson, M, Ali, A, de Cerain Salsamendi, A, Lasfar, A, Carnero, A, Azqueta, A, Amedei, A, Charles, A, Collins, A, Ward, A, Salzberg, A, Colacci, A, Olsen, A, Berg, A, Barclay, B, Zhou, B, Blanco Aparicio, C, Baglole, C, Dong, C, Mondello, C, Hsu, C, Naus, C, Yedjou, C, Curran, C, Laird, D, Koch, D, Carlin, D, Felsher, D, Roy, D, Brown, D, Ratovitski, E, Ryan, E, Corsini, E, Rojas, E, Moon, E, Laconi, E, Marongiu, F, Al Mulla, F, Chiaradonna, F, Darroudi, F, Martin, F, Van Schooten, F, Goldberg, G, Wagemaker, G, Nangami, G, Calaf, G, Williams, G, Wolf, G, Koppen, G, Brunborg, G, Kim Lyerly, H, Krishnan, H, Hamid, H, Yasaei, H, Sone, H, Kondoh, H, Salem, H, Hsu, H, Park, H, Koturbash, I, Miousse, I, Ivana Scovassi, A, Klaunig, J, Vondráček, J, Raju, J, Roman, J, Wise, J, Whitfield, J, Woodrick, J, Christopher, J, Ochieng, J, Martinez Leal, J, Weisz, J, Kravchenko, J, Sun, J, Prudhomme, K, Narayanan, K, Cohen Solal, K, Moorwood, K, Gonzalez, L, Soucek, L, Jian, L, D'Abronzo, L, Lin, L, Li, L, Gulliver, L, Mccawley, L, Memeo, L, Vermeulen, L, Leyns, L, Zhang, L, Valverde, M, Khatami, M, Romano, M, Chapellier, M, Williams, M, Wade, M, Manjili, M, Lleonart, M, Xia, M, Gonzalez, M, Karamouzis, M, Kirsch Volders, M, Vaccari, M, Kuemmerle, N, Singh, N, Cruickshanks, N, Kleinstreuer, N, Van Larebeke, N, Ahmed, N, Ogunkua, O, Krishnakumar, P, Vadgama, P, Marignani, P, Ghosh, P, Ostrosky Wegman, P, Thompson, P, Dent, P, Heneberg, P, Darbre, P, Leung, P, Nangia Makker, P, Cheng, Q, Brooks Robey, R, Al Temaimi, R, Roy, R, Andrade Vieira, R, Sinha, R, Mehta, R, Vento, R, Di Fiore, R, Ponce Cusi, R, Dornetshuber Fleiss, R, Nahta, R, Castellino, R, Palorini, R, Hamid, R, Langie, S, Eltom, S, Brooks, S, Ryeom, S, Wise, S, Bay, S, Harris, S, Papagerakis, S, Romano, S, Pavanello, S, Eriksson, S, Forte, S, Casey, S, Luanpitpong, S, Lee, T, Otsuki, T, Chen, T, Massfelder, T, Sanderson, T, Guarnieri, T, Hultman, T, Dormoy, V, Odero Marah, V, Sabbisetti, V, Maguer Satta, V, Kimryn Rathmell, W, Engström, W, Decker, W, Bisson, W, Rojanasakul, Y, Luqmani, Y, Chen, Z, Hu, Z, CHIARADONNA, FERDINANDO, PALORINI, ROBERTA, and Hu, Z.

Abstract

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

Published
2015

14. Metabolic reprogramming and dysregulated metabolism: Cause, consequence and/or enabler of environmental carcinogenesis?

Author

Brooks Robey, R, Weisz, J, Kuemmerle, N, Salzberg, A, Berg, A, Brown, D, Kubik, L, Palorini, R, Al Mulla, F, Al Temaimi, R, Colacci, A, Mondello, C, Raju, J, Woodrick, J, Ivana Scovassi, A, Singh, N, Vaccari, M, Roy, R, Forte, S, Memeo, L, Salem, H, Amedei, A, Hamid, R, Williams, G, Lowe, L, Meyer, J, Martin, F, Bisson, W, Chiaradonna, F, Ryan, E, PALORINI, ROBERTA, CHIARADONNA, FERDINANDO, Ryan, E., Brooks Robey, R, Weisz, J, Kuemmerle, N, Salzberg, A, Berg, A, Brown, D, Kubik, L, Palorini, R, Al Mulla, F, Al Temaimi, R, Colacci, A, Mondello, C, Raju, J, Woodrick, J, Ivana Scovassi, A, Singh, N, Vaccari, M, Roy, R, Forte, S, Memeo, L, Salem, H, Amedei, A, Hamid, R, Williams, G, Lowe, L, Meyer, J, Martin, F, Bisson, W, Chiaradonna, F, Ryan, E, PALORINI, ROBERTA, CHIARADONNA, FERDINANDO, and Ryan, E.

Abstract

Environmental contributions to cancer development are widely accepted, but only a fraction of all pertinent exposures have probably been identified. Traditional toxicological approaches to the problem have largely focused on the effects of individual agents at singular endpoints. As such, they have incompletely addressed both the pro-carcinogenic contributions of environmentally relevant low-dose chemical mixtures and the fact that exposures can influence multiple cancer associated endpoints over varying timescales. Of these endpoints, dysregulated metabolism is one of the most common and recognizable features of cancer, but its specific roles in exposure-associated cancer development remain poorly understood. Most studies have focused on discrete aspects of cancer metabolism and have incompletely considered both its dynamic integrated nature and the complex controlling influences of substrate availability, external trophic signals and environmental conditions. Emerging high throughput approaches to environmental risk assessment also do not directly address the metabolic causes or consequences of changes in gene expression. As such, there is a compelling need to establish common or complementary frameworks for further exploration that experimentally and conceptually consider the gestalt of cancer metabolism and its causal relationships to both carcinogenesis and the development of other cancer hallmarks. A literature review to identify environmentally relevant exposures unambiguously linked to both cancer development and dysregulated metabolism suggests major gaps in our understanding of exposure-associated carcinogenesis and metabolic reprogramming. Although limited evidence exists to support primary causal roles for metabolism in carcinogenesis, the universality of altered cancer metabolism underscores its fundamental biological importance, and multiple pleiomorphic, even dichotomous, roles for metabolism in promoting, antagonizing or otherwise enabling the develo

Published
2015

15. Numb Expression Contributes to the Maintenance of an Undifferentiated State in Human Epidermis

Author

Iannolo, G, Sciuto, Maria Rita, Buccheri, S, Colarossi, C, De Maria Marchiano, Ruggero, Memeo, L, Conaldi, Pg., Sciuto MR, De Maria R (ORCID:0000-0003-2255-0583), Iannolo, G, Sciuto, Maria Rita, Buccheri, S, Colarossi, C, De Maria Marchiano, Ruggero, Memeo, L, Conaldi, Pg., Sciuto MR, and De Maria R (ORCID:0000-0003-2255-0583)

Abstract

The epidermis is a stratified epithelium with a stem cell subpopulation in the basal layer that constantly replicates and periodically detaches from the base, undergoing a differentiation process that involves various developmen- tal signals and regulatory pathways. During the last 10 years, a number of studies tried to elucidate the intricate scenario that maintains the epithelial shield during the entire life span. In our study, we investigated the role of Numb in the skin compartment and, in particular, its involvement in stem cell maintenance. Numb expression in the skin compartment was assessed by immunofluorescence and immunohistochemistry analysis. We evaluated Numb expression in primary epithelial cells at various differentiative stages. Moreover, we overexpressed Numb in the isolated population enriched for undifferentiated progenitors to establish its involvement in in vitro differ- entiation. We demonstrated that Numb in high-proliferating epithelial undifferentiated progenitors contributes to the maintenance of an undifferentiated state. This regulation involves the E3 ligases Itch binding. Moreover, the analysis of a cohort of cutaneous carcinomas showed that Numb is highly expressed in squamous cell carcinoma (SCC), where we observed a direct correlation between the expression of Numb and Ki-67. Our data indicate for the first time that Numb is involved in the maintenance of the undifferentiated proliferating stem cell pool in the epithelial basal layer and its expression could become a new marker in skin cancer.

Published
2015

16. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: The challenge ahead

Author

Goodson, W., Lowe, L., Carpenter, D., Gilbertson, M., Ali, A., de Cerain Salsamendi, A., Lasfar, A., Carnero, A., Azqueta, A., Amedei, A., Charles, A., Collins, A., Ward, A., Salzberg, A., Colacci, A., Olsen, A., Berg, A., Barclay, B., Zhou, B., Blanco-Aparicio, C., Baglole, C., Dong, C., Mondello, C., Hsu, C., Naus, C., Yedjou, C., Curran, C., Laird, D., Koch, D., Carlin, D., Felsher, D., Roy, D., Brown, D., Ratovitski, E., Ryan, E., Corsini, E., Rojas, E., Moon, E., Laconi, E., Marongiu, F., Al-Mulla, F., Chiaradonna, F., Darroudi, F., Martin, F., Van Schooten, F., Goldberg, G., Wagemaker, G., Nangami, G., Calaf, G., Williams, G., Wolf, G., Koppen, G., Brunborg, G., Kim Lyerly, H., Krishnan, H., Hamid, H., Yasaei, H., Sone, H., Kondoh, H., Salem, H., Hsu, H., Park, H., Koturbash, I., Miousse, I., Ivana Scovassi, A., Klaunig, J., Vondrácek, J., Raju, J., Roman, J., Wise, J., Whitfield, J., Woodrick, J., Christopher, J., Ochieng, J., Martinez-Leal, J., Weisz, J., Kravchenko, J., Sun, J., Prudhomme, K., Narayanan, K., Cohen-Solal, K., Moorwood, K., Gonzalez, L., Soucek, L., Jian, Le, D'Abronzo, L., Lin, L., Li, L., Gulliver, L., McCawley, L., Memeo, L., Vermeulen, L., Leyns, L., Zhang, L., Goodson, W., Lowe, L., Carpenter, D., Gilbertson, M., Ali, A., de Cerain Salsamendi, A., Lasfar, A., Carnero, A., Azqueta, A., Amedei, A., Charles, A., Collins, A., Ward, A., Salzberg, A., Colacci, A., Olsen, A., Berg, A., Barclay, B., Zhou, B., Blanco-Aparicio, C., Baglole, C., Dong, C., Mondello, C., Hsu, C., Naus, C., Yedjou, C., Curran, C., Laird, D., Koch, D., Carlin, D., Felsher, D., Roy, D., Brown, D., Ratovitski, E., Ryan, E., Corsini, E., Rojas, E., Moon, E., Laconi, E., Marongiu, F., Al-Mulla, F., Chiaradonna, F., Darroudi, F., Martin, F., Van Schooten, F., Goldberg, G., Wagemaker, G., Nangami, G., Calaf, G., Williams, G., Wolf, G., Koppen, G., Brunborg, G., Kim Lyerly, H., Krishnan, H., Hamid, H., Yasaei, H., Sone, H., Kondoh, H., Salem, H., Hsu, H., Park, H., Koturbash, I., Miousse, I., Ivana Scovassi, A., Klaunig, J., Vondrácek, J., Raju, J., Roman, J., Wise, J., Whitfield, J., Woodrick, J., Christopher, J., Ochieng, J., Martinez-Leal, J., Weisz, J., Kravchenko, J., Sun, J., Prudhomme, K., Narayanan, K., Cohen-Solal, K., Moorwood, K., Gonzalez, L., Soucek, L., Jian, Le, D'Abronzo, L., Lin, L., Li, L., Gulliver, L., McCawley, L., Memeo, L., Vermeulen, L., Leyns, L., and Zhang, L.

Abstract

© The Author 2015. Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

Published
2015

19. Unique Osteoid Osteoma of the Frontal Sinus From the Late Roman Empire

Author

Maria Teresa Magro, Carmine Lubritto, Lorenzo Memeo, Francesco M Galassi, Rodolfo Brancato, Elena Varotto, Varotto, E., Magro, M. T., Brancato, R., Lubritto, C., Memeo, L., Galassi, F. M., Brancato, R, Galassi, F M, Lubritto, C, Magro, M T, Memeo, L, and Varotto, E

Subjects
Osteoid osteoma, Frontal sinus, business.industry, General Medicine, Anatomy, medicine.disease, Funerary Archaeology, Ancient Sicily, Anthropology, Paleopathology, Osteoid Osteoma, Roman Empire, medicine.anatomical_structure, Otorhinolaryngology, medicine, Surgery, business, Paleopathology
Abstract

The paper is a report of a unique case of a tumor - a case of Osteoid Osteoma - in an ancient skeleton from the cemetery of Pianotta di Calatabiano (Eastern Sicily), dating to the Late Roman Period.

Published
2019

20. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Author

Dustin G. Brown, Tove Hultman, Judith Weisz, H. Kim Lyerly, Paola A. Marignani, Ann-Karin Olsen, Rabindra Roy, Kim Moorwood, Masoud H. Manjili, Monica Vaccari, Jesse Roman, Hasiah Ab Hamid, Kalan R. Prudhomme, Periyadan K. Krishnakumar, Chenfang Dong, Tiziana Guarnieri, Leandro S. D'Abronzo, Gloria M. Calaf, Amelia K Charles, Emanuela Corsini, Yunus A. Luqmani, Graeme Williams, Louis Vermeulen, Pankaj Vadgama, Sarah N Bay, Véronique Maguer-Satta, Sabine A. S. Langie, Christian C. Naus, Le Jian, Gladys N. Nangami, Lorenzo Memeo, Stephanie C. Casey, Thomas Sanderson, Takemi Otsuki, Nichola Cruickshanks, William H. Bisson, Sudjit Luanpitpong, Jonathan Whitfield, Ahmed Lasfar, Yon Rojanasakul, A. Ivana Scovassi, Shelley A. Harris, Ferdinando Chiaradonna, Richard Ponce-Cusi, Gregory T. Wolf, Valérian Dormoy, Roslida Abd Hamid, Hyun Ho Park, Matilde E. Lleonart, William K. Decker, Maria Romano, Leroy Lowe, Fabio Marongiu, Jan Vondráček, Chiara Mondello, Luc Leyns, Josiah Ochieng, Pratima Nangia-Makker, Edward A. Ratovitski, Zhiwei Hu, Jayadev Raju, Hemad Yasaei, Rafaela Andrade-Vieira, Jordan Woodrick, Hideko Sone, Harini Krishnan, W. Kimryn Rathmell, Andrew Collins, Luoping Zhang, Barry J. Barclay, Amaya Azqueta, Laura Soucek, Marc A. Williams, David O. Carpenter, Roberta Palorini, Rita Nahta, Juan Fernando Martinez-Leal, Firouz Darroudi, Rita Dornetshuber-Fleiss, James E. Klaunig, Elizabeth P. Ryan, Qiang Shawn Cheng, Arthur Berg, Andrew Ward, Gudrun Koppen, Tao Chen, Petr Heneberg, Michael Gilbertson, Amedeo Amedei, Sakina E. Eltom, Ezio Laconi, Joseph Christopher, Hiroshi Kondoh, Neetu Singh, Danielle J Carlin, Marion Chapellier, Michalis V. Karamouzis, Rekha Mehta, Tae-Jin Lee, Annamaria Colacci, Venkata S. Sabbisetti, Mark Wade, Micheline Kirsch-Volders, Patricia Ostrosky-Wegman, Isabelle R. Miousse, Patricia A. Thompson, Philippa D. Darbre, Frederik J. van Schooten, Sofia Pavanello, Igor Koturbash, Binhua P. Zhou, Ranjeet Kumar Sinha, Anna C. Salzberg, Mahara Valverde, Fahd Al-Mulla, Julia Kravchenko, Nicole Kleinstreuer, Carolyn J. Baglole, Menghang Xia, Samira A. Brooks, Amancio Carnero, Gunnar Brunborg, Sandra S. Wise, Daniel C. Koch, John Pierce Wise, Rabeah Al-Temaimi, Laetitia Gonzalez, Lisa J. McCawley, R. Brooks Robey, Gary S. Goldberg, Thierry Massfelder, Linda S M Gulliver, Olugbemiga Ogunkua, Emilio Rojas, Eun-Yi Moon, Lin Li, Silvana Papagerakis, Nik van Larebeke, Adela Lopez de Cerain Salsamendi, Staffan Eriksson, Simona Romano, Dean W. Felsher, Paramita M. Ghosh, Karine A. Cohen-Solal, Paul Dent, Jun Sun, Carmen Blanco-Aparicio, Riccardo Di Fiore, Chia-Wen Hsu, Mahin Khatami, Kannan Badri Narayanan, Francis Martin, Colleen S. Curran, Dale W. Laird, William H. Goodson, Abdul Manaf Ali, Valerie Odero-Marah, Michael J. Gonzalez, Renza Vento, Liang Tzung Lin, Clement G. Yedjou, Hosni Salem, Hsue-Yin Hsu, Zhenbang Chen, Nuzhat Ahmed, Gerard Wagemaker, Sandra Ryeom, Stefano Forte, Debasish Roy, Nancy B. Kuemmerle, Robert C. Castellino, Po Sing Leung, Wilhelm Engström, National Institute of Environmental Health Sciences (US), Research Council of Norway, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Red Temática de Investigación Cooperativa en Cáncer (España), European Commission, Junta de Andalucía, Ministerio de Educación y Ciencia (España), Ministero dell'Istruzione, dell'Università e della Ricerca, University of Oslo, Regione Emilia Romagna, National Institutes of Health (US), Consejo Nacional de Ciencia y Tecnología (México), Associazione Italiana per la Ricerca sul Cancro, National Research Foundation of Korea, Ministry of Education, Science and Technology (South Korea), Fondo Nacional de Desarrollo Científico y Tecnológico (Chile), Ministry of Education, Culture, Sports, Science and Technology (Japan), Japan Science and Technology Agency, Ministry of Science and Technology (Taiwan), Arkansas Biosciences Institute, Czech Science Foundation, Fundación Fero, Swim Across America, American Cancer Society, Research Foundation - Flanders, Austrian Science Fund, Institut National de la Santé et de la Recherche Médicale (France), Natural Sciences and Engineering Research Council of Canada, Farmacologie en Toxicologie, RS: NUTRIM - R4 - Gene-environment interaction, Goodson, William H, Lowe, Leroy, Carpenter, David O, Gilbertson, Michael, Manaf Ali, Abdul, Lopez de Cerain Salsamendi, Adela, Lasfar, Ahmed, Carnero, Amancio, Azqueta, Amaya, Amedei, Amedeo, Charles, Amelia K, Collins, Andrew R, Ward, Andrew, Salzberg, Anna C, Colacci, Annamaria, Olsen, Ann Karin, Berg, Arthur, Barclay, Barry J, Zhou, Binhua P, Blanco Aparicio, Carmen, Baglole, Carolyn J, Dong, Chenfang, Mondello, Chiara, Hsu, Chia Wen, Naus, Christian C, Yedjou, Clement, Curran, Colleen S, Laird, Dale W, Koch, Daniel C, Carlin, Danielle J, Felsher, Dean W, Roy, Debasish, Brown, Dustin G, Ratovitski, Edward, Ryan, Elizabeth P, Corsini, Emanuela, Rojas, Emilio, Moon, Eun Yi, Laconi, Ezio, Marongiu, Fabio, Al Mulla, Fahd, Chiaradonna, Ferdinando, Darroudi, Firouz, Martin, Francis L, Van Schooten, Frederik J, Goldberg, Gary S, Wagemaker, Gerard, Nangami, Gladys N, Calaf, Gloria M, Williams, Graeme, Wolf, Gregory T, Koppen, Gudrun, Brunborg, Gunnar, Lyerly, H. Kim, Krishnan, Harini, Ab Hamid, Hasiah, Yasaei, Hemad, Sone, Hideko, Kondoh, Hiroshi, Salem, Hosni K, Hsu, Hsue Yin, Park, Hyun Ho, Koturbash, Igor, Miousse, Isabelle R, Scovassi, A. Ivana, Klaunig, James E, Vondráček, Jan, Raju, Jayadev, Roman, Jesse, Wise, John Pierce, Whitfield, Jonathan R, Woodrick, Jordan, Christopher, Joseph A, Ochieng, Josiah, Martinez Leal, Juan Fernando, Weisz, Judith, Kravchenko, Julia, Sun, Jun, Prudhomme, Kalan R, Narayanan, Kannan Badri, Cohen Solal, Karine A, Moorwood, Kim, Gonzalez, Laetitia, Soucek, Laura, Jian, Le, D'Abronzo, Leandro S, Lin, Liang Tzung, Li, Lin, Gulliver, Linda, Mccawley, Lisa J, Memeo, Lorenzo, Vermeulen, Loui, Leyns, Luc, Zhang, Luoping, Valverde, Mahara, Khatami, Mahin, Romano, MARIA FIAMMETTA, Chapellier, Marion, Williams, Marc A, Wade, Mark, Manjili, Masoud H, Lleonart, Matilde E, Xia, Menghang, Gonzalez, Michael J, Karamouzis, Michalis V, Kirsch Volders, Micheline, Vaccari, Monica, Kuemmerle, Nancy B, Singh, Neetu, Cruickshanks, Nichola, Kleinstreuer, Nicole, van Larebeke, Nik, Ahmed, Nuzhat, Ogunkua, Olugbemiga, Krishnakumar, P. K, Vadgama, Pankaj, Marignani, Paola A, Ghosh, Paramita M, Ostrosky Wegman, Patricia, Thompson, Patricia A, Dent, Paul, Heneberg, Petr, Darbre, Philippa, Sing Leung, Po, Nangia Makker, Pratima, Cheng, Qiang Shawn, Robey, R. Brook, Al Temaimi, Rabeah, Roy, Rabindra, Andrade Vieira, Rafaela, Sinha, Ranjeet K, Mehta, Rekha, Vento, Renza, Di Fiore, Riccardo, Ponce Cusi, Richard, Dornetshuber Fleiss, Rita, Nahta, Rita, Castellino, Robert C, Palorini, Roberta, Abd Hamid, Roslida, Langie, Sabine A. S, Eltom, Sakina E, Brooks, Samira A, Ryeom, Sandra, Wise, Sandra S, Bay, Sarah N, Harris, Shelley A, Papagerakis, Silvana, Romano, Simona, Pavanello, Sofia, Eriksson, Staffan, Forte, Stefano, Casey, Stephanie C, Luanpitpong, Sudjit, Lee, Tae Jin, Otsuki, Takemi, Chen, Tao, Massfelder, Thierry, Sanderson, Thoma, Guarnieri, Tiziana, Hultman, Tove, Dormoy, Valérian, Odero Marah, Valerie, Sabbisetti, Venkata, Maguer Satta, Veronique, Rathmell, W. Kimryn, Engström, Wilhelm, Decker, William K, Bisson, William H, Rojanasakul, Yon, Luqmani, Yunu, Chen, Zhenbang, Hu, Zhiwei, Goodson, W., Lowe, L., Carpenter, D., Gilbertson, M., Ali, A., de Cerain Salsamendi, A., Lasfar, A., Carnero, A., Azqueta, A., Amedei, A., Charles, A., Collins, A., Ward, A., Salzberg, A., Colacci, A., Olsen, A., Berg, A., Barclay, B., Zhou, B., Blanco-Aparicio, C., Baglole, C., Dong, C., Mondello, C., Hsu, C., Naus, C., Yedjou, C., Curran, C., Laird, D., Koch, D., Carlin, D., Felsher, D., Roy, D., Brown, D., Ratovitski, E., Ryan, E., Corsini, E., Rojas, E., Moon, E., Laconi, E., Marongiu, F., Al-Mulla, F., Chiaradonna, F., Darroudi, F., Martin, F., Van Schooten, F., Goldberg, G., Wagemaker, G., Nangami, G., Calaf, G., Williams, G., Wolf, G., Koppen, G., Brunborg, G., Kim Lyerly, H., Krishnan, H., Hamid, H., Yasaei, H., Sone, H., Kondoh, H., Salem, H., Hsu, H., Park, H., Koturbash, I., Miousse, I., Ivana Scovassi, A., Klaunig, J., Vondráček, J., Raju, J., Roman, J., Wise, J., Whitfield, J., Woodrick, J., Christopher, J., Ochieng, J., Martinez-Leal, J., Weisz, J., Kravchenko, J., Sun, J., Prudhomme, K., Narayanan, K., Cohen-Solal, K., Moorwood, K., Gonzalez, L., Soucek, L., Jian, L., D'Abronzo, L., Lin, L., Li, L., Gulliver, L., Mccawley, L., Memeo, L., Vermeulen, L., Leyns, L., Zhang, L., Valverde, M., Khatami, M., Romano, M., Chapellier, M., Williams, M., Wade, M., Manjili, M., Lleonart, M., Xia, M., Gonzalez, M., Karamouzis, M., Kirsch-Volders, M., Vaccari, M., Kuemmerle, N., Singh, N., Cruickshanks, N., Kleinstreuer, N., Van Larebeke, N., Ahmed, N., Ogunkua, O., Krishnakumar, P., Vadgama, P., Marignani, P., Ghosh, P., Ostrosky-Wegman, P., Thompson, P., Dent, P., Heneberg, P., Darbre, P., Leung, P., Nangia-Makker, P., Cheng, Q., Brooks Robey, R., Al-Temaimi, R., Roy, R., Andrade-Vieira, R., Sinha, R., Mehta, R., Vento, R., Di Fiore, R., Ponce-Cusi, R., Dornetshuber-Fleiss, R., Nahta, R., Castellino, R., Palorini, R., Hamid, R., Langie, S., Eltom, S., Brooks, S., Ryeom, S., Wise, S., Bay, S., Harris, S., Papagerakis, S., Romano, S., Pavanello, S., Eriksson, S., Forte, S., Casey, S., Luanpitpong, S., Lee, T., Otsuki, T., Chen, T., Massfelder, T., Sanderson, T., Guarnieri, T., Hultman, T., Dormoy, V., Odero-Marah, V., Sabbisetti, V., Maguer-Satta, V., Kimryn Rathmell, W., Engström, W., Decker, W., Bisson, W., Rojanasakul, Y., Luqmani, Y., Chen, Z., Hu, Z., Goodson, W.H., Carpenter, D.O., Ali, A.M., de Cerain Salsamendi, A.L., Charles, A.K., Collins, A.R., Salzberg, A.C., Olsen, A.-K., Barclay, B.J., Zhou, B.P., Baglole, C.J., Hsu, C.-W., Naus, C.C., Curran, C.S., Laird, D.W., Koch, D.C., Carlin, D.J., Felsher, D.W., Brown, D.G., Ryan, E.P., Moon, E.-Y., Martin, F.L., Van Schooten, F.J., Goldberg, G.S., Calaf, G.M., Wolf, G.T., Hamid, H.A., Salem, H.K., Hsu, H.-Y., Park, H.H., Miousse, I.R., Klaunig, J.E., Vondracek, J., Wise, J.P., Whitfield, J.R., Christopher, J.A., Martinez-Leal, J.F., Prudhomme, K.R., Narayanan, K.B., Cohen-Solal, K.A., D'Abronzo, L.S., Lin, L.-T., Mccawley, L.J., Romano, M.F., Williams, M.A., Manjili, M.H., Gonzalez, M.J., Karamouzis, M.V., Kuemmerle, N.B., Krishnakumar, P.K., Marignani, P.A., Ghosh, P.M., Leung, P.S., Cheng, Q.S., Sinha, R.K., Castellino, R.C., Hamid, R.A., Langie, S.A.S., Brooks, S.A., Wise, S.S., Bay, S.N., Harris, S.A., Casey, S.C., Lee, T.-J., Engstrom, W., Decker, W.K., Bisson, W.H., sans affiliation, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), We gratefully acknowledge the support of the National Institute of Health-National Institute of Environmental Health Sciences (NIEHS) conference grant travel support (R13ES023276), Glenn Rice, Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA also deserves thanks for his thoughtful feedback and inputs on the manuscript, William H.Goodson III was supported by the California Breast Cancer Research Program, Clarence Heller Foundation and California Pacific Medical Center Foundation, Abdul M.Ali would like to acknowledge the financial support of the University of Sultan Zainal Abidin, Malaysia, Ahmed Lasfar was supported by an award from the Rutgers Cancer Institute of New Jersey, Ann-Karin Olsen and Gunnar Brunborg were supported by the Research Council of Norway (RCN) through its Centres of Excellence funding scheme (223268/F50), Amancio Carnero’s lab was supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0306-2012), Matilde E. Lleonart was supported by a trienal project grant PI12/01104 and by project CP03/00101 for personal support. Amaya Azqueta would like to thank the Ministerio de Educacion y Ciencia (‘Juande la Cierva’ programme, 2009) of the Spanish Government for personal support, Amedeo Amedei was supported by the Italian Ministry of University and Research (2009FZZ4XM_002), and the University of Florence (ex60%2012), Andrew R.Collins was supported by the University of Oslo, Annamaria Colacci was supported by the Emilia-Romagna Region - Project ‘Supersite’ in Italy, Carolyn Baglole was supported by a salary award from the Fonds de recherche du Quebec-Sante (FRQ-S), Chiara Mondello’s laboratory is supported by Fondazione Cariplo in Milan, Italy (grant n. 2011-0370), Christian C.Naus holds a Canada Research Chair, Clement Yedjou was supported by a grant from the National Institutes of Health (NIH-NIMHD grant no. G12MD007581), Daniel C.Koch is supported by the Burroughs Wellcome Fund Postdoctoral Enrichment Award and the Tumor Biology Training grant: NIH T32CA09151, Dean W. Felsher would like to acknowledge the support of United States Department of Health and Human Services, NIH grants (R01 CA170378 PQ22, R01 CA184384, U54 CA149145, U54 CA151459, P50 CA114747 and R21 CA169964), Emilio Rojas would like to thank CONACyT support 152473, Ezio Laconi was supported by AIRC (Italian Association for Cancer Research, grant no. IG 14640) and by the Sardinian Regional Government (RAS), Eun-Yi Moon was supported by grants from the Public Problem-Solving Program (NRF-015M3C8A6A06014500) and Nuclear R&D Program (#2013M2B2A9A03051296 and 2010-0018545) through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (MEST) in Korea, Fahd Al-Mulla was supported by the Kuwait Foundation for the Advancement of Sciences (2011-1302-06), Ferdinando Chiaradonna is supported by SysBioNet, a grant for the Italian Roadmap of European Strategy Forum on Research Infrastructures (ESFRI) and by AIRC (Associazione Italiana Ricerca sul Cancro, IG 15364), Francis L.Martin acknowledges funding from Rosemere Cancer Foundation, he also thanks Lancashire Teaching Hospitals NHS trust and the patients who have facilitated the studies he has undertaken over the course of the last 10 years, Gary S.Goldberg would like to acknowledge the support of the New Jersey Health Foundation, Gloria M.Calaf was supported by Fondo Nacional de Ciencia y Tecnología (FONDECYT), Ministerio de Educación de Chile (MINEDUC), Universidad de Tarapacá (UTA), Gudrun Koppen was supported by the Flemish Institute for Technological Research (VITO), Belgium, Hemad Yasaei was supported from a triennial project grant (Strategic Award) from the National Centre for the Replacement, Refinement and Reduction (NC3Rs) of animals in research (NC.K500045.1 and G0800697), Hiroshi Kondoh was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Science and Technology Agency and by JST, CREST, Hsue-Yin Hsu was supported by the Ministry of Science and Technology of Taiwan (NSC93-2314-B-320-006 and NSC94-2314-B-320-002), Hyun Ho Park was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology (2012R1A2A2A01010870) and a grant from the Korea Healthcare Technology R&D project, Ministry of Health and Welfare, Republic of Korea (HI13C1449), Igor Koturbash is supported by the UAMS/NIH Clinical and Translational Science Award (UL1TR000039 and KL2TR000063) and the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000, Jan Vondráček acknowledges funding from the Czech Science Foundation (13-07711S), Jesse Roman thanks the NIH for their support (CA116812), John Pierce Wise Sr. and Sandra S.Wise were supported by National Institute of Environmental Health Sciences (ES016893 to J.P.W.) and the Maine Center for Toxicology and Environmental Health, Jonathan Whitfield acknowledges support from the FERO Foundation in Barcelona, Spain, Joseph Christopher is funded by Cancer Research UK and the International Journal of Experimental Pathology, Julia Kravchenko is supported by a philanthropic donation by Fred and Alice Stanback, Jun Sun is supported by a Swim Across America Cancer Research Award, Karine A.Cohen-Solal is supported by a research scholar grant from the American Cancer Society (116683-RSG-09-087-01-TBE), Laetitia Gonzalez received a postdoctoral fellowship from the Fund for Scientific Research–Flanders (FWO-Vlaanderen) and support by an InterUniversity Attraction Pole grant (IAP-P7-07), Laura Soucek is supported by grant #CP10/00656 from the Miguel Servet Research Contract Program and acknowledges support from the FERO Foundation in Barcelona, Spain, Liang-Tzung Lin was supported by funding from the Taipei Medical University (TMU101-AE3-Y19), Linda Gulliver is supported by a Genesis Oncology Trust (NZ) Professional Development Grant, and the Faculty of Medicine, University of Otago, Dunedin, New Zealand, Louis Vermeulen is supported by a Fellowship of the Dutch Cancer Society (KWF, UVA2011-4969) and a grant from the AICR (14–1164), Mahara Valverde would like to thank CONACyT support 153781, Masoud H. Manjili was supported by the office of the Assistant Secretary of Defense for Health Affairs (USA) through the Breast Cancer Research Program under Award No. W81XWH-14-1-0087 Neetu Singh was supported by grant #SR/FT/LS-063/2008 from the Department of Science and Technology, Government of India, Nicole Kleinstreuer is supported by NIEHS contracts (N01-ES 35504 and HHSN27320140003C), P.K. Krishnakumar is supported by the Funding (No. T.K. 11-0629) of King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia, Paola A.Marignani is supported by the Dalhousie Medical Research Foundation, The Beatrice Hunter Cancer Institute and CIHR and the Nova Scotia Lung Association, Paul Dent is the holder of the Universal Inc.Chair in Signal Transduction Research and is supported with funds from PHS grants from the NIH (R01-CA141704, R01-CA150214, R01-DK52825 and R01-CA61774), Petr Heneberg was supported by the Charles University in Prague projects UNCE 204015 and PRVOUK P31/2012, and by the Czech Science Foundation projects P301/12/1686 and 15-03834Y, Po Sing Leung was supported by the Health and Medical Research Fund of Food and Health Bureau, Hong Kong Special Administrative Region, Ref. No: 10110021, Qiang Cheng was supported in part by grant NSF IIS-1218712, R. Brooks Robey is supported by the United States Department of Veterans Affairs, Rabindra Roy was supported by United States Public Health Service Grants (RO1 CA92306, RO1 CA92306-S1 and RO1 CA113447), Rafaela Andrade-Vieira is supported by the Beatrice Hunter Cancer Research Institute and the Nova Scotia Health Research Foundation, Renza Vento was partially funded by European Regional Development Fund, European Territorial Cooperation 2007–13 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–13) and grants from the Italian Ministry of Education, University and Research (MIUR) ex-60%, 2007, Riccardo Di Fiore was a recipient of fellowship granted by European Regional Development Fund, European Territorial Cooperation 2007–2013 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–2013), Rita Dornetshuber-Fleiss was supported by the Austrian Science Fund (FWF, project number T 451-B18) and the Johanna Mahlke, geb.-Obermann-Stiftung, Roberta Palorini is supported by a SysBioNet fellowship, Roslida Abd Hamid is supported by the Ministry of Education, Malaysia-Exploratory Research Grant Scheme-Project no: ERGS/1-2013/5527165, Sabine A.S.Langie is the beneficiary of a postdoctoral grant from the AXA Research Fund and the Cefic-LRI Innovative Science Award 2013, Sakina Eltom is supported by NIH grant SC1CA153326, Samira A.Brooks was supported by National Research Service Award (T32 ES007126) from the National Institute of Environmental Health Sciences and the HHMI Translational Medicine Fellowship, Sandra Ryeom was supported by The Garrett B. Smith Foundation and the TedDriven Foundation, Thierry Massfelder was supported by the Institut National de la Santé et de la Recherche Médicale INSERM and Université de Strasbourg, Thomas Sanderson is supported by the Canadian Institutes of Health Research (CIHR, MOP-115019), the Natural Sciences and Engineering Council of Canada (NSERC, 313313) and the California Breast Cancer Research Program (CBCRP, 17UB-8703), Tiziana Guarnieri is supported by a grant from Fundamental Oriented Research (RFO) to the Alma Mater Studiorum University of Bologna, Bologna, Italy and thanks the Fondazione Cassa di Risparmio di Bologna and the Fondazione Banca del Monte di Bologna e Ravenna for supporting the Center for Applied Biomedical Research, S.Orsola-Malpighi University Hospital, Bologna, Italy, W.Kimryn Rathmell is supported by the V Foundation for Cancer Research and the American Cancer Society, William K.Decker was supported in part by grant RP110545 from the Cancer Prevention Research Institute of Texas, William H.Bisson was supported with funding from the NIH P30 ES000210, Yon Rojanasakul was supported with NIH grant R01-ES022968, Zhenbang Chen is supported by NIH grants (MD004038, CA163069 and MD007593), Zhiwei Hu is grateful for the grant support from an institutional start-up fund from The Ohio State University College of Medicine and The OSU James Comprehensive Cancer Center (OSUCCC) and a Seed Award from the OSUCCC Translational Therapeutics Program., Sans affiliation, Courcelles, Michel, Goodson, W, Lowe, L, Carpenter, D, Gilbertson, M, Ali, A, de Cerain Salsamendi, A, Lasfar, A, Carnero, A, Azqueta, A, Amedei, A, Charles, A, Collins, A, Ward, A, Salzberg, A, Colacci, A, Olsen, A, Berg, A, Barclay, B, Zhou, B, Blanco Aparicio, C, Baglole, C, Dong, C, Mondello, C, Hsu, C, Naus, C, Yedjou, C, Curran, C, Laird, D, Koch, D, Carlin, D, Felsher, D, Roy, D, Brown, D, Ratovitski, E, Ryan, E, Corsini, E, Rojas, E, Moon, E, Laconi, E, Marongiu, F, Al Mulla, F, Chiaradonna, F, Darroudi, F, Martin, F, Van Schooten, F, Goldberg, G, Wagemaker, G, Nangami, G, Calaf, G, Williams, G, Wolf, G, Koppen, G, Brunborg, G, Kim Lyerly, H, Krishnan, H, Hamid, H, Yasaei, H, Sone, H, Kondoh, H, Salem, H, Hsu, H, Park, H, Koturbash, I, Miousse, I, Ivana Scovassi, A, Klaunig, J, Vondráček, J, Raju, J, Roman, J, Wise, J, Whitfield, J, Woodrick, J, Christopher, J, Ochieng, J, Martinez Leal, J, Weisz, J, Kravchenko, J, Sun, J, Prudhomme, K, Narayanan, K, Cohen Solal, K, Moorwood, K, Gonzalez, L, Soucek, L, Jian, L, D'Abronzo, L, Lin, L, Li, L, Gulliver, L, Mccawley, L, Memeo, L, Vermeulen, L, Leyns, L, Zhang, L, Valverde, M, Khatami, M, Romano, M, Chapellier, M, Williams, M, Wade, M, Manjili, M, Lleonart, M, Xia, M, Gonzalez, M, Karamouzis, M, Kirsch Volders, M, Vaccari, M, Kuemmerle, N, Singh, N, Cruickshanks, N, Kleinstreuer, N, Van Larebeke, N, Ahmed, N, Ogunkua, O, Krishnakumar, P, Vadgama, P, Marignani, P, Ghosh, P, Ostrosky Wegman, P, Thompson, P, Dent, P, Heneberg, P, Darbre, P, Leung, P, Nangia Makker, P, Cheng, Q, Brooks Robey, R, Al Temaimi, R, Roy, R, Andrade Vieira, R, Sinha, R, Mehta, R, Vento, R, Di Fiore, R, Ponce Cusi, R, Dornetshuber Fleiss, R, Nahta, R, Castellino, R, Palorini, R, Hamid, R, Langie, S, Eltom, S, Brooks, S, Ryeom, S, Wise, S, Bay, S, Harris, S, Papagerakis, S, Romano, S, Pavanello, S, Eriksson, S, Forte, S, Casey, S, Luanpitpong, S, Lee, T, Otsuki, T, Chen, T, Massfelder, T, Sanderson, T, Guarnieri, T, Hultman, T, Dormoy, V, Odero Marah, V, Sabbisetti, V, Maguer Satta, V, Kimryn Rathmell, W, Engström, W, Decker, W, Bisson, W, Rojanasakul, Y, Luqmani, Y, Chen, Z, and Hu, Z

Subjects
Cancer Research, Carcinogenesis, [SDV]Life Sciences [q-bio], METHOXYCHLOR-INDUCED ALTERATIONS, Review, Pharmacology, MESH: Carcinogens, Environmental, Carcinogenic synergies, Chemical mixtures, Neoplasms, MESH: Animals, MESH: Neoplasms, Carcinogenesi, Risk assessment, Cancer, ACTIVATED PROTEIN-KINASES, Medicine (all), Low dose, 1. No poverty, Cumulative effects, BREAST-CANCER CELLS, General Medicine, Environmental exposure, MESH: Carcinogenesis, BIO/10 - BIOCHIMICA, EPITHELIAL-MESENCHYMAL TRANSITION, 3. Good health, [SDV] Life Sciences [q-bio], Environmental Carcinogenesis, ESTROGEN-RECEPTOR-ALPHA, Human, MESH: Environmental Exposure, ENDOCRINE-DISRUPTING CHEMICALS, TARGETING TISSUE FACTOR, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Prototypical chemical disruptors, Exposure, [SDV.CAN] Life Sciences [q-bio]/Cancer, Environmental health, medicine, [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, Carcinogen, Environmental carcinogenesis, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, MESH: Humans, Animal, POLYBROMINATED DIPHENYL ETHERS, Environmental Exposure, medicine.disease, MESH: Hazardous Substances, Carcinogens, Environmental, MIGRATION INHIBITORY FACTOR, VASCULAR ENDOTHELIAL-CELLS, Hazardous Substance, Neoplasm
Abstract

Goodson, William H. et al., © The Author 2015. Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology., We gratefully acknowledge the support of the National Institute of Health-National Institute of Environmental Health Sciences (NIEHS) conference grant travel support (R13ES023276); Glenn Rice, Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA also deserves thanks for his thoughtful feedback and inputs on the manuscript; William H.Goodson III was supported by the California Breast Cancer Research Program, Clarence Heller Foundation and California Pacific Medical Center Foundation; Abdul M.Ali would like to acknowledge the financial support of the University of Sultan Zainal Abidin, Malaysia; Ahmed Lasfar was supported by an award from the Rutgers Cancer Institute of New Jersey; Ann-Karin Olsen and Gunnar Brunborg were supported by the Research Council of Norway (RCN) through its Centres of Excellence funding scheme (223268/F50), Amancio Carnero’s lab was supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0306-2012); Matilde E. Lleonart was supported by a trienal project grant PI12/01104 and by project CP03/00101 for personal support. Amaya Azqueta would like to thank the Ministerio de Educacion y Ciencia (‘Juande la Cierva’ programme, 2009) of the Spanish Government for personal support; Amedeo Amedei was supported by the Italian Ministry of University and Research (2009FZZ4XM_002), and the University of Florence (ex60%2012); Andrew R.Collins was supported by the University of Oslo; Annamaria Colacci was supported by the Emilia-Romagna Region - Project ‘Supersite’ in Italy; Carolyn Baglole was supported by a salary award from the Fonds de recherche du Quebec-Sante (FRQ-S); Chiara Mondello’s laboratory is supported by Fondazione Cariplo in Milan, Italy (grant n. 2011-0370); Christian C.Naus holds a Canada Research Chair; Clement Yedjou was supported by a grant from the National Institutes of Health (NIH-NIMHD grant no. G12MD007581); Daniel C.Koch is supported by the Burroughs Wellcome Fund Postdoctoral Enrichment Award and the Tumor Biology Training grant: NIH T32CA09151; Dean W. Felsher would like to acknowledge the support of United States Department of Health and Human Services, NIH grants (R01 CA170378 PQ22, R01 CA184384, U54 CA149145, U54 CA151459, P50 CA114747 and R21 CA169964); Emilio Rojas would like to thank CONACyT support 152473, Ezio Laconi was supported by AIRC (Italian Association for Cancer Research, grant no. IG 14640) and by the Sardinian Regional Government (RAS); Eun-Yi Moon was supported by grants from the Public Problem-Solving Program (NRF-015M3C8A6A06014500) and Nuclear R&D Program (#2013M2B2A9A03051296 and 2010-0018545) through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (MEST) in Korea; Fahd Al-Mulla was supported by the Kuwait Foundation for the Advancement of Sciences (2011-1302-06); Ferdinando Chiaradonna is supported by SysBioNet, a grant for the Italian Roadmap of European Strategy Forum on Research Infrastructures (ESFRI) and by AIRC (Associazione Italiana Ricerca sul Cancro; IG 15364); Francis L.Martin acknowledges funding from Rosemere Cancer Foundation; he also thanks Lancashire Teaching Hospitals NHS trust and the patients who have facilitated the studies he has undertaken over the course of the last 10 years; Gary S.Goldberg would like to acknowledge the support of the New Jersey Health Foundation; Gloria M.Calaf was supported by Fondo Nacional de Ciencia y Tecnología (FONDECYT), Ministerio de Educación de Chile (MINEDUC), Universidad de Tarapacá (UTA); Gudrun Koppen was supported by the Flemish Institute for Technological Research (VITO), Belgium; Hemad Yasaei was supported from a triennial project grant (Strategic Award) from the National Centre for the Replacement, Refinement and Reduction (NC3Rs) of animals in research (NC.K500045.1 and G0800697); Hiroshi Kondoh was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Science and Technology Agency and by JST, CREST; Hsue-Yin Hsu was supported by the Ministry of Science and Technology of Taiwan (NSC93-2314-B-320-006 and NSC94-2314-B-320-002); Hyun Ho Park was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology (2012R1A2A2A01010870) and a grant from the Korea Healthcare Technology R&D project, Ministry of Health and Welfare, Republic of Korea (HI13C1449); Igor Koturbash is supported by the UAMS/NIH Clinical and Translational Science Award (UL1TR000039 and KL2TR000063) and the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000; Jan Vondráček acknowledges funding from the Czech Science Foundation (13-07711S); Jesse Roman thanks the NIH for their support (CA116812), John Pierce Wise Sr. and Sandra S.Wise were supported by National Institute of Environmental Health Sciences (ES016893 to J.P.W.) and the Maine Center for Toxicology and Environmental Health; Jonathan Whitfield acknowledges support from the FERO Foundation in Barcelona, Spain; Joseph Christopher is funded by Cancer Research UK and the International Journal of Experimental Pathology; Julia Kravchenko is supported by a philanthropic donation by Fred and Alice Stanback; Jun Sun is supported by a Swim Across America Cancer Research Award; Karine A.Cohen-Solal is supported by a research scholar grant from the American Cancer Society (116683-RSG-09-087-01-TBE); Laetitia Gonzalez received a postdoctoral fellowship from the Fund for Scientific Research–Flanders (FWO-Vlaanderen) and support by an InterUniversity Attraction Pole grant (IAP-P7-07); Laura Soucek is supported by grant #CP10/00656 from the Miguel Servet Research Contract Program and acknowledges support from the FERO Foundation in Barcelona, Spain; Liang-Tzung Lin was supported by funding from the Taipei Medical University (TMU101-AE3-Y19); Linda Gulliver is supported by a Genesis Oncology Trust (NZ) Professional Development Grant, and the Faculty of Medicine, University of Otago, Dunedin, New Zealand; Louis Vermeulen is supported by a Fellowship of the Dutch Cancer Society (KWF, UVA2011-4969) and a grant from the AICR (14–1164); Mahara Valverde would like to thank CONACyT support 153781; Masoud H. Manjili was supported by the office of the Assistant Secretary of Defense for Health Affairs (USA) through the Breast Cancer Research Program under Award No. W81XWH-14-1-0087 Neetu Singh was supported by grant #SR/FT/LS-063/2008 from the Department of Science and Technology, Government of India; Nicole Kleinstreuer is supported by NIEHS contracts (N01-ES 35504 and HHSN27320140003C); P.K. Krishnakumar is supported by the Funding (No. T.K. 11-0629) of King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia; Paola A.Marignani is supported by the Dalhousie Medical Research Foundation, The Beatrice Hunter Cancer Institute and CIHR and the Nova Scotia Lung Association; Paul Dent is the holder of the Universal Inc.Chair in Signal Transduction Research and is supported with funds from PHS grants from the NIH (R01-CA141704, R01-CA150214, R01-DK52825 and R01-CA61774); Petr Heneberg was supported by the Charles University in Prague projects UNCE 204015 and PRVOUK P31/2012, and by the Czech Science Foundation projects P301/12/1686 and 15-03834Y; Po Sing Leung was supported by the Health and Medical Research Fund of Food and Health Bureau, Hong Kong Special Administrative Region, Ref. No: 10110021; Qiang Cheng was supported in part by grant NSF IIS-1218712; R. Brooks Robey is supported by the United States Department of Veterans Affairs; Rabindra Roy was supported by United States Public Health Service Grants (RO1 CA92306, RO1 CA92306-S1 and RO1 CA113447); Rafaela Andrade-Vieira is supported by the Beatrice Hunter Cancer Research Institute and the Nova Scotia Health Research Foundation, Renza Vento was partially funded by European Regional Development Fund, European Territorial Cooperation 2007–13 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–13) and grants from the Italian Ministry of Education, University and Research (MIUR) ex-60%, 2007; Riccardo Di Fiore was a recipient of fellowship granted by European Regional Development Fund, European Territorial Cooperation 2007–2013 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–2013); Rita Dornetshuber-Fleiss was supported by the Austrian Science Fund (FWF, project number T 451-B18) and the Johanna Mahlke, geb.-Obermann-Stiftung; Roberta Palorini is supported by a SysBioNet fellowship; Roslida Abd Hamid is supported by the Ministry of Education, Malaysia-Exploratory Research Grant Scheme-Project no: ERGS/1-2013/5527165; Sabine A.S.Langie is the beneficiary of a postdoctoral grant from the AXA Research Fund and the Cefic-LRI Innovative Science Award 2013; Sakina Eltom is supported by NIH grant SC1CA153326; Samira A.Brooks was supported by National Research Service Award (T32 ES007126) from the National Institute of Environmental Health Sciences and the HHMI Translational Medicine Fellowship; Sandra Ryeom was supported by The Garrett B. Smith Foundation and the TedDriven Foundation; Thierry Massfelder was supported by the Institut National de la Santé et de la Recherche Médicale INSERM and Université de Strasbourg; Thomas Sanderson is supported by the Canadian Institutes of Health Research (CIHR; MOP-115019), the Natural Sciences and Engineering Council of Canada (NSERC; 313313) and the California Breast Cancer Research Program (CBCRP; 17UB-8703); Tiziana Guarnieri is supported by a grant from Fundamental Oriented Research (RFO) to the Alma Mater Studiorum University of Bologna, Bologna, Italy and thanks the Fondazione Cassa di Risparmio di Bologna and the Fondazione Banca del Monte di Bologna e Ravenna for supporting the Center for Applied Biomedical Research, S.Orsola-Malpighi University Hospital, Bologna, Italy; W.Kimryn Rathmell is supported by the V Foundation for Cancer Research and the American Cancer Society; William K.Decker was supported in part by grant RP110545 from the Cancer Prevention Research Institute of Texas; William H.Bisson was supported with funding from the NIH P30 ES000210; Yon Rojanasakul was supported with NIH grant R01-ES022968; Zhenbang Chen is supported by NIH grants (MD004038, CA163069 and MD007593); Zhiwei Hu is grateful for the grant support from an institutional start-up fund from The Ohio State University College of Medicine and The OSU James Comprehensive Cancer Center (OSUCCC) and a Seed Award from the OSUCCC Translational Therapeutics Program.

Published
2015

21. Recapitulating thyroid cancer histotypes through engineering embryonic stem cells

Author

Veronica Veschi, Alice Turdo, Chiara Modica, Francesco Verona, Simone Di Franco, Miriam Gaggianesi, Elena Tirrò, Sebastiano Di Bella, Melania Lo Iacono, Vincenzo Davide Pantina, Gaetana Porcelli, Laura Rosa Mangiapane, Paola Bianca, Aroldo Rizzo, Elisabetta Sciacca, Irene Pillitteri, Veronica Vella, Antonino Belfiore, Maria Rita Bongiorno, Giuseppe Pistone, Lorenzo Memeo, Lorenzo Colarossi, Dario Giuffrida, Cristina Colarossi, Paolo Vigneri, Matilde Todaro, Giorgio Stassi, Veschi, V., Turdo, A., Modica, C., Verona, F., Di Franco, S., Gaggianesi, M., Tirrò, E., Di Bella, S., Lo Iacono, M., Pantina, V.D., Porcelli, G., Mangiapane, L.R., Bianca, P., Rizzo, A., Sciacca, E., Pillitteri, I., Vella, V., Belfiore, A., Bongiorno, M.R., Pistone, G., Memeo, L., Colarossi, L., Giuffrida, D., Colarossi, C., Vigneri, P., Todaro, M., and Stassi, G.

Subjects
Multidisciplinary, General Physics and Astronomy, General Chemistry, General Biochemistry, Genetics and Molecular Biology, Thyroid cancer, thyroid progenitor cells, genetic mutation model, CD44, TIMP1, KISS1, KISS1R
Abstract

Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. The cell subpopulation in the lineage hierarchy that serves as cell of origin for the different TC histotypes is unknown. Human embryonic stem cells (hESCs) with appropriate in vitro stimulation undergo sequential differentiation into thyroid progenitor cells (TPCs-day 22), which maturate into thyrocytes (day 30). Here, we create follicular cell-derived TCs of all the different histotypes based on specific genomic alterations delivered by CRISPR-Cas9 in hESC-derived TPCs. Specifically, TPCs harboring BRAFV600E or NRASQ61R mutations generate papillary or follicular TC, respectively, whereas addition of TP53R248Q generate undifferentiated TCs. Of note, TCs arise by engineering TPCs, whereas mature thyrocytes have a very limited tumorigenic capacity. The same mutations result in teratocarcinomas when delivered in early differentiating hESCs. Tissue Inhibitor of Metalloproteinase 1 (TIMP1)/Matrix metallopeptidase 9 (MMP9)/Cluster of differentiation 44 (CD44) ternary complex, in cooperation with Kisspeptin receptor (KISS1R), is involved in TC initiation and progression. Increasing radioiodine uptake, KISS1R and TIMP1 targeting may represent a therapeutic adjuvant option for undifferentiated TCs.

Published
2023

22. STARD3: A Prospective Target for Cancer Therapy

Author

Kanwal Asif, Isabella Caligiuri, Vincenzo Canzonieri, Flavio Rizzolio, Tiziano Tuccinardi, Lorenzo Memeo, Stefano Palazzolo, Salvatore Parisi, Carlotta Granchi, Yahima Frión-Herrera, Asif, K., Memeo, L., Palazzolo, S., Frion-Herrera, Y., Parisi, S., Caligiuri, I., Canzonieri, V., Granchi, C., Tuccinardi, T., and Rizzolio, F.

Subjects
Cancer Research, Inhibitor, Cell division, medicine.medical_treatment, steroidogenic acute regulatory transfer proteins, Cell, targeted drugs, STARD3, Review, Metastasis, Cancer, Cholesterol, Inhibitors, Steroidogenic acute regulatory transfer proteins, Targeted drugs, inhibitors, medicine, cancer, RC254-282, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, cholesterol, medicine.disease, Radiation therapy, medicine.anatomical_structure, Oncology, Cancer cell, Cancer research, lipids (amino acids, peptides, and proteins), Steroidogenic acute regulatory transfer protein, business, Plant lipid transfer proteins
Abstract

Simple Summary Alterations in cholesterol level play an important role in cancer development. Lipid transfer proteins (LTPs) are involved in cholesterol distribution between organelles. Among LTPs, some members of steroidogenic acute regulatory-related lipid transfer (START) protein family regulate the cholesterol transportation between organelles and have been revealed as critical for cancer development. This review highlights the recent discoveries of the StAR-related lipid transfer protein domain 3 (STARD3) member of START proteins in cancer development and progression. Blocking cholesterol transportation through the inhibition of STARD3 activity could be an important strategy to treat cancer. Abstract Cancer is one of the major causes of death in developed countries and current therapies are based on surgery, chemotherapeutic agents, and radiation. To overcome side effects induced by chemo- and radiotherapy, in recent decades, targeted therapies have been proposed in second and even first lines. Targeted drugs act on the essential pathways involved in tumor induction, progression, and metastasis, basically all the hallmark of cancers. Among emerging pathways, the cholesterol metabolic pathway is a strong candidate for this purpose. Cancer cells have an accelerated metabolic rate and require a continuous supply of cholesterol for cell division and membrane renewal. Steroidogenic acute regulatory related lipid transfer (START) proteins are a family of proteins involved in the transfer of lipids and some of them are important in non-vesicular cholesterol transportation within the cell. The alteration of their expression levels is implicated in several diseases, including cancers. In this review, we report the latest discoveries on StAR-related lipid transfer protein domain 3 (STARD3), a member of the START family, which has a potential role in cancer, focusing on the structural and biochemical characteristics and mechanisms that regulate its activity. The role of the STARD3 protein as a molecular target for the development of cancer therapies is also discussed. As STARD3 is a key protein in the cholesterol movement in cancer cells, it is of interest to identify inhibitors able to block its activity.

Published
2021

23. Cancer organoids in basic science and translational medicine

Author

Vincenzo Canzonieri, Lorenzo Memeo, Flavio Rizzolio, Memeo, L., Canzonieri, V., and Rizzolio, F.

Subjects
0301 basic medicine, Oncology, Organoid, Cancer Research, medicine.medical_specialty, Basic science, education, Cancer therapy, MEDLINE, Settore BIO/11 - Biologia Molecolare, Organoids, cancer therapy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Medicine, RC254-282, health care economics and organizations, business.industry, Translational medicine, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer, social sciences, medicine.disease, humanities, n/a, Editorial, 030104 developmental biology, 030220 oncology & carcinogenesis, business
Abstract

Organoids are revolutionizing approaches to cancer therapy and even diagnosis [...]

Published
2021

24. Microfluidic organoids‐on‐a‐chip: Quantum leap in cancer research

Author

Vincenzo Canzonieri, Flavio Rizzolio, Lorenzo Memeo, Gloria Saorin, Fahriye Duzagac, Duzagac, F., Saorin, G., Memeo, L., Canzonieri, V., and Rizzolio, F.

Subjects
0301 basic medicine, Organoid, Cancer Research, Computer science, Settore MED/06 - Oncologia Medica, Microfluidics, microfluidics, Nanotechnology, Review, Organ-on-a-chip, lcsh:RC254-282, Living biobanks, Organoids, Organs‐on‐a‐chip, Tumoroids, 03 medical and health sciences, 0302 clinical medicine, Settore BIO/10 - Biochimica, Living biobank, organoids, organs-on-a-chip, tumoroids, living biobanks, Chip, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer treatment, 030104 developmental biology, Oncology, Microfluidic, Settore CHIM/09 - Farmaceutico Tecnologico Applicativo, 030220 oncology & carcinogenesis, Bioinspiration
Abstract

Simple Summary Organoids, also known as self-organized 3D organ-like clusters, represent almost a physiological system for studying cells, stem cells, tissues, and diseases, especially cancer. Microfluidic organ-on-a-chip technology has gained beneficial interest in recent years due to its potential to be a pioneer in developing personalized treatments with a precise control of many parameters such as flow conditions and nutrient supply in a microscale. Further, the dynamic nature of such personalized systems also relies on the ability to easily combine the read-outs from blood samples, urine samples, biopsies, and primary tissues. This fast-evolving innovative technology precisely fit with the concept of precision medicine, which holds an infinite potential for personalized cancer treatments. Abstract Organ-like cell clusters, so-called organoids, which exhibit self-organized and similar organ functionality as the tissue of origin, have provided a whole new level of bioinspiration for ex vivo systems. Microfluidic organoid or organs-on-a-chip platforms are a new group of micro-engineered promising models that recapitulate 3D tissue structure and physiology and combines several advantages of current in vivo and in vitro models. Microfluidics technology is used in numerous applications since it allows us to control and manipulate fluid flows with a high degree of accuracy. This system is an emerging tool for understanding disease development and progression, especially for personalized therapeutic strategies for cancer treatment, which provide well-grounded, cost-effective, powerful, fast, and reproducible results. In this review, we highlight how the organoid-on-a-chip models have improved the potential of efficiency and reproducibility of organoid cultures. More widely, we discuss current challenges and development on organoid culture systems together with microfluidic approaches and their limitations. Finally, we describe the recent progress and potential utilization in the organs-on-a-chip practice.

Published
2021

25. Cancer Stem Cells in Thyroid Tumors: From the Origin to Metastasis

Author

Melania Lo Iacono, Stefano Forte, Dario Giuffrida, Alice Turdo, Miriam Gaggianesi, Veronica Veschi, Caterina D’Accardo, Matilde Todaro, Francesco Verona, Lorenzo Memeo, Gaetana Porcelli, Veschi V., Verona F., Lo Iacono M., D'Accardo C., Porcelli G., Turdo A., Gaggianesi M., Forte S., Giuffrida D., Memeo L., and Todaro M.

Subjects
0301 basic medicine, cancer stem cells, Endocrinology, Diabetes and Metabolism, thyroid tumors, 030209 endocrinology & metabolism, Tumor initiation, Review, Biology, medicine.disease_cause, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Metastasis, Histones, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Cancer stem cell, medicine, Tumor Microenvironment, Humans, Thyroid Neoplasms, Neoplasm Metastasis, Thyroid cancer, Tumor microenvironment, lcsh:RC648-665, Thyroid, Cancer, DNA Methylation, medicine.disease, microenvironment, MicroRNAs, immune system, 030104 developmental biology, medicine.anatomical_structure, epigenetic alterations, Cancer research, Neoplastic Stem Cells, Carcinogenesis
Abstract

Thyroid tumors are extremely heterogeneous varying from almost benign tumors with good prognosis as papillary or follicular tumors, to the undifferentiated ones with severe prognosis. Recently, several models of thyroid carcinogenesis have been described, mostly hypothesizing a major role of the thyroid cancer stem cell (TCSC) population in both cancer initiation and metastasis formation. However, the cellular origin of TCSC is still incompletely understood. Here, we review the principal epigenetic mechanisms relevant to TCSC origin and maintenance in both well-differentiated and anaplastic thyroid tumors. Specifically, we describe the alterations in DNA methylation, histone modifiers, and microRNAs (miRNAs) involved in TCSC survival, focusing on the potential of targeting aberrant epigenetic modifications for developing novel therapeutic approaches. Moreover, we discuss the bidirectional relationship between TCSCs and immune cells. The cells of innate and adaptive response can promote the TCSC-driven tumorigenesis, and conversely, TCSCs may favor the expansion of immune cells with protumorigenic functions. Finally, we evaluate the role of the tumor microenvironment and the complex cross-talk of chemokines, hormones, and cytokines in regulating thyroid tumor initiation, progression, and therapy refractoriness. The re-education of the stromal cells can be an effective strategy to fight thyroid cancer. Dissecting the genetic and epigenetic landscape of TCSCs and their interactions with tumor microenvironment cells is urgently needed to select more appropriate treatment and improve the outcome of patients affected by advanced differentiated and undifferentiated thyroid cancers.

Published
2020

26. Cancer Stem Cell Biomarkers Predictive of Radiotherapy Response in Rectal Cancer: A Systematic Review

Author

Cristina Colarossi, Marzia Mare, Lorenzo Colarossi, Dario Giuffrida, Alice Turdo, Veronica Veschi, Lorenzo Memeo, Giorgio Stassi, Mare M., Colarossi L., Veschi V., Turdo A., Giuffrida D., Memeo L., Stassi G., and Colarossi C.

Subjects
Oncology, Neo-adjuvant radiotherapy, medicine.medical_specialty, Colorectal cancer, medicine.medical_treatment, Review, QH426-470, Radiosensitivity, Cancer stem cell, Radioresistance, Internal medicine, Biomarkers, Tumor, Genetics, medicine, Humans, Genetics (clinical), Rectal cancer (RC), biology, Rectal Neoplasms, Cancer stem cells, Genitourinary system, business.industry, CD44, Therapeutic effect, medicine.disease, Organoids, Radiation therapy, Treatment Outcome, Systematic review, In vitro radiotherapy, Neoplastic Stem Cells, biology.protein, business
Abstract

Background: Rectal cancer (RC) is one of the most commonly diagnosed and particularly challenging tumours to treat due to its location in the pelvis and close proximity to critical genitourinary organs. Radiotherapy (RT) is recognised as a key component of therapeutic strategy to treat RC, promoting the downsizing and downstaging of large RCs in neoadjuvant settings, although its therapeutic effect is limited due to radioresistance. Evidence from experimental and clinical studies indicates that the likelihood of achieving local tumour control by RT depends on the complete eradication of cancer stem cells (CSC), a minority subset of tumour cells with stemness properties. Methods: A systematic literature review was conducted by querying two scientific databases (Pubmed and Scopus). The search was restricted to papers published from 2009 to 2021. Results: After assessing the quality and the risk of bias, a total of 11 studies were selected as they mainly focused on biomarkers predictive of RT-response in CSCs isolated from patients affected by RC. Specifically these studies showed that elevated levels of CD133, CD44, ALDH1, Lgr5 and G9a are associated with RT-resistance and poor prognosis. Conclusions: This review aimed to provide an overview of the current scenario of in vitro and in vivo studies evaluating the biomarkers predictive of RT-response in CSCs derived from RC patients.

Published
2021

27. Cancer Extracellular Vesicles: Next-Generation Diagnostic and Drug Delivery Nanotools

Author

Tiziano Tuccinardi, Agostino Steffan, Vincenzo Canzonieri, Tiziana Perin, Stefano Palazzolo, Mohamad Hadla, Fahriye Duzagac, Lorenzo Memeo, Flavio Rizzolio, Isabella Caligiuri, Palazzolo, S., Memeo, L., Hadla, M., Duzagac, F., Steffan, A., Perin, T., Canzonieri, V., Tuccinardi, T., Caligiuri, I., and Rizzolio, F.

Subjects
0301 basic medicine, Cancer Research, Settore BIO/11 - Biologia Molecolare, Review, lcsh:RC254-282, Extracellular vesicles, Cancer, Diagnostics, Drug delivery, Microvesicles, Nanomedicine, 03 medical and health sciences, 0302 clinical medicine, Microvesicle, medicine, Extracellular, Diagnostic, Liquid biopsy, chemistry.chemical_classification, Chemistry, Biomolecule, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Cell biology, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Extracellular vesicle
Abstract

Simple Summary Extracellular vesicles (EVs) are secreted continuously from different cell types. The composition of EVs, like proteins, nucleic acids and lipids is linked with the cells of origin and they are involved in cell-cell communication. The presence of EVs in the majority of the body fluids makes them attractive to investigate and define their role in physiological and in pathological processes. This review is focused on EVs with dimensions between 30 and 150 nm like exosomes (EEVs). We described the biogenesis of EEVs, methods for isolation and their role in cancer as innovative diagnostic tools and new drug delivery systems. Abstract Nanosized extracellular vesicles (EVs) with dimensions ranging from 100 to 1000 nm are continuously secreted from different cells in their extracellular environment. They are able to encapsulate and transfer various biomolecules, such as nucleic acids, proteins, and lipids, that play an essential role in cell‒cell communication, reflecting a novel method of extracellular cross-talk. Since EVs are present in large amounts in most bodily fluids, challengeable hypotheses are analyzed to unlock their potential roles. Here, we review EVs by discussing their specific characteristics (structure, formation, composition, and isolation methods), focusing on their key role in cell biology. Furthermore, this review will summarize the biomedical applications of EVs, in particular those between 30 and 150 nm (like exosomes), as next-generation diagnostic tools in liquid biopsy for cancer and as novel drug delivery vehicles.

Published
2020

28. Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression

Author

Lorenzo Memeo, Jayadev Raju, Amedeo Amedei, Dustin G. Brown, Rafaela Andrade-Vieira, Jordan Woodrick, Dale W. Laird, Fahd Al-Mulla, Neetu Singh, Gary S. Goldberg, Debasish Roy, Rabeah Al-Temaimi, Paul Dent, William H. Bisson, Paola A. Marignani, Jan Vondráček, Gloria M. Calaf, Richard Ponce-Cusi, Karine A. Cohen-Solal, Riccardo Di Fiore, Rita Nahta, Annamaria Colacci, Hosni Salem, Robert C. Castellino, Elizabeth P. Ryan, Nichola Cruickshanks, Harini Krishnan, Chiara Mondello, Christian C. Naus, Mark Wade, Rabindra Roy, Monica Vaccari, Stefano Forte, Sarah N Bay, Roslida Abd Hamid, Ahmed Lasfar, A. Ivana Scovassi, Renza Vento, Nahta, R., Al-Mulla, F., Al-Temaimi, R., Amedei, A., Andrade-Vieira, R., Bay, S., Brown, D., Calaf, G., Castellino, R., Cohen-Solal, K., Colacci, A., Cruickshanks, N., Dent, P., Di Fiore, R., Forte, S., Goldberg, G., Hamid, R., Krishnan, H., Laird, D., Lasfar, A., Marignani, P., Memeo, L., Mondello, C., Naus, C., Ponce-Cusi, R., Raju, J., Roy, D., Roy, R., Ryan, E., Salem, H., Ivana Scovassi, A., Singh, N., Vaccari, M., Vento, R., Vondráček, J., Wade, M., Woodrick, J., and Bisson, W.

Subjects
Cancer Research, Review, Hazardous Substances, chemistry.chemical_compound, Neoplasms, Animals, Humans, Medicine, biology, Animal, business.industry, Medicine (all), Retinoblastoma protein, Contact inhibition, Cancer, Environmental Exposure, General Medicine, Environmental exposure, Evasion (ethics), medicine.disease, Cell biology, chemistry, Hazardous Substance, Immunology, Cancer cell, biology.protein, Neoplasm, Signal transduction, Growth inhibition, business, Human, Signal Transduction
Abstract

As part of the Halifax Project, this review brings attention to the potential effects of environmental chemicals on important molecular and cellular regulators of the cancer hallmark of evading growth suppression. Specifically, we review the mechanisms by which cancer cells escape the growth-inhibitory signals of p53, retinoblastoma protein, transforming growth factor-beta, gap junctions and contact inhibition. We discuss the effects of selected environmental chemicals on these mechanisms of growth inhibition and cross-reference the effects of these chemicals in other classical cancer hallmarks.

Published
2015

29. Interleukin 3- receptor targeted exosomes inhibit in vitro and in vivo chronic myelogenous Leukemia cell growth

Author

Francesca Monteleone, Riccardo Alessandro, Girolamo Cirrincione, Stefania Raimondo, Giacomo De Leo, Simona Fontana, Daniele Bellavia, Samuele Raccosta, Stefano Forte, Gianluca Giavaresi, Marta Cristaldi, Mauro Manno, Lorenzo Memeo, Agostina Patinella, Patrizia Diana, Giovanna Calabrese, Bellavia, D., Raimondo, S., Calabrese, G., Forte, S., Cristaldi, M., Patinella, A., Memeo, L., Manno, M., Raccosta, S., Diana, P., Cirrincione, G., Giavaresi, G., Monteleone, F., Fontana, S., Leo, G., and Alessandro, R.

Subjects
0301 basic medicine, Medicine (miscellaneous), Pharmacology, Engineered exosome, Exosomes, Interleukin 3, Antineoplastic Agent, Mice, HEK293 Cell, hemic and lymphatic diseases, Drug Carrier, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Drug Carriers, Chronic myeloid leukemia, Myeloid leukemia, Drug delivery, Drug resistance, Engineered exosomes, Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Disease Models, Animal, HEK293 Cells, Heterografts, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Receptors, Interleukin-3, Treatment Outcome, 3. Good health, Heterograft, Research Paper, medicine.drug, Human, 03 medical and health sciences, In vivo, medicine, neoplasms, business.industry, Animal, Imatinib, medicine.disease, Microvesicles, Exosome, 030104 developmental biology, Imatinib mesylate, Cancer cell, business, Chronic myelogenous leukemia
Abstract

Despite Imatinib (IM), a selective inhibitor of Bcr-Abl, having led to improved prognosis in Chronic Myeloid Leukemia (CML) patients, acquired resistance and long-term adverse effects is still being encountered. There is, therefore, urgent need to develop alternative strategies to overcome drug resistance. According to the molecules expressed on their surface, exosomes can target specific cells. Exosomes can also be loaded with a variety of molecules, thereby acting as a vehicle for the delivery of therapeutic agents. In this study, we engineered HEK293T cells to express the exosomal protein Lamp2b, fused to a fragment of Interleukin 3 (IL3). The IL3 receptor (IL3-R) is overexpressed in CML blasts compared to normal hematopoietic cells and thus is able to act as a receptor target in a cancer drug delivery system. Here we show that IL3L exosomes, loaded with Imatinib or with BCR-ABL siRNA, are able to target CML cells and inhibit in vitro and in vivo cancer cell growth.

Published
2017

30. Metabolic reprogramming and dysregulated metabolism: Cause, consequence and/or enabler of environmental carcinogenesis?

Author

Stefano Forte, Arthur Berg, Graeme Williams, Ferdinando Chiaradonna, Francis Martin, Monica Vaccari, Annamaria Colacci, Dustin G. Brown, Amedeo Amedei, Judith Weisz, Roslida Abd Hamid, R. Brooks Robey, Jordan Woodrick, Nancy B. Kuemmerle, Rabeah Al-Temaimi, William H. Bisson, Lorenzo Memeo, Roberta Palorini, Hosni Salem, Neetu Singh, Joel N. Meyer, Jayadev Raju, A. Ivana Scovassi, Chiara Mondello, Laura L. Kubik, Rabindra Roy, Fahd Al-Mulla, Elizabeth P. Ryan, Leroy Lowe, Anna C. Salzberg, Brooks Robey, R, Weisz, J, Kuemmerle, N, Salzberg, A, Berg, A, Brown, D, Kubik, L, Palorini, R, Al Mulla, F, Al Temaimi, R, Colacci, A, Mondello, C, Raju, J, Woodrick, J, Ivana Scovassi, A, Singh, N, Vaccari, M, Roy, R, Forte, S, Memeo, L, Salem, H, Amedei, A, Hamid, R, Williams, G, Lowe, L, Meyer, J, Martin, F, Bisson, W, Chiaradonna, F, and Ryan, E

Subjects
Cancer Research, Carcinogenesis, Metabolic reprogramming, Computational biology, Review, Pharmacology, Biology, medicine.disease_cause, Neoplasms, medicine, Animals, Humans, Carcinogenesi, Environmental risk assessment, Animal, General Medicine, Environmental exposure, Environmental Exposure, BIO/10 - BIOCHIMICA, Carcinogens, Environmental, Enabling, Cancer metabolism, Environmental Carcinogenesis, Neoplasm, Cancer development, Human
Abstract

Environmental contributions to cancer development are widely accepted, but only a fraction of all pertinent exposures have probably been identified. Traditional toxicological approaches to the problem have largely focused on the effects of individual agents at singular endpoints. As such, they have incompletely addressed both the pro-carcinogenic contributions of environmentally relevant low-dose chemical mixtures and the fact that exposures can influence multiple cancer-associated endpoints over varying timescales. Of these endpoints, dysregulated metabolism is one of the most common and recognizable features of cancer, but its specific roles in exposure-associated cancer development remain poorly understood. Most studies have focused on discrete aspects of cancer metabolism and have incompletely considered both its dynamic integrated nature and the complex controlling influences of substrate availability, external trophic signals and environmental conditions. Emerging high throughput approaches to environmental risk assessment also do not directly address the metabolic causes or consequences of changes in gene expression. As such, there is a compelling need to establish common or complementary frameworks for further exploration that experimentally and conceptually consider the gestalt of cancer metabolism and its causal relationships to both carcinogenesis and the development of other cancer hallmarks. A literature review to identify environmentally relevant exposures unambiguously linked to both cancer development and dysregulated metabolism suggests major gaps in our understanding of exposure-associated carcinogenesis and metabolic reprogramming. Although limited evidence exists to support primary causal roles for metabolism in carcinogenesis, the universality of altered cancer metabolism underscores its fundamental biological importance, and multiple pleiomorphic, even dichotomous, roles for metabolism in promoting, antagonizing or otherwise enabling the development and selection of cancer are suggested.

Published
2015

31. Analysis by TeloView ® Technology Predicts the Response of Hodgkin's Lymphoma to First-Line ABVD Therapy.

Author

Knecht H, Johnson N, Bienz MN, Brousset P, Memeo L, Shifrin Y, Alikhah A, Louis SF, and Mai S

Abstract

Classic Hodgkin's lymphoma (cHL) is a curable cancer with a disease-free survival rate of over 10 years. Over 80% of diagnosed patients respond favorably to first-line chemotherapy, but few biomarkers exist that can predict the 15-20% of patients who experience refractory or early relapsed disease. To date, the identification of patients who will not respond to first-line therapy based on disease staging and traditional clinical risk factor analysis is still not possible. Three-dimensional (3D) telomere analysis using the TeloView ® software platform has been shown to be a reliable tool to quantify genomic instability and to inform on disease progression and patients' response to therapy in several cancers. It also demonstrated telomere dysfunction in cHL elucidating biological mechanisms related to disease progression. Here, we report 3D telomere analysis on a multicenter cohort of 156 cHL patients. We used the cohort data as a training data set and identified significant 3D telomere parameters suitable to predict individual patient outcomes at the point of diagnosis. Multivariate analysis using logistic regression procedures allowed for developing a predictive scoring model using four 3D telomere parameters as predictors, including the proportion of t-stumps (very short telomeres), which has been a prominent predictor for cHL patient outcome in a previously published study using TeloView ® analysis. The percentage of t-stumps was by far the most prominent predictor to identify refractory/relapsing (RR) cHL prior to initiation of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) therapy. The model characteristics include an AUC of 0.83 in ROC analysis and a sensitivity and specificity of 0.82 and 0.78 respectively.

Published
2024
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32. Colitis cystica profunda associated with diverticulosis and calcification mimicking colorectal carcinoma: a case report and a brief literature review.

Author

Rosano GN, Aiello E, Pisheh SK, Deiana E, Memeo L, and Colarossi C

Subjects
Humans, Diagnosis, Differential, Colitis pathology, Colitis diagnosis, Cysts pathology, Cysts diagnosis, Male, Diverticulum pathology, Diverticulum diagnosis, Aged, Middle Aged, Diverticulosis, Colonic pathology, Diverticulosis, Colonic diagnosis, Diverticulosis, Colonic complications, Female, Calcinosis pathology, Calcinosis diagnosis, Colorectal Neoplasms pathology, Colorectal Neoplasms diagnosis
Abstract

Colitis cystica profunda (CCP) is a rare, uncommon and nonneoplastic condition that can occur anywhere in gastrointestinal tract, but its main occurrence is in the rectum and sigmoid colon. It is characterized by the presence of mucin filled cysts, lined by benign epithelium, beneath the muscularis mucosae, usually confined to the submucosa, and it can clinically and radiologically mimic a neoplasm. Here we report a rare case of CCP in a patient with a 2-months history of abdominal pain and severe anemia, associated with diverticulosis. The knowledge of this entity and its differential diagnosis, in particular with the intestinal mucinous adenocarcinoma, is necessary, as it can be a clinically and histological mimic of a malignant neoplasm., (Copyright © 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Published
2024
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33. ARID1A Mutations in Gastric Cancer: A Review with Focus on Clinicopathological Features, Molecular Background and Diagnostic Interpretation.

Author

Angelico G, Attanasio G, Colarossi L, Colarossi C, Montalbano M, Aiello E, Di Vendra F, Mare M, Orsi N, and Memeo L

Abstract

AT-rich interaction domain 1 ( ARID1A ) is a pivotal gene with a significant role in gastrointestinal tumors which encodes a protein referred to as BAF250a or SMARCF1, an integral component of the SWI/SNF (SWItch/sucrose non-fermentable) chromatin remodeling complex. This complex is instrumental in regulating gene expression by modifying the structure of chromatin to affect the accessibility of DNA. Mutations in ARID1A have been identified in various gastrointestinal cancers, including colorectal, gastric, and pancreatic cancers. These mutations have the potential to disrupt normal SWI/SNF complex function, resulting in aberrant gene expression and potentially contributing to the initiation and progression of these malignancies. ARID1A mutations are relatively common in gastric cancer, particularly in specific adenocarcinoma subtypes. Moreover, such mutations are more frequently observed in specific molecular subtypes, such as microsatellite stable (MSS) cancers and those with a diffuse histological subtype. Understanding the presence and implications of ARID1A mutations in GC is of paramount importance for tailoring personalized treatment strategies and assessing prognosis, particularly given their potential in predicting patient response to novel treatment strategies including immunotherapy, poly(ADP) ribose polymerase (PARP) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors.

Published
2024
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35. Role of Hippo pathway dysregulation from gastrointestinal premalignant lesions to cancer.

Author

Schiavoni G, Messina B, Scalera S, Memeo L, Colarossi C, Mare M, Blandino G, Ciliberto G, Bon G, and Maugeri-Saccà M

Subjects
Animals, Drosophila melanogaster, Signal Transduction, Gastrointestinal Tract, Hippo Signaling Pathway, Neoplasms drug therapy
Abstract

Background: First identified in Drosophila melanogaster, the Hippo pathway is considered a major regulatory cascade controlling tissue homeostasis and organ development. Hippo signaling components include kinases whose activity regulates YAP and TAZ final effectors. In response to upstream stimuli, YAP and TAZ control transcriptional programs involved in cell proliferation, cytoskeletal reorganization and stemness., Main Text: While fine tuning of Hippo cascade components is essential for maintaining the balance between proliferative and non-proliferative signals, pathway signaling is frequently dysregulated in gastrointestinal cancers. Also, YAP/TAZ aberrant activation has been described in conditions characterized by chronic inflammation that precede cancer development, suggesting a role of Hippo effectors in triggering carcinogenesis. In this review, we summarize the architecture of the Hippo pathway and discuss the involvement of signaling cascade unbalances in premalignant lesions of the gastrointestinal tract, providing a focus on the underlying molecular mechanisms., Conclusions: The biology of premalignant Hippo signaling dysregulation needs further investigation in order to elucidate the evolutionary trajectories triggering cancer inititation and develop effective early therapeutic strategies targeting the Hippo/YAP pathway., (© 2024. The Author(s).)

Published
2024
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36. Tumor Infiltrating Lymphocytes (TILS) and PD-L1 Expression in Breast Cancer: A Review of Current Evidence and Prognostic Implications from Pathologist's Perspective.

Author

Angelico G, Broggi G, Tinnirello G, Puzzo L, Vecchio GM, Salvatorelli L, Memeo L, Santoro A, Farina J, Mulé A, Magro G, and Caltabiano R

Abstract

With the rise of novel immunotherapies able to stimulate the antitumor immune response, increasing literature concerning the immunogenicity of breast cancer has been published in recent years. Numerous clinical studies have been conducted in order to identify novel biomarkers that could reflect the immunogenicity of BC and predict response to immunotherapy. In this regard, TILs have emerged as an important immunological biomarker related to the antitumor immune response in BC. TILs are more frequently observed in triple-negative breast cancer and HER2+ subtypes, where increased TIL levels have been linked to a better response to neoadjuvant chemotherapy and improved survival. PD-L1 is a type 1 transmembrane protein ligand expressed on T lymphocytes, B lymphocytes, and antigen-presenting cells and is considered a key inhibitory checkpoint involved in cancer immune regulation. PD-L1 immunohistochemical expression in breast cancer is observed in about 10-30% of cases and is extremely variable based on tumor stage and molecular subtypes. Briefly, TNBC shows the highest percentage of PD-L1 positivity, followed by HER2+ tumors. On the other hand, PD-L1 is rarely expressed (0-10% of cases) in hormone-receptor-positive BC. The prognostic role of PD-L1 expression in BC is still controversial since different immunohistochemistry (IHC) clones, cut-off points, and scoring systems have been utilized across published studies. In the present paper, an extensive review of the current knowledge of the immune landscape of BC is provided. TILS and PD-L1 expression across different BC subtypes are discussed, providing a guide for their pathological assessment and reporting.

Published
2023
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37. The ideal reporting of RAS testing in colorectal adenocarcinoma: a pathologists' perspective.

Author

Malapelle U, Angerilli V, Pepe F, Fontanini G, Lonardi S, Scartozzi M, Memeo L, Pruneri G, Marchetti A, Perrone G, and Fassan M

Abstract

RAS gene mutational status represents an imperative predictive biomarker to be tested in the clinical management of metastatic colorectal adenocarcinoma. Even if it is one of the most studied biomarkers in the era of precision medicine, several pre-analytical and analytical factors may still impasse an adequate reporting of RAS status in clinical practice, with significant therapeutic consequences. Thus, pathologists should be aware on the main topics related to this molecular evaluation: (i) adopt diagnostic limit of detections adequate to avoid the interference of sub-clonal cancer cell populations; (ii) choose the most adequate diagnostic strategy according to the available sample and its qualification for molecular testing; (iii) provide all the information regarding the mutation detected, since many RAS mutation-specific targeted therapeutic approaches are in development and will enter into routine clinical practice. In this review, we give a comprehensive description of the current scenario about RAS gene mutational testing in the clinic focusing on the pathologist's role in patient selection for targeted therapies., (Copyright © 2023 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Published
2023
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38. Recapitulating thyroid cancer histotypes through engineering embryonic stem cells.

Author

Veschi V, Turdo A, Modica C, Verona F, Di Franco S, Gaggianesi M, Tirrò E, Di Bella S, Iacono ML, Pantina VD, Porcelli G, Mangiapane LR, Bianca P, Rizzo A, Sciacca E, Pillitteri I, Vella V, Belfiore A, Bongiorno MR, Pistone G, Memeo L, Colarossi L, Giuffrida D, Colarossi C, Vigneri P, Todaro M, and Stassi G

Subjects
Humans, Receptors, Kisspeptin-1 genetics, Tissue Inhibitor of Metalloproteinase-1 genetics, Embryonic Stem Cells, Proto-Oncogene Proteins B-raf genetics, Mutation, Iodine Radioisotopes, Thyroid Neoplasms genetics
Abstract

Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. The cell subpopulation in the lineage hierarchy that serves as cell of origin for the different TC histotypes is unknown. Human embryonic stem cells (hESCs) with appropriate in vitro stimulation undergo sequential differentiation into thyroid progenitor cells (TPCs-day 22), which maturate into thyrocytes (day 30). Here, we create follicular cell-derived TCs of all the different histotypes based on specific genomic alterations delivered by CRISPR-Cas9 in hESC-derived TPCs. Specifically, TPCs harboring BRAF V600E or NRAS Q61R mutations generate papillary or follicular TC, respectively, whereas addition of TP53 R248Q generate undifferentiated TCs. Of note, TCs arise by engineering TPCs, whereas mature thyrocytes have a very limited tumorigenic capacity. The same mutations result in teratocarcinomas when delivered in early differentiating hESCs. Tissue Inhibitor of Metalloproteinase 1 (TIMP1)/Matrix metallopeptidase 9 (MMP9)/Cluster of differentiation 44 (CD44) ternary complex, in cooperation with Kisspeptin receptor (KISS1R), is involved in TC initiation and progression. Increasing radioiodine uptake, KISS1R and TIMP1 targeting may represent a therapeutic adjuvant option for undifferentiated TCs., (© 2023. The Author(s).)

Published
2023
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39. Hippo pathway dysregulation in gastric cancer: from Helicobacter pylori infection to tumor promotion and progression.

Author

Messina B, Lo Sardo F, Scalera S, Memeo L, Colarossi C, Mare M, Blandino G, Ciliberto G, Maugeri-Saccà M, and Bon G

Subjects
Humans, Cell Transformation, Neoplastic, Helicobacter pylori, Protein Serine-Threonine Kinases metabolism, Transcription Factors genetics, Transcription Factors metabolism, Helicobacter Infections genetics, Hippo Signaling Pathway, Stomach Neoplasms genetics, Stomach Neoplasms microbiology
Abstract

The Hippo pathway plays a critical role for balancing proliferation and differentiation, thus regulating tissue homeostasis. The pathway acts through a kinase cascade whose final effectors are the Yes-associated protein (YAP) and its paralog transcriptional co‑activator with PDZ‑binding motif (TAZ). In response to a variety of upstream signals, YAP and TAZ activate a transcriptional program that modulates cellular proliferation, tissue repair after injury, stem cell fate decision, and cytoskeletal reorganization. Hippo pathway signaling is often dysregulated in gastric cancer and in Helicobacter pylori-induced infection, suggesting a putative role of its deregulation since the early stages of the disease. In this review, we summarize the architecture and regulation of the Hippo pathway and discuss how its dysregulation fuels the onset and progression of gastric cancer. In this setting, we also focus on the crosstalk between Hippo and other established oncogenic signaling pathways. Lastly, we provide insights into the therapeutic approaches targeting aberrant YAP/TAZ activation and discuss the related clinical perspectives and challenges., (© 2023. The Author(s).)

Published
2023
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40. SCLC: Epidemiology, Risk Factors, Genetic Susceptibility, Molecular Pathology, Screening, and Early Detection.

Author

Wang Q, Gümüş ZH, Colarossi C, Memeo L, Wang X, Kong CY, and Boffetta P

Subjects
Male, Female, Humans, Genetic Predisposition to Disease, Pathology, Molecular, Early Detection of Cancer methods, Risk Factors, Lung Neoplasms diagnosis, Lung Neoplasms epidemiology, Lung Neoplasms genetics, Small Cell Lung Carcinoma diagnosis, Small Cell Lung Carcinoma epidemiology, Small Cell Lung Carcinoma genetics
Abstract

We review research regarding the epidemiology, risk factors, genetic susceptibility, molecular pathology, and early detection of SCLC, a deadly tumor that accounts for 14% of lung cancers. We first summarize the changing incidences of SCLC globally and in the United States among males and females. We then review the established risk factor (i.e., tobacco smoking) and suspected nonsmoking-related risk factors for SCLC, and emphasize the importance of continued effort in tobacco control worldwide. Review of genetic susceptibility and molecular pathology suggests different molecular pathways in SCLC development compared with other types of lung cancer. Last, we comment on the limited utility of low-dose computed tomography screening in SCLC and on several promising blood-based molecular biomarkers as potential tools in SCLC early detection., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Published
2023
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41. Destroying the Shield of Cancer Stem Cells: Natural Compounds as Promising Players in Cancer Therapy.

Author

Lo Iacono M, Gaggianesi M, Bianca P, Brancato OR, Muratore G, Modica C, Roozafzay N, Shams K, Colarossi L, Colarossi C, Memeo L, Turdo A, Veschi V, Di Franco S, Todaro M, and Stassi G

Abstract

In a scenario where eco-sustainability and a reduction in chemotherapeutic drug waste are certainly a prerogative to safeguard the biosphere, the use of natural products (NPs) represents an alternative therapeutic approach to counteract cancer diseases. The presence of a heterogeneous cancer stem cell (CSC) population within a tumor bulk is related to disease recurrence and therapy resistance. For this reason, CSC targeting presents a promising strategy for hampering cancer recurrence. Increasing evidence shows that NPs can inhibit crucial signaling pathways involved in the maintenance of CSC stemness and sensitize CSCs to standard chemotherapeutic treatments. Moreover, their limited toxicity and low costs for large-scale production could accelerate the use of NPs in clinical settings. In this review, we will summarize the most relevant studies regarding the effects of NPs derived from major natural sources, e.g., food, botanical, and marine species, on CSCs, elucidating their use in pre-clinical and clinical studies.

Published
2022
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42. Third- and Late Line Treatments of Metastatic Gastric Cancer: Still More to Be Done.

Author

Mare M, Memeo L, Colarossi C, and Giuffrida D

Subjects
B7-H1 Antigen, Humans, Trastuzumab therapeutic use, Antineoplastic Agents therapeutic use, Stomach Neoplasms drug therapy
Abstract

In recent years, advances of anticancer and supportive therapies have determined a gradual improvement in survival rates and patients' general conditions in metastatic gastric cancer (mGC), allowing them to receive further treatments. The choice of treatment is driven by performance status, age, stage of disease, number of metastatic sites and time from the first to third line of treatment. Targets such as microsatellite instability, PD-L1 expression, and HER2 overexpression or amplification may be addressed to personalise treatment and prolong survival. Despite a growing number of third line options that have provided clinicians with greater opportunities to customise treatments, up to date few agents have been demonstrated as effective after two standard lines for mGC; for these reasons, chemotherapy, immunotherapy, and targeted therapy were all widely investigated in both phase II and phase III studies. Overall, TAS-102, apatinib, regorafenib, nilotinib, trastuzumab, and pembrolizumab were demonstrated to be valid options in the third line scenario for mGC patient refractory to at least two lines of therapy. A multimodal approach based on chemotherapy, immunotherapy, targeted agents, a personalised nutritional programme as well as the research of new predictive biomarkers may pave the way to new strategies to identify the best treatment for each patient.

Published
2022
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43. Endoscopic laser en bloc removal of bladder tumor. Surgical radicality and improvement of the pathological diagnostic accuracy.

Author

Leonardi R, Calarco A, Falcone L, Grasso V, Frisenda M, Tufano A, Viscuso P, Rossi A, and Memeo L

Subjects
Aged, Humans, Middle Aged, Urinary Bladder pathology, Urologic Surgical Procedures methods, Urinary Bladder Neoplasms pathology, Urinary Bladder Neoplasms surgery
Abstract

Introduction: Bladder cancer is one of the most common tumors among the general population. The first surgical approach to the tumor is often the transurethral resection with monopolar or bipolar loop. Recently, laser energy has become an alternative for resection of small bladder tumor, because it allows to obtain high quality samples with the "en bloc" technique. Our study aims to show the results of endoscopic diode laser treatment of bladder tumor up to three centimeters in maximum diameter., Materials and Methods: 189 patients underwent "en bloc" resection with diode dual length laser (980 nm-1470 nm). Follow up was over 12 months. Patients age range was from 45 to 75 years. Maximum diameter of the lesions was 3.0 cm. For each patient, a cold forceps biopsy sample was performed., Results: All samples collected presented detrusorial layer. Pathological exam showed: 28 (14.8%) Ta, G1-G2; 7 (3.7%) T3, G2-G3; 14 (7.4%) T1, G2-G3 and 140 ( 74.1%) Ta, G2-G3. No complications occurred during or after surgery. At a median follow-up period of 6 months, we had no recurrence in the previous site of tumor. In the follow up at 3/6/12 months in 4 cases we had recurrence in different sites of bladder wall., Conclusions: Laser "en bloc" resection is an effective, feasible, and safe treatment for bladder tumor. It could be a valid alternative to monopolar and bipolar resection in small bladder cancer treatment.

Published
2022
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44. Medullary Carcinoma of the Gastrointestinal Tract: Report on Two Cases with Immunohistochemical and Molecular Features.

Author

Colarossi C, Mare M, La Greca G, De Zuanni M, Colarossi L, Aiello E, Piombino E, and Memeo L

Abstract

Medullary carcinoma of the colon is a rare histological variant characterized by a poorly differentiated morphology, an aberrant immunophenotype, and microsatellite instability. Despite the lack of glandular differentiation, medullary carcinoma is reported to have a good prognosis. It is typically located in the right colon and frequently affects older women. Due to its clinical, histological, biological, and genetic peculiarity, medullary carcinoma requires an accurate diagnosis and the awareness of this diagnostic possibility. We describe the morphological, immunohistochemical, and molecular findings of two interesting cases, the first one in the right colon of a patient and the second one in the terminal ileum of a patient with Crohn's disease. Deeper knowledge of all the biological and clinical features will allow appropriate and specific treatment of this tumor in the future.

Published
2021
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45. Cancer Stem Cell Biomarkers Predictive of Radiotherapy Response in Rectal Cancer: A Systematic Review.

Author

Mare M, Colarossi L, Veschi V, Turdo A, Giuffrida D, Memeo L, Stassi G, and Colarossi C

Subjects
Humans, Rectal Neoplasms metabolism, Treatment Outcome, Biomarkers, Tumor metabolism, Neoplastic Stem Cells metabolism, Rectal Neoplasms radiotherapy
Abstract

Background: Rectal cancer (RC) is one of the most commonly diagnosed and particularly challenging tumours to treat due to its location in the pelvis and close proximity to critical genitourinary organs. Radiotherapy (RT) is recognised as a key component of therapeutic strategy to treat RC, promoting the downsizing and downstaging of large RCs in neoadjuvant settings, although its therapeutic effect is limited due to radioresistance. Evidence from experimental and clinical studies indicates that the likelihood of achieving local tumour control by RT depends on the complete eradication of cancer stem cells (CSC), a minority subset of tumour cells with stemness properties., Methods: A systematic literature review was conducted by querying two scientific databases (Pubmed and Scopus). The search was restricted to papers published from 2009 to 2021., Results: After assessing the quality and the risk of bias, a total of 11 studies were selected as they mainly focused on biomarkers predictive of RT-response in CSCs isolated from patients affected by RC. Specifically these studies showed that elevated levels of CD133, CD44, ALDH1, Lgr5 and G9a are associated with RT-resistance and poor prognosis., Conclusions: This review aimed to provide an overview of the current scenario of in vitro and in vivo studies evaluating the biomarkers predictive of RT-response in CSCs derived from RC patients.

Published
2021
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46. STARD3: A Prospective Target for Cancer Therapy.

Author

Asif K, Memeo L, Palazzolo S, Frión-Herrera Y, Parisi S, Caligiuri I, Canzonieri V, Granchi C, Tuccinardi T, and Rizzolio F

Abstract

Cancer is one of the major causes of death in developed countries and current therapies are based on surgery, chemotherapeutic agents, and radiation. To overcome side effects induced by chemo- and radiotherapy, in recent decades, targeted therapies have been proposed in second and even first lines. Targeted drugs act on the essential pathways involved in tumor induction, progression, and metastasis, basically all the hallmark of cancers. Among emerging pathways, the cholesterol metabolic pathway is a strong candidate for this purpose. Cancer cells have an accelerated metabolic rate and require a continuous supply of cholesterol for cell division and membrane renewal. Steroidogenic acute regulatory related lipid transfer (START) proteins are a family of proteins involved in the transfer of lipids and some of them are important in non-vesicular cholesterol transportation within the cell. The alteration of their expression levels is implicated in several diseases, including cancers. In this review, we report the latest discoveries on StAR-related lipid transfer protein domain 3 (STARD3), a member of the START family, which has a potential role in cancer, focusing on the structural and biochemical characteristics and mechanisms that regulate its activity. The role of the STARD3 protein as a molecular target for the development of cancer therapies is also discussed. As STARD3 is a key protein in the cholesterol movement in cancer cells, it is of interest to identify inhibitors able to block its activity.

Published
2021
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47. Clear Cell Carcinoma Arising in an Abdominal Wall Cesarean Section Scar: A Case Report With Description of Pathological and Molecular Features.

Author

Colarossi C, Picardo MC, Colarossi L, Deiana E, D'Agata C, Fichera C, Aiello E, Giannone G, and Memeo L

Abstract

Clear cell carcinoma is a clinically and biologically distinct type of carcinoma predominantly encountered in the ovary and endometrium. In the ovary, it is frequently associated with endometriosis, which is a well-known risk factor. Endometriosis has often been described in the abdominal wall of women who had a cesarean section; however, malignant transformation is a very rare event, occurring in <1% of cases. The authors report a case involving a 52-year-old woman with an abdominal wall nodule at a cesarean section scar. Radiology revealed a mass, measuring 8 cm in size, in the abdominal wall suggestive of a soft tissue tumor. After resection, histology revealed the presence of clear, eosinophilic, and hobnail cells, which, together with immunohistochemical and molecular findings, enabled the diagnosis of clear cell carcinoma of the abdominal wall. The present report describes the clinical, radiological, pathological, and molecular features of an unusual abdominal lesion that represents a rare but challenging diagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Colarossi, Picardo, Colarossi, Deiana, D'Agata, Fichera, Aiello, Giannone and Memeo.)

Published
2021
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48. Sclerosing Mesenteritis, a Rare Cause of Mesenteric Mass in a Young Adult: A Case Report.

Author

Piombino E, D'Agata C, Picardo MC, Caltavuturo C, Magro G, Colarossi C, and Memeo L

Abstract

Sclerosing mesenteritis (SM) is a rare fibroinflammatory disorder that involves mesenteric adipose tissue, more frequently localized in the small intestine, with an insidious clinical presentation having symptoms related to mass effect, usually resulting in bowel obstruction, mesenteric ischemia, as well as rapid weight loss. We report a case of a 23-year-old male presenting with palpable abdominal mass, mesogastric pain, and a history of rapid weight loss, who underwent exploratory laparoscopy. A hemorrhagic and gelatinous nodular tumor mass of the mesentery was identified and the surgical procedure was converted to a laparotomic approach. Histologically, the mass was composed of a proliferation of bland-looking spindle cells with slightly eosinophilic cytoplasm and elongated normochromatic nuclei with mild nuclear atypia, haphazardly set in a collagenized stroma; fat necrosis and inflammatory cells (lymphocytes, plasma-cells, and histiocytes) were also evident. The diagnosis of sclerosing mesenteritis was made. Our case emphasizes that histology remains pre-eminent for a correct diagnosis of SM, as pre-operative radiological-based diagnosis is non-specific., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Piombino, D'Agata, Picardo, Caltavuturo, Magro, Colarossi and Memeo.)

Published
2021
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49. Adipose stem cell niche reprograms the colorectal cancer stem cell metastatic machinery.

Author

Di Franco S, Bianca P, Sardina DS, Turdo A, Gaggianesi M, Veschi V, Nicotra A, Mangiapane LR, Lo Iacono M, Pillitteri I, van Hooff S, Martorana F, Motta G, Gulotta E, Lentini VL, Martorana E, Fiori ME, Vieni S, Bongiorno MR, Giannone G, Giuffrida D, Memeo L, Colarossi L, Mare M, Vigneri P, Todaro M, De Maria R, Medema JP, and Stassi G

Subjects
Adipose Tissue metabolism, Animals, Colonic Neoplasms genetics, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Hepatocyte Growth Factor genetics, Hepatocyte Growth Factor metabolism, Humans, Interleukin-6 genetics, Interleukin-6 metabolism, Male, Mice, Mice, SCID, MicroRNAs genetics, MicroRNAs metabolism, Neoplasm Metastasis, Stem Cells cytology, Stem Cells metabolism, Zinc Finger E-box Binding Homeobox 2 genetics, Zinc Finger E-box Binding Homeobox 2 metabolism, Adipose Tissue cytology, Cellular Reprogramming, Colonic Neoplasms physiopathology, Neoplastic Stem Cells cytology, Stem Cell Niche
Abstract

Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored.Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease., (© 2021. The Author(s).)

Published
2021
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