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5. Pharmacological inhibition of CDK4/6 impairs diffuse pleural mesothelioma 3D spheroid growth and reduces viability of cisplatin-resistant cells.

Author

Costa, Aurora, Forte, Iris Maria, Pentimalli, Francesca, Iannuzzi, Carmelina Antonella, Alfano, Luigi, Capone, Francesca, Camerlingo, Rosa, Calabrese, Alessandra, von Arx, Claudia, Dominguez, Reyes Benot, Quintiliani, Massimiliano, De Laurentiis, Michelino, Morrione, Andrea, and Giordano, Antonio

Subjects
CELL survival, CYCLIN-dependent kinases, MESOTHELIOMA, CYCLIN-dependent kinase inhibitors, CELL cycle, CISPLATIN, PLEURA cancer, PLEURA diseases
Abstract

Introduction: Diffuse pleural mesothelioma (DPM) of the pleura is a highly aggressive and treatment-resistant cancer linked to asbestos exposure. Despite multimodal treatment, the prognosis for DPM patients remains very poor, with an average survival of 2 years from diagnosis. Cisplatin, a platinum-based chemotherapy drug, is commonly used in the treatment of DPM. However, the development of resistance to cisplatin significantly limits its effectiveness, highlighting the urgent need for alternative therapeutic strategies. New selective inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have shown promise in various malignancies by inhibiting cell cycle progression and suppressing tumor growth. Recent studies have indicated the potential of abemaciclib for DPM therapy, and a phase II clinical trial has shown preliminary encouraging results. Methods: Here, we tested abemaciclib, palbociclib, and ribociclib on a panel of DPM cell lines and non-tumor mesothelial(MET-5A) cells. Results: Specifically, we focused on abemaciclib, which was the mosteffective cytotoxic agent on all the DPM cell lines tested. Abemaciclib reduced DPM cell viability, clonogenic potential, and ability to grow as three-dimensional (3D) spheroids. In addition, abemaciclib induced prolonged effects, thereby impairing second-generation sphere formation and inducing G0/G1 arrest and apoptosis/necrosis. Interestingly, single silencing of RB family members did not impair cell response to abemaciclib, suggesting that they likely complement each other in triggering abemaciclib's cytostatic effect. Interestingly, abemaciclib reduced the phosphorylation of AKT, which is hyperactive in DPM and synergized with the pharmacological AKT inhibitor (AKTi VIII). Abemaciclib also synergized with cisplatin and reduced the viability of DPM cells with acquired resistance to cisplatin. Discussion: Overall, our results suggest that CDK4/6 inhibitors alone or in combination with standard of care should be further explored for DPM therapy. [ABSTRACT FROM AUTHOR]

Published
2024
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7. CSF-1R in Cancer: More than a Myeloid Cell Receptor

Author

Cersosimo, Francesca, primary, Lonardi, Silvia, additional, Ulivieri, Cristina, additional, Martini, Paolo, additional, Morrione, Andrea, additional, Vermi, William, additional, Giordano, Antonio, additional, and Giurisato, Emanuele, additional

Published
2024
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11. Orexins and Prostate Cancer: State of the Art and Potential Experimental and Therapeutic Perspectives.

Author

COSTAGLIOLA, ANNA, LOMBARDI, RENATO, LIGUORI, GIOVANNA, MORRIONE, ANDREA, and GIORDANO, ANTONIO

Abstract

Prostate cancer (PCa) is the second most common cancer in humans. Peptides have recently been used as targeted therapeutics in cancers, due to their extensive multi-functional applications. Two hypothalamic peptides, orexins A (OXA) and B (OXB) and their specific receptors, orexin receptor 1 (OX1R) and 2 (OX2R), orchestrate several biological processes in the central nervous system and peripheral organs. However, in addition to their role in physiological responses, orexins are involved in numerous inflammatory and/or neoplastic pathologies. The presence and expression of orexins in different cancer models, including prostate cancer, and their role in inducing pro- or anti-apoptotic responses in tumor cell lines, suggest that the orexinergic system might have potential therapeutic action or function as a diagnostic marker in PCa. In addition to the traditional animal models for studying human PCa, the canine model might also serve as an additional tool, due to its clinical similarities with human prostate cancer. [ABSTRACT FROM AUTHOR]

Published
2023
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12. Progranulin Oncogenic Network in Solid Tumors

Author

Ventura, Elisa, primary, Ducci, Giacomo, additional, Benot Dominguez, Reyes, additional, Ruggiero, Valentina, additional, Belfiore, Antonino, additional, Sacco, Elena, additional, Vanoni, Marco, additional, Iozzo, Renato V., additional, Giordano, Antonio, additional, and Morrione, Andrea, additional

Published
2023
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13. The Effect of Sex on Disease Stage and Survival after Radical Cystectomy in Non-Urothelial Variant-Histology Bladder Cancer

Author

Flammia, Rocco Simone, primary, Tufano, Antonio, additional, Chierigo, Francesco, additional, Würnschimmel, Christoph, additional, Hoeh, Benedikt, additional, Sorce, Gabriele, additional, Tian, Zhen, additional, Anceschi, Umberto, additional, Leonardo, Costantino, additional, Del Giudice, Francesco, additional, Terrone, Carlo, additional, Giordano, Antonio, additional, Morrione, Andrea, additional, Saad, Fred, additional, Shariat, Shahrokh F., additional, Briganti, Alberto, additional, Montorsi, Francesco, additional, Chun, Felix K. H., additional, Gallucci, Michele, additional, and Karakiewicz, Pierre I., additional

Published
2023
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15. Progranulin Oncogenic Network in Solid Tumors

Author

Ventura, E, Ducci, G, Benot Dominguez, R, Ruggiero, V, Belfiore, A, Sacco, E, Vanoni, M, Iozzo, R, Giordano, A, Morrione, A, Ventura, Elisa, Ducci, Giacomo, Benot Dominguez, Reyes, Ruggiero, Valentina, Belfiore, Antonino, Sacco, Elena, Vanoni, Marco, Iozzo, Renato V, Giordano, Antonio, Morrione, Andrea, Ventura, E, Ducci, G, Benot Dominguez, R, Ruggiero, V, Belfiore, A, Sacco, E, Vanoni, M, Iozzo, R, Giordano, A, Morrione, A, Ventura, Elisa, Ducci, Giacomo, Benot Dominguez, Reyes, Ruggiero, Valentina, Belfiore, Antonino, Sacco, Elena, Vanoni, Marco, Iozzo, Renato V, Giordano, Antonio, and Morrione, Andrea

Abstract

Progranulin is a pleiotropic growth factor with important physiological roles in embryogenesis and maintenance of adult tissue homeostasis. While-progranulin deficiency is associated with a broad range of pathological conditions affecting the brain, such as frontotemporal dementia and neuronal ceroid lipofuscinosis, progranulin upregulation characterizes many tumors, including brain tumors, multiple myeloma, leiomyosarcoma, mesothelioma and epithelial cancers such as ovarian, liver, breast, bladder, adrenal, prostate and kidney carcinomas. The increase of progranulin levels in tumors might have diagnostic and prognostic significance. In cancer, progranulin has a pro-tumorigenic role by promoting cancer cell proliferation, migration, invasiveness, anchorage-independent growth and resistance to chemotherapy. In addition, progranulin regulates the tumor microenvironment, affects the function of cancer-associated fibroblasts, and modulates tumor immune surveillance. However, the molecular mechanisms of progranulin oncogenic function are not fully elucidated. In bladder cancer, progranulin action relies on the activation of its functional signaling receptor EphA2. Notably, more recent data suggest that progranulin can also modulate a functional crosstalk between multiple receptor-tyrosine kinases, demonstrating a more complex and context-dependent role of progranulin in cancer. Here, we will review what is currently known about the function of progranulin in tumors, with a focus on its molecular mechanisms of action and regulation.

Published
2023

16. Progranulin Oncogenic Network in Solid Tumors

Author

Ventura, Elisa, Ducci, Giacomo, Dominguez, Reyes Benot, Ruggiero, Valentina, Belfiore, Antonino, Sacco, Elena, Vanoni, Marco, Iozzo, Renato V, Giordano, Antonio, Morrione, Andrea, Ventura, Elisa, Ducci, Giacomo, Dominguez, Reyes Benot, Ruggiero, Valentina, Belfiore, Antonino, Sacco, Elena, Vanoni, Marco, Iozzo, Renato V, Giordano, Antonio, and Morrione, Andrea

Abstract

Progranulin is a pleiotropic growth factor with important physiological roles in embryogenesis and maintenance of adult tissue homeostasis. While-progranulin deficiency is associated with a broad range of pathological conditions affecting the brain, such as frontotemporal dementia and neuronal ceroid lipofuscinosis, progranulin upregulation characterizes many tumors, including brain tumors, multiple myeloma, leiomyosarcoma, mesothelioma and epithelial cancers such as ovarian, liver, breast, bladder, adrenal, prostate and kidney carcinomas. The increase of progranulin levels in tumors might have diagnostic and prognostic significance. In cancer, progranulin has a pro-tumorigenic role by promoting cancer cell proliferation, migration, invasiveness, anchorage-independent growth and resistance to chemotherapy. In addition, progranulin regulates the tumor microenvironment, affects the function of cancer-associated fibroblasts, and modulates tumor immune surveillance. However, the molecular mechanisms of progranulin oncogenic function are not fully elucidated. In bladder cancer, progranulin action relies on the activation of its functional signaling receptor EphA2. Notably, more recent data suggest that progranulin can also modulate a functional crosstalk between multiple receptor-tyrosine kinases, demonstrating a more complex and context-dependent role of progranulin in cancer. Here, we will review what is currently known about the function of progranulin in tumors, with a focus on its molecular mechanisms of action and regulation.

Published
2023

24. Prognostic Significance of Organ-Specific Metastases in Patients with Metastatic Upper Tract Urothelial Carcinoma

Author

Tufano, Antonio, primary, Cordua, Nadia, additional, Nardone, Valerio, additional, Ranavolo, Raffaele, additional, Flammia, Rocco Simone, additional, D’Antonio, Federica, additional, Borea, Federica, additional, Anceschi, Umberto, additional, Leonardo, Costantino, additional, Morrione, Andrea, additional, and Giordano, Antonio, additional

Published
2022
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29. Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells

Author

Vella, Veronica, primary, Giuliano, Marika, additional, La Ferlita, Alessandro, additional, Pellegrino, Michele, additional, Gaudenzi, Germano, additional, Alaimo, Salvatore, additional, Massimino, Michele, additional, Pulvirenti, Alfredo, additional, Dicitore, Alessandra, additional, Vigneri, Paolo, additional, Vitale, Giovanni, additional, Malaguarnera, Roberta, additional, Morrione, Andrea, additional, Sims, Andrew H., additional, Ferro, Alfredo, additional, Maggiolini, Marcello, additional, Lappano, Rosamaria, additional, De Francesco, Ernestina Marianna, additional, and Belfiore, Antonino, additional

Published
2021
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34. DDR1 Affects Metabolic Reprogramming in Breast Cancer Cells by Cross-Talking to the Insulin/IGF System

Author

Vella, Veronica, primary, Giuliano, Marika, additional, Nicolosi, Maria Luisa, additional, Majorana, Maria Giovanna, additional, Marć, Małgorzata Anna, additional, Muoio, Maria Grazia, additional, Morrione, Andrea, additional, Maggiolini, Marcello, additional, Lappano, Rosamaria, additional, De Francesco, Ernestina Marianna, additional, and Belfiore, Antonino, additional

Published
2021
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37. Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 Modulates Aggressiveness of Ewing Sarcoma by Regulating the CD164-CXCR4 Axis

Author

Mancarella, Caterina, Caldoni, Giulia, Ribolsi, Irene, Parra, Alessandro, Manara, Maria Cristina, Mercurio, Arthur M, Morrione, Andrea, Scotlandi, Katia, Mancarella, Caterina, Caldoni, Giulia, Ribolsi, Irene, Parra, Alessandro, Manara, Maria Cristina, Mercurio, Arthur M, Morrione, Andrea, and Scotlandi, Katia

Abstract

Ewing sarcoma (EWS) is the second most common bone and soft tissue-associated malignancy in children and young adults. It is driven by the fusion oncogene EWS/FLI1 and characterized by rapid growth and early metastasis. We have previously discovered that the mRNA binding protein IGF2BP3 constitutes an important biomarker for EWS as high expression of IGF2BP3 in primary tumors predicts poor prognosis of EWS patients. We additionally demonstrated that IGF2BP3 enhances anchorage-independent growth and migration of EWS cells suggesting that IGF2BP3 might work as molecular driver and predictor of EWS progression. The aim of this study was to further define the role of IGF2BP3 in EWS progression. We demonstrated that high IGF2BP3 mRNA expression levels correlated with EWS metastasis and disease progression in well-characterized EWS tumor specimens. EWS tumors with high IGF2BP3 levels were characterized by a specific gene signature enriched in chemokine-mediated signaling pathways. We also discovered that IGF2BP3 regulated the expression of CXCR4 through CD164. Significantly, CD164 and CXCR4 colocalized at the plasma membrane of EWS cells upon CXCL12 stimulation. We further demonstrated that IGF2BP3, CD164, and CXCR4 expression levels correlated in clinical samples and the IGF2BP3/CD164/CXCR4 signaling pathway promoted motility of EWS cells in response to CXCL12 and under hypoxia conditions. The data presented identified CD164 and CXCR4 as novel IGF2BP3 downstream functional effectors indicating that the IGF2BP3/CD164/CXCR4 oncogenic axis may work as critical modulator of EWS aggressiveness. In addition, IGF2BP3, CD164, and CXCR4 expression levels may constitute a novel biomarker panel predictive of EWS progression.

Published
2020

47. Proepithelin is an autocrine growth factor for bladder cancer

Author

Lovat, Francesca, Bitto, Alessandro, Xu, Shi-Qiong, Fassan, Matteo, Goldoni, Silvia, Metalli, David, Wubah, Vera, McCue, Peter, Serrero, Ginette, Gomella, Leonard G., Baffa, Raffaele, Iozzo, Renato V., and Morrione, Andrea

Published
2009

50. Insulin-like growth factor II stimulates the cell proliferation through the insulin receptor

Author

Morrione, Andrea, Valentinis, Barbara, Xu, Shi-Qiong, Yumet, Gladys, Louvi, Angeliki, Efstratiadis, Argiris, and Baserga, Renato

Subjects
Insulin-like growth factors -- Physiological aspects, Insulin -- Receptors, Cell proliferation -- Research, Science and technology
Abstract

R- cells are 3T3-like fibroblasts generated from mouse embryos nullizygous for a targeted disruption of the genes encoding the type 1 insulin-like growth factor (IGF) receptor (IGF1R). These cells fail to proliferate in serum-free medium supplemented with purified growth factors, in contrast to their wild-type counterparts. However, when R- cells overexpress the insulin receptor from a stably integrated plasmid, R-/IR cells, they become capable of growing in serum-free medium supplemented solely with insulin or IGF-II, but not with IGF.I. Moreover, the introduction into R-/IR cells of an additional plasmid expressing IGF-II causes these cells to proliferate in serum-free medium without growth factor supplementation. From these results, we conclude that IGF-II can stimulate cell proliferation not only through its cognate IGF1R but also through the insulin receptor.

Published
1997

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