19 results on '"Isabela W Cunha"'
Search Results
2. Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy
- Author
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Simeon U Springer, Chung-Hsin Chen, Maria Del Carmen Rodriguez Pena, Lu Li, Christopher Douville, Yuxuan Wang, Joshua David Cohen, Diana Taheri, Natalie Silliman, Joy Schaefer, Janine Ptak, Lisa Dobbyn, Maria Papoli, Isaac Kinde, Bahman Afsari, Aline C Tregnago, Stephania M Bezerra, Christopher VandenBussche, Kazutoshi Fujita, Dilek Ertoy, Isabela W Cunha, Lijia Yu, Trinity J Bivalacqua, Arthur P Grollman, Luis A Diaz, Rachel Karchin, Ludmila Danilova, Chao-Yuan Huang, Chia-Tung Shun, Robert J Turesky, Byeong Hwa Yun, Thomas A Rosenquist, Yeong-Shiau Pu, Ralph H Hruban, Cristian Tomasetti, Nickolas Papadopoulos, Ken W Kinzler, Bert Vogelstein, Kathleen G Dickman, and George J Netto
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liquid biopsy ,cancer ,urine ,bladder ,renal pelvis ,ureter ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Current non-invasive approaches for detection of urothelial cancers are suboptimal. We developed a test to detect urothelial neoplasms using DNA recovered from cells shed into urine. UroSEEK incorporates massive parallel sequencing assays for mutations in 11 genes and copy number changes on 39 chromosome arms. In 570 patients at risk for bladder cancer (BC), UroSEEK was positive in 83% of those who developed BC. Combined with cytology, UroSEEK detected 95% of patients who developed BC. Of 56 patients with upper tract urothelial cancer, 75% tested positive by UroSEEK, including 79% of those with non-invasive tumors. UroSEEK detected genetic abnormalities in 68% of urines obtained from BC patients under surveillance who demonstrated clinical evidence of recurrence. The advantages of UroSEEK over cytology were evident in low-grade BCs; UroSEEK detected 67% of cases whereas cytology detected none. These results establish the foundation for a new non-invasive approach for detection of urothelial cancer.
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- 2018
- Full Text
- View/download PDF
3. Gene expression profiling in leiomyosarcomas and undifferentiated pleomorphic sarcomas: SRC as a new diagnostic marker.
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Rolando A R Villacis, Sara M Silveira, Mateus C Barros-Filho, Fabio A Marchi, Maria A C Domingues, Cristovam Scapulatempo-Neto, Samuel Aguiar, Ademar Lopes, Isabela W Cunha, and Silvia R Rogatto
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Medicine ,Science - Abstract
BackgroundUndifferentiated Pleomorphic Sarcoma (UPS) and high-grade Leiomyosarcoma (LMS) are soft tissue tumors with an aggressive clinical behavior, frequently developing local recurrence and distant metastases. Despite several gene expression studies involving soft tissue sarcomas, the potential to identify molecular markers has been limited, mostly due to small sample size, in-group heterogeneity and absence of detailed clinical data.Materials and methodsGene expression profiling was performed for 22 LMS and 22 UPS obtained from untreated patients. To assess the relevance of the gene signature, a meta-analysis was performed using five published studies. Four genes (BAD, MYOCD, SRF and SRC) selected from the gene signature, meta-analysis and functional in silico analysis were further validated by quantitative PCR. In addition, protein-protein interaction analysis was applied to validate the data. SRC protein immunolabeling was assessed in 38 UPS and 52 LMS.ResultsWe identified 587 differentially expressed genes between LMS and UPS, of which 193 corroborated with other studies. Cluster analysis of the data failed to discriminate LMS from UPS, although it did reveal a distinct molecular profile for retroperitoneal LMS, which was characterized by the over-expression of smooth muscle-specific genes. Significantly higher levels of expression for BAD, SRC, SRF, and MYOCD were confirmed in LMS when compared with UPS. SRC was the most value discriminator to distinguish both sarcomas and presented the highest number of interaction in the in silico protein-protein analysis. SRC protein labeling showed high specificity and a positive predictive value therefore making it a candidate for use as a diagnostic marker in LMS.ConclusionsRetroperitoneal LMS presented a unique gene signature. SRC is a putative diagnostic marker to differentiate LMS from UPS.
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- 2014
- Full Text
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4. Does the Addition of Mutations of CTNNB1 S45F to Clinical Factors Allow Prediction of Local Recurrence in Patients With a Desmoid Tumor? A Local Recurrence Risk Model
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Fabio F. E. Pinto, Celso A. L. Mello, Suely A. Nakagawa, Wu Tu Chung, Giovana T. Torrezan, Bruna D. F. Barros, Isabela W. Cunha, Vinícius F. Calsavara, Dirce M. Carraro, and Ademar Lopes
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Orthopedics and Sports Medicine ,Surgery ,General Medicine - Published
- 2023
5. Supplementary Figure 2 from ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis
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Anamaria A. Camargo, Roger Chammas, Mari C. Sogayar, Silvio Zanata, Fernando F. Soares, André L. Carvalho, Maria do Socorro Maciel, Vladmir C.C. Lima, Isabela W. Cunha, Karina B. Ribeiro, Fabiana Melo, Tamara Machado, Daniela F Ierardi, Mariana F. Granato, Ricardo Moura, Valéria A. Paixão, Angelita Muras, Michele D.M. Costa, Felícia P. Cavalher, Fabrício F. Costa, Érico T. Costa, and Newton V. Verbisck
- Abstract
Supplementary Figure 2 from ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis
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- 2023
6. Supplementary Table 1 from ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis
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Anamaria A. Camargo, Roger Chammas, Mari C. Sogayar, Silvio Zanata, Fernando F. Soares, André L. Carvalho, Maria do Socorro Maciel, Vladmir C.C. Lima, Isabela W. Cunha, Karina B. Ribeiro, Fabiana Melo, Tamara Machado, Daniela F Ierardi, Mariana F. Granato, Ricardo Moura, Valéria A. Paixão, Angelita Muras, Michele D.M. Costa, Felícia P. Cavalher, Fabrício F. Costa, Érico T. Costa, and Newton V. Verbisck
- Abstract
Supplementary Table 1 from ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis
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- 2023
7. Supplementary Figure 1 from ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis
- Author
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Anamaria A. Camargo, Roger Chammas, Mari C. Sogayar, Silvio Zanata, Fernando F. Soares, André L. Carvalho, Maria do Socorro Maciel, Vladmir C.C. Lima, Isabela W. Cunha, Karina B. Ribeiro, Fabiana Melo, Tamara Machado, Daniela F Ierardi, Mariana F. Granato, Ricardo Moura, Valéria A. Paixão, Angelita Muras, Michele D.M. Costa, Felícia P. Cavalher, Fabrício F. Costa, Érico T. Costa, and Newton V. Verbisck
- Abstract
Supplementary Figure 1 from ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis
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- 2023
8. Data from ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis
- Author
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Anamaria A. Camargo, Roger Chammas, Mari C. Sogayar, Silvio Zanata, Fernando F. Soares, André L. Carvalho, Maria do Socorro Maciel, Vladmir C.C. Lima, Isabela W. Cunha, Karina B. Ribeiro, Fabiana Melo, Tamara Machado, Daniela F Ierardi, Mariana F. Granato, Ricardo Moura, Valéria A. Paixão, Angelita Muras, Michele D.M. Costa, Felícia P. Cavalher, Fabrício F. Costa, Érico T. Costa, and Newton V. Verbisck
- Abstract
The ADAM23 gene is frequently silenced in different types of tumors, and, in breast tumors, silencing is correlated with tumor progression, suggesting that it might be associated with the acquisition of a metastatic phenotype. ADAM23 exerts its function mainly through the disintegrin domain, because its metalloprotease domain is inactive. Analysis of ADAM23 binding to integrins has revealed a specific interaction with αvβ3 integrin mediated by the disintegrin domain. Altered expression of αvβ3 integrin has been observed in different types of tumors, and expression of this integrin in the activated form has been shown to promote metastasis formation. Here, we investigated the possibility that interaction between ADAM23 and αvβ3 integrin might negatively modulate αvβ3 activation during metastatic progression. ADAM23 expression was knocked down using short hairpin RNA in the MDA-MB-435 cell line, which has been extensively used as a model for αvβ3 integrin activation. Ablation of ADAM23 enhanced αvβ3 integrin activation by at least 2- to 4-fold and ADAM23 knockdown cells showed enhanced migration and adhesion to classic αvβ3 integrin ligands. Ablation of ADAM23 expression also enhanced pulmonary tumor cell arrest in immunodeficient mice. To complement our findings with clinical evidence, we showed that silencing of ADAM23 gene by DNA promoter hypermethylation in a collection of 94 primary breast tumors was significantly associated with lower distant metastases–free and disease-specific survivals and was an independent prognostic factor for poor disease outcome. Our results strongly support a functional role of ADAM23 during metastatic progression by negatively modulating αvβ3 integrin activation. [Cancer Res 2009;69(13):5546–52]
- Published
- 2023
9. Supplementary Figure 3 from ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis
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Anamaria A. Camargo, Roger Chammas, Mari C. Sogayar, Silvio Zanata, Fernando F. Soares, André L. Carvalho, Maria do Socorro Maciel, Vladmir C.C. Lima, Isabela W. Cunha, Karina B. Ribeiro, Fabiana Melo, Tamara Machado, Daniela F Ierardi, Mariana F. Granato, Ricardo Moura, Valéria A. Paixão, Angelita Muras, Michele D.M. Costa, Felícia P. Cavalher, Fabrício F. Costa, Érico T. Costa, and Newton V. Verbisck
- Abstract
Supplementary Figure 3 from ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis
- Published
- 2023
10. Supplementary Table 2 from ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis
- Author
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Anamaria A. Camargo, Roger Chammas, Mari C. Sogayar, Silvio Zanata, Fernando F. Soares, André L. Carvalho, Maria do Socorro Maciel, Vladmir C.C. Lima, Isabela W. Cunha, Karina B. Ribeiro, Fabiana Melo, Tamara Machado, Daniela F Ierardi, Mariana F. Granato, Ricardo Moura, Valéria A. Paixão, Angelita Muras, Michele D.M. Costa, Felícia P. Cavalher, Fabrício F. Costa, Érico T. Costa, and Newton V. Verbisck
- Abstract
Supplementary Table 2 from ADAM23 Negatively Modulates αvβ3 Integrin Activation during Metastasis
- Published
- 2023
11. Patient-Derived Renal Cell Carcinoma Xenografts Capture Tumor Genetic Profiles and Aggressive Behaviors
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Adriano O. Beserra, Ethiene C. Estevan, Stephania M. Bezerra, Giovana T. Torrezan, Amanda Ikegami, Humberto Dellê, Isabela W. Cunha, Isabella T. Meira, Dirce M. Carraro, Primo N. Lara, Stenio C. Zequi, Vilma R. Martins, and Tiago G. Santos
- Subjects
Oncology ,Nephrology ,urologic and male genital diseases ,female genital diseases and pregnancy complications - Abstract
BACKGROUND: Patient-derived xenografts (PDX) have emerged as one of the most promising model systems to study cancer biology and to develop new antineoplastic drugs. Renal cell carcinoma (RCC) represents up to 90% of all kidney tumors, exhibits aggressive behavior, and has a propensity for metastasis. At diagnosis, 30% of patients with RCC have metastases, while up to 50% of those with localized disease treated with curative protocols experience recurrence. OBJECTIVE: This study aimed to establish an RCC PDX platform to identify novel clinical and molecular biomarkers of recurrence risk in order to facilitate precision medicine. METHODS: Tumor samples were obtained from surgical specimens of 87 RCC patients; fragments were implanted in immunodeficient NOD/SCID/gamma (NSG) mice. 17 Fragments were implanted subcutaneously in an initial group while a second group of 70 samples were implanted orthotopically in the subcapsular space. RESULTS: A total of 19 PDX developed only after orthotopic implantation, and included 15 cases of clear cell RCC subtype, 3 cases of papillary subtype, and 1 unclassifiable tumor. 1 PDX of clear cell RCC recapitulated the phenotype of vena caval tumor thrombus extension that had been diagnosed in the source patient. PDX characterization by immunohistochemistry and targeted sequencing indicated that all PDXs preserved RCC identity and major molecular alterations. Moreover, the capacity of tumor engraftment was a strong prognostic indicator for patients with locally advanced disease. CONCLUSION: Taken together, these results suggest that the orthotopic xenograft model of RCC represents a suitable tool to study RCC biology, identify biomarkers, and to test therapeutic candidates.
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- 2022
12. How current assay approval policies are leading to unintended imprecision medicine
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Torsten O. Nielsen, David L. Rimm, John M. S. Bartlett, Cecily Quinn, Roberto Salgado, Ian A. Cree, Anne Vibeke Lænkholm, Andrew M. Bellizzi, Isabela W Cunha, Isabel Alvarado-Cabrero, Gábor Cserni, and Moch Holger
- Subjects
Clinical Trials as Topic ,medicine.medical_specialty ,Insurance, Health ,business.industry ,MEDLINE ,Precision medicine ,Biomarkers, Pharmacological ,Oncology ,Risk Factors ,Neoplasms ,Drug approval ,Humans ,Medicine ,Immunotherapy ,Precision Medicine ,business ,Intensive care medicine ,Drug Approval - Published
- 2020
13. Insights Into the Somatic Mutation Burden of Hepatoblastomas From Brazilian Patients
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Talita Ferreira Marques Aguiar, Maria Prates Rivas, Silvia Costa, Mariana Maschietto, Tatiane Rodrigues, Juliana Sobral de Barros, Anne Caroline Barbosa, Renan Valieris, Gustavo R. Fernandes, Debora R. Bertola, Monica Cypriano, Silvia Regina Caminada de Toledo, Angela Major, Israel Tojal, Maria Lúcia de Pinho Apezzato, Dirce Maria Carraro, Carla Rosenberg, Cecilia Maria Lima da Costa, Isabela W. Cunha, Stephen Frederick Sarabia, Dolores-López Terrada, and Ana Cristina Victorino Krepischi
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0301 basic medicine ,Cancer Research ,Hepatoblastoma ,Candidate gene ,Somatic cell ,Biology ,lcsh:RC254-282 ,CX3CL1 ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,medicine ,CEP164 ,CTNNB1 ,Gene ,Exome sequencing ,Original Research ,Hepatocyte differentiation ,Cancer ,mutational signature ,hepatoblastoma ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,digestive system diseases ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,cytokine receptor interaction ,Cancer research ,chemokine signaling - Abstract
Hepatoblastoma is a very rare embryonal liver cancer supposed to arise from the impairment of hepatocyte differentiation during embryogenesis. In this study, we investigated by exome sequencing the burden of somatic mutations in a cohort of 10 hepatoblastomas, including a congenital case. Our data disclosed a low mutational background and pointed out to a novel set of candidate genes for hepatoblastoma biology, which were shown to impact gene expression levels. Only three recurrently mutated genes were detected: CTNNB1 and two novel candidates, CX3CL1 and CEP164. A relevant finding was the identification of a recurrent mutation (A235G) in two hepatoblastomas at the CX3CL1 gene; evaluation of RNA and protein expression revealed upregulation of CX3CL1 in tumors. The analysis was replicated in two independents cohorts, substantiating that an activation of the CX3CL1/CX3CR1 pathway occurs in hepatoblastomas. In inflammatory regions of hepatoblastomas, CX3CL1/CX3CR1 were not detected in the infiltrated lymphocytes, in which they should be expressed in normal conditions, whereas necrotic regions exhibited negative labeling in tumor cells, but strongly positive infiltrated lymphocytes. Altogether, these data suggested that CX3CL1/CX3CR1 upregulation may be a common feature of hepatoblastomas, potentially related to chemotherapy response and progression. In addition, three mutational signatures were identified in hepatoblastomas, two of them with predominance of either the COSMIC signatures 1 and 6, found in all cancer types, or the COSMIC signature 29, mostly related to tobacco chewing habit; a third novel mutational signature presented an unspecific pattern with an increase of C>A mutations. Overall, we present here novel candidate genes for hepatoblastoma, with evidence that CX3CL1/CX3CR1 chemokine signaling pathway is likely involved with progression, besides reporting specific mutational signatures.
- Published
- 2020
14. Non-invasive detection of bladder cancer through the analysis of driver gene mutations and aneuploidy
- Author
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Simeon Springer, Maria Del Carmen Rodriguez Pena, Lu Li, Christopher Douville, Yuxuan Wang, Josh Cohen, Diana Taheri, Bahman Afsari, Natalie Silliman, Joy Schaeffer, Janine Ptak, Lisa Dobbyn, Maria Papoli, Isaac Kinde, Aline C. Tregnago, Stephania M. Bezerra, Christopher VandenBussche, Kazutoshi Fujita, Dilek Ertoy, Isabela W. Cunha, Lijia Yu, Mark Schoenberg, Trinity J. Bivalacqua, Kathleen G. Dickman, Arthur P. Grollman, Luis A. Diaz, Rachel Karchin, Ralph Hruban, Cristian Tomasetti, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, and George J. Netto
- Subjects
0303 health sciences ,medicine.medical_specialty ,Bladder cancer ,business.industry ,Aneuploidy ,Chromosome ,Urine ,Gene mutation ,medicine.disease ,Gastroenterology ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Cytology ,medicine ,Dysuria ,Microscopic hematuria ,medicine.symptom ,business ,030304 developmental biology - Abstract
Current non-invasive approaches for bladder cancer (BC) detection are suboptimal. We report the development of non-invasive molecular test for BC using DNA recovered from cells shed into urine. This “UroSEEK” test incorporates assays for mutations in 11 genes and copy number changes on 39 chromosome arms. We first evaluated 570 urine samples from patients at risk for BC (microscopic hematuria or dysuria). UroSEEK was positive in 83% of patients that developed BC, but in only 7% of patients who did not develop BC. Combined with cytology, 95% of patients that developed BC were positive. We then evaluated 322 urine samples from patients soon after their BCs had been surgically resected. UroSEEK detected abnormalities in 66% of the urine samples from these patients, sometimes up to 4 years prior to clinical evidence of residual neoplasia, while cytology was positive in only 25% of such urine samples. The advantages of UroSEEK over cytology were particularly evident in low-grade tumors, wherein cytology detected none while UroSEEK detected 67% of 49 cases. These results establish the foundation for a new, non-invasive approach to the detection of BC in patients at risk for initial or recurrent disease.
- Published
- 2017
15. Evaluation of estrogen receptor alpha, estrogen receptor beta, progesterone receptor, and cKIT expression in desmoids tumors and their role in determining treatment options
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Gabriel A C, Santos, Isabela W, Cunha, Rafael M, Rocha, Celso A L, Mello, Gustavo C, Guimarães, José H, Fregnani, and Ademar, Lopes
- Subjects
Adult ,Male ,Estrogen Receptor alpha ,Middle Aged ,Microarray Analysis ,Survival Rate ,Fibromatosis, Aggressive ,Proto-Oncogene Proteins c-kit ,Recurrence ,Risk Factors ,Estrogen Receptor beta ,Humans ,Female ,Receptors, Progesterone - Abstract
The present study evaluates the protein expression of estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), progesterone receptor (PR) and cKIT in a wide number of desmoids tumors and their role in determining treatment options. Fifty-nine cases classified as muscle aponeurotic fibromatosis were selected. Samples were grouped by tumor location in: head and neck, extremity and abdominal/trunk; type of resection of the primary tumor (complete resection with adequate margins, marginal resection and resection with inadequate margins); type of treatment (exclusive surgery, surgery followed by radiation therapy and surgery followed by tamoxifen or cyclooxygenase inhibitor). A tissue microarray (TMA) was built and the immunohistochemical reactions were performed against ERalpha, ERbeta, PR, and c-kit. All cases were negative for ERalpha, PR and c-KIT. 53/59 cases were positive for ERbeta. No significant difference was observed among clinical variables and the ERbeta status. The estimated 5 and 10 year local recurrence free survival (LRFS) for the patients with complete or marginal resection was 75% and 75%, respectively. Tumor location (p = 0.006) and type of resection (p = 0.001) were predictive of local relapse in the univariate analysis. All patients treated with post-operative tamoxifen were LRFS (p = 0.035). Head and neck and extremities lesions showed higher recurrence rates compared to abdominal/trunk lesions. Marginal resection was associated with local recurrence. In conclusion, although this is a retrospective study, the results presented can contribute to better understanding of the mechanisms under desmoid tumor development and can propose tamoxifen as a therapeutic option to be tested in prospective trials.
- Published
- 2010
16. ADAM23 negatively modulates alpha(v)beta(3) integrin activation during metastasis
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Newton V, Verbisck, Erico T, Costa, Fabrício F, Costa, Felícia P, Cavalher, Michele D M, Costa, Angelita, Muras, Valéria A, Paixão, Ricardo, Moura, Mariana F, Granato, Daniela F, Ierardi, Tamara, Machado, Fabiana, Melo, Karina B, Ribeiro, Isabela W, Cunha, Vladmir C C, Lima, Maria do Socorro, Maciel, André L, Carvalho, Fernando F, Soares, Silvio, Zanata, Mari C, Sogayar, Roger, Chammas, and Anamaria A, Camargo
- Subjects
Lung Neoplasms ,DNA, Neoplasm ,Mice, SCID ,DNA Methylation ,Integrin alphaVbeta3 ,Polymerase Chain Reaction ,ADAM Proteins ,Mice ,Cell Movement ,Cell Line, Tumor ,Cell Adhesion ,Animals ,Humans ,Female ,RNA, Catalytic ,Neoplasm Metastasis - Abstract
The ADAM23 gene is frequently silenced in different types of tumors, and, in breast tumors, silencing is correlated with tumor progression, suggesting that it might be associated with the acquisition of a metastatic phenotype. ADAM23 exerts its function mainly through the disintegrin domain, because its metalloprotease domain is inactive. Analysis of ADAM23 binding to integrins has revealed a specific interaction with alpha(v)beta(3) integrin mediated by the disintegrin domain. Altered expression of alpha(v)beta(3) integrin has been observed in different types of tumors, and expression of this integrin in the activated form has been shown to promote metastasis formation. Here, we investigated the possibility that interaction between ADAM23 and alpha(v)beta(3) integrin might negatively modulate alpha(v)beta(3) activation during metastatic progression. ADAM23 expression was knocked down using short hairpin RNA in the MDA-MB-435 cell line, which has been extensively used as a model for alpha(v)beta(3) integrin activation. Ablation of ADAM23 enhanced alpha(v)beta(3) integrin activation by at least 2- to 4-fold and ADAM23 knockdown cells showed enhanced migration and adhesion to classic alpha(v)beta(3) integrin ligands. Ablation of ADAM23 expression also enhanced pulmonary tumor cell arrest in immunodeficient mice. To complement our findings with clinical evidence, we showed that silencing of ADAM23 gene by DNA promoter hypermethylation in a collection of 94 primary breast tumors was significantly associated with lower distant metastases-free and disease-specific survivals and was an independent prognostic factor for poor disease outcome. Our results strongly support a functional role of ADAM23 during metastatic progression by negatively modulating alpha(v)beta(3) integrin activation.
- Published
- 2009
17. Abstract C25: The 16p13.3 genomic gain in prostate cancer: A role for PDK1 in disease progression
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M. Gleave, Khalil Choucair, Eleonora Scarlata, Maisa Yoshimoto, Simone Chevalier, Fadi Brimo, Isabela W Cunha, Ladan Fazli, Karl-Philippe Guérard, Joshua Ejdelman, Kanishka Sircar, Armen Aprikian, Jacques Lapointe, and Jeremy A. Squire
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,medicine.diagnostic_test ,business.industry ,Cancer ,Chromosome ,medicine.disease ,Metastasis ,Prostate-specific antigen ,Prostate cancer ,medicine.anatomical_structure ,Prostate ,Internal medicine ,medicine ,business ,Lymph node ,Fluorescence in situ hybridization - Abstract
Prostate cancer (PCa) is a leading cause of cancer death and distinguishing life threatening tumors from indolent ones is a major challenge. The identification and characterization of genomic alterations associated with advanced disease may lead to the development of new markers of progression and more efficient therapeutic approaches. Array-CGH data have shown that gain of chromosome 16p13.3 to be associated with lymph node (LN) metastases of PCa, but this region remained uncharacterized. Our goal was to establish the prognostic value of 16p13.3 gain, and identify the cancer relevant genes residing within this region. In this study, we performed Fluorescence In Situ Hybridization (FISH) to detect the copy number gain of chromosome 16p13.3 in 75 PCa samples including 10 lymph node (LN) metastases and their matched primary tumors, 9 transurethral resections of prostate (TURP) tissue samples of castration-resistant prostate cancer (CRPC), and 46 additional primary PCa specimens with clinicopathological parameters. We detected the gain in 5/10 LN metastases and 3/5 matched primary tumors, 3/9 CRPC samples, and 9/46 (20 %) primary tumors. In the latter set of samples, the 16p13.3 alteration was associated with high Gleason score (P=0.002) and elevated pre operative prostate specific antigen (PSA) levels (P=0.047). The levels of 16p13.3 gain were higher in LN metastasis and CRPC specimens compared to primary PCa (P>0.05). Chromosome mapping revealed a focal gain that spans PDPK1 encoding the 3-Phosphoinositide-dependent protein kinase-1 (PDK1). RNA interference-mediated knock down of PDK1 in three different PCa cell lines reduced cell motility without affecting growth and re-expressing PDK1 rescued motility (P>0.05). Our results support that the 16p13.3 gain is relevant to PCa progression and may represent an early marker of metastasis, since retrieved in primary PCa which is sampled by biopsies at time of diagnosis. PDK1 is implicated in PCa cell motility, a critical step for progression to metastasis. These findings provide further rationale for considering PDK1 as a target for cancer therapies and the development of new specific inhibitors of PDK1. Citation Format: Khalil Choucair, Fadi Brimo, Isabela W Cunha, Armen Aprikian, Martin Gleave, Jacques Lapointe, Karl-Philippe Guérard, Joshua Ejdelman, Simone Chevalier, Maisa Yoshimoto, Eleonora Scarlata, Ladan Fazli, Kanishka Sircar, Jeremy A. Squire. The 16p13.3 genomic gain in prostate cancer: A role for PDK1 in disease progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C25.
- Published
- 2012
18. GLUT1 expression in malignant tumors and its use as an immunodiagnostic marker
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Kátia C. Carvalho, Isabela W. Cunha, Rafael M. Rocha, Fernanda R. Ayala, Mariana M. Cajaíba, Maria D. Begnami, Rafael S. Vilela, Geise R. Paiva, Rodrigo G. Andrade, and Fernando A. Soares
- Subjects
Glucose transporter 1 ,Immunohistochemistry ,Protein expression ,PET-scan ,Malignant tumors ,Medicine (General) ,R5-920 - Abstract
OBJECTIVE: To analyze glucose transporter 1 expression patterns in malignant tumors of various cell types and evaluate their diagnostic value by immunohistochemistry. INTRODUCTION: Glucose is the major source of energy for cells, and glucose transporter 1 is the most common glucose transporter in humans. Glucose transporter 1 is aberrantly expressed in several tumor types. Studies have implicated glucose transporter 1 expression as a prognostic and diagnostic marker in tumors, primarily in conjunction with positron emission tomography scan data. METHODS: Immunohistochemistry for glucose transporter 1 was performed in tissue microarray slides, comprising 1955 samples of malignant neoplasm from different cell types. RESULTS: Sarcomas, lymphomas, melanomas and hepatoblastomas did not express glucose transporter 1. Fortyseven per cent of prostate adenocarcinomas were positive, as were 29% of thyroid, 10% of gastric and 5% of breast adenocarcinomas. Thirty-six per cent of squamous cell carcinomas of the head and neck were positive, as were 42% of uterine cervix squamous cell carcinomas. Glioblastomas and retinoblastomas showed membranous glucose transporter 1 staining in 18.6% and 9.4% of all cases, respectively. Squamous cell carcinomas displayed membranous expression, whereas adenocarcinomas showed cytoplasmic glucose transporter 1 expression. CONCLUSION: Glucose transporter 1 showed variable expression in various tumor types. Its absence in sarcomas, melanomas, hepatoblastomas and lymphomas suggests that other glucose transporters mediate the glycolytic pathway in these tumors. The data suggest that glucose transporter 1 is a valuable immunohistochemical marker that can be used to identify patients for evaluation by positron emission tomography scan. The function of cytoplasmic glucose transporter 1 in adenocarcinomas must be further examined.
- Published
- 2011
- Full Text
- View/download PDF
19. Tissue-based molecular markers in upper tract urothelial carcinoma and their prognostic implications
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Ricardo L. Favaretto, Stênio C. Zequi, Renato A. R. Oliveira, Thiago Santana, Walter H. Costa, Isabela W. Cunha, and Gustavo C. Guimarães
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Carcinoma ,Biomarkers ,Prognosis ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
ABSTRACT Upper tract urothelial carcinoma (UTUC) is a rare and aggressive disease that is associated with high rates of recurrence and death. Radical nephroureterectomy (RNU) with excision of the bladder cuff is considered the standard of care for high-risk UTUC, whereas kidney-sparing techniques can be indicated for select patients with low-risk disease. There is a significant lack of clinical and pathological prognostic factors for stratifying patients with regard to making treatment decisions. Incorporation of tissue-based molecular markers into prognostic tools could help accurately stratify patients for clinical decision-making in this heterogeneous disease. Although the number of studies on tissue-based markers in UTUC has risen dramatically in the past several years—many of which are based on single centers and small cohorts, with a low level of evidence—many discrepancies remain between their results. Nevertheless, certain biomarkers are promising tools, necessitating prospective multi-institution studies to validate their function.
- Full Text
- View/download PDF
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