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NF-kB regulation in the renal cell carcinoma after endostatin gene therapy


Renal cell carcinomas (RCCs) comprise 2 to 3% of all human cancers and are the most aggressive of all urological cancers. The most common form of RCC is the clear-cell renal cell carcinoma (RCCcc) that is characterized by frequent inactivation of the von Hippel-Lindau (VHL) gene. Loss-of-function mutations in VHL lead to transcriptional up-regulation of multiple angiogenic factors. Nuclear factor kappa B (NF-ºB) is a family of transcription factors that plays a critical role in many biological processes. NF-kB serves as a key responder to changes in the environment. In RCC, the NF-kB activity is correlated with the increase of many pro-angiogenic and apoptotic factors including VEGF, EGF, bcl-2 and p53. It has also been demonstrated that increased NF-ºB activity is associated with the development and progression of RCC. Endostatin (ES) is a fragment of collagen XVIII with antiangiogenic activity. In vitro, ES inhibits the proliferation and migration of endothelial cells and leads to the increase of apoptosis. In vivo, many experimental assays have shown its efficacy in several different kinds of tumors. Gene therapy can be defined as the introduction of a normal, functional gene into cells, with the purpose of correcting a genetic or acquired disorder. Retrovirus vectors constitute one of the promising gene delivery systems that have been used in gene therapy. Previous works of our group have demonstrated the efficacy of ES gene therapy for both primary and metastatic RCC. In both models, ES has caused microenviromental alterations. Besides the reduction of microvessel density, ES gene therapy was able to increase the tumor-infiltrating T lymphocytes and the antitumor cytokines. We believe that ES therapy causes alterations in the tumor and stroma cellular signaling pathway. In this research project, we will evaluate the possible regulation of NF-KB in metastatic tumor cells after ES treatment. We will further search for new information on the cell biology of CCRm and knowledge that might help finding new therapeutic options to be combined with ES therapy. (AU)

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Scientific publications (4)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
BRAGA, MARINA SOUZA; TURACA, THIAGO LAURO; FOGUER, KAREN; BARBOSA CHAVES, KAREN CRISTINA; PESQUERO, JOAO BOSCO; CHAMMAS, ROGER; SCHOR, NESTOR; BELLINI, MARIA HELENA. Vascular endothelial growth factor as a biomarker for endostatin gene therapy. BIOMEDICINE & PHARMACOTHERAPY, v. 67, n. 6, p. 511-515, . (10/18969-0)
BRAGA, MARINA DE SOUZA; DA SILVA PAIVA, KATIUCIA BATISTA; FOGUER, KAREN; BARBOSA CHAVES, KAREN CRISTINA; LIMA, LARISSA DE SA; SCAVONE, CRISTOFORO; BELLINI, MARIA HELENA. Involvement of the NF-kappa B/p50/Bcl-3 complex in response to antiangiogenic therapy in a mouse model of metastatic renal cell carcinoma. BIOMEDICINE & PHARMACOTHERAPY, v. 68, n. 7, p. 873-879, . (10/18969-0)
BRAGA, MARINA DE SOUZA; CHAVES, KAREN BARBOSA; CHAMMAS, ROGER; SCHOR, NESTOR; BELLINI, MARIA HELENA. Endostatin neoadjuvant gene therapy extends survival in an orthotopic metastatic mouse model of renal cell carcinoma. BIOMEDICINE & PHARMACOTHERAPY, v. 66, n. 4, p. 237-241, . (10/18969-0)
BARBOSA CHAVES, KAREN CRISTINA; TURACA, LAURO THIAGO; PESQUERO, JOAO BOSCO; MENNECIER, GREGORY; ZAIDAN DAGLI, MARIA LUCIA; CHAMMAS, ROGER; SCHOR, NESTOR; BELLINI, MARIA HELENA. Fibronectin expression is decreased in metastatic renal cell carcinoma following endostatin gene therapy. BIOMEDICINE & PHARMACOTHERAPY, v. 66, n. 6, p. 464-468, . (09/12518-9, 10/18969-0)

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