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Evaluation of the relation between tumor angiogenesis and lymphangiogenesis in medullary thyroid carcinomas

Grant number: 12/02248-7
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): June 01, 2012
Effective date (End): May 31, 2015
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Janete Maria Cerutti
Grantee:Marta Miyazawa
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil


RET gene is an oncogene located on chromossome 10q11.2 that encodes a tyrosine kinase transmembrane receptor associated to cell growth, migration, and differentiation signaling pathways. Mutations that activates RET in germinative cell lines are associated to the inherited dominant autosomal syndrome called Multiple Endocrine Neoplasia type 2 that presents Medullary Thyroid Carcinoma (MTC) as a main component. MTC metastasizes through blood or lymphatic vessels. These biological phenomena occur by angiogenesis and lymphangiogenesis, respectively. Despite the fact that it is well-known that Vascular Endothelial Growth Factor (VEGF) binds to its receptor VEGFR and initiates endothelial cell proliferation, almost nothing is known about their involvement and mechanisms in the process of MTC metastasis.Interestingly, RET (RET/PTC) gene rearrangement, present in papillary thyroid carciomas, modulates the expression of many genes that could be involved on tumor growth and angiogenesis, such as CXCL12 and CXCR4. It is also known that Tumor-Associated Macrophages (TAM) are attracted by CXCL12 and VEGF, and can promote angiogenesis and tumor metastasis. Therefore, we propose to investigate p.G533C mutation on gene RET associated to inherited MTC genesis modulating different VEGF isoforms, VEGFR, and other mediators involved on the process of angiogenesis and lymphangiogenesis on tumor progression. Besides, we propose to evaluate the role of macrophages associated to MTC in these processes by non-canonical pathways by the development of a coculture model. We do believe that this research project can also identify new genes modulated by these mutations involved on this disease progression, as well as other possible therapeutic targets for the MTC treatment.

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Scientific publications
(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)
ARAUJO, ALINE NEVES; CAMACHO, CLEBER PINTO; MENDES, THAIS BIUDE; LINDSEY, SUSAN CHOW; MORAES, LAIS; MIYAZAWA, MARTA; DELCELO, ROSANA; PELLEGRINO, RENATA; MAZZOTTI, DIEGO ROBLES; MACIEL, RUI MONTEIRO DE BARROS; et al. Comprehensive Assessment of Copy Number Alterations Uncovers Recurrent AIFM3 and DLK1 Copy Gain in Medullary Thyroid Carcinoma. CANCERS, v. 13, n. 2, . (10/13833-2, 14/06570-6, 17/06487-0, 12/02248-7)

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