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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