An immunohistochemical study of MERTK, Axl and TYRO3 proteins in head and neck primary mucosal melanomas

• Grant number: 14/17189-1
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: January 05, 2015
• End date: April 29, 2015
• Field of knowledge: Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
• Principal Investigator: Silvia Vanessa Lourenço
• Grantee: Ricardo Hsieh
• Supervisor: Manju L. Prasad
• Host Institution: Faculdade de Odontologia (FO). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Yale University, United States
• Associated to the scholarship: 12/25431-1 - MELANOMAS OF SUN PROTECTED SITES: IMMUNOHISTOCHEMICAL AND PIROSEQUENCING STUDY OF MITF AND C-KIT CASCADES, BP.PD

Abstract

Primary melanomas of the head and neck account for 0.7%-3.8% of all melanomas and involve the sinonasal cavity, oral cavity, pharynx, larynx, and upper esophagus. Head and neck Primary Mucosal Melanomas are usually associated with poor clinical outcomes, with 5-year disease-free survival rates ranging from 0% to 20% and poor local and distant control. Melanocytes migrate to endodermally derived and, less frequently, ectodermally derived mucosa. The function of such melanocytes is unknown, but there is evidence of their antimicrobial and immunological function, such as antigen presentation and cytokine production. The ethiopathogenesis of mucosal melanomas is unknown, but they are believed to develop more often in areas with preexisting melanosis. A recent consensus claims that genetic alterations in intracellular signaling cascades constitute the pathogenetic mechanism of melanoma.The malignant transformation of melanocytes occurs through sequential accumulation of genetic and molecular alterations. Although the pathogenetic mechanisms of the development of melanoma remain obscure, certain genes and metabolic pathways undergo changes. Several pathways are involved in primary clonal alteration, including the induction of cell proliferation (proliferative pathway), circumvention of cell senescence (senescence pathway), and reduction of apoptosis (apoptotic pathway). The progressive understanding of these general, basic molecular mechanisms may lead to a future of more specific and successful therapies to MMs. However, identification of the ideal pathway member of therapeutic target for maximal benefits remains a challenge.There is substantial evidence that hyperactive receptor tyrosine kinase (RTK) signaling mediates the development and progression of melanoma, based on the prominent function of RTKs in transmitting extracellular signals to intracellular effectors and the significance of homotypic and heterotypic cell-cell interactions in cancers. In 2011, a study showed that RTKs including MET, RON, HER3, AXL and IGF1R are active in melanoma, but few RTKs have been studied and associated to the melanoma biology.The TAM family of RTKs (including MERTK, AXL and TYRO3) functionally engage in cooperative or distinct signaling, depending on the model system; there is evidence that TAMs play a key role in cancer pathogenesis.Mucosal Melanoma heterogeneity can result from differential expression of molecules such as RTKs, because they are frequently ectopically expressed, overexpressed or hyperactivated in tumor cells and they are very attractive targets for cancer therapy. So we propose an International Cooperative Study between the Yale University and the University of São Paulo to investigate the expression of TAM family of receptor tyrosine kinase proteins, including MERTK, AXL and TYRO3 in 53 cases of primary mucosal melanomas of the head and neck by immunohistochemistry. (AU)