Cancer stem cells: functional study of genes involved in tumorigenesis in the central nervous system

• Grant number: 07/05721-7
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2008
• End date: May 31, 2010
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Oswaldo Keith Okamoto
• Grantee: Oswaldo Keith Okamoto
• Host Institution: Departamento de Neurologia e Neurocirurgia. Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

The primary aim of this study is to better understand the underlying molecular mechanism leading to tumorigenesis and the possible link between cancer and stem cell biology. This type of knowledge is relevant for the development of alternative therapeutic approaches of tumor suppression. One fundamental issue in cancer therapeutics is the elucidation of the molecular and cellular basis of the disease. Recently, tumorigenic stem-like cells, known as cancer stem cells, have been reported in solid tumors. In the central nervous system, such subset of cells displaying stem cell characteristics and tumorigenic capability are characterized by expression of the stem cell marker CD133. Emergent therapeutic strategies in cancer have been focusing on molecular pathways involved in neoplastic transformation. Potentially curative approaches, however, must target pathways altered in cancer stem cells so that any chance of tumor recurrence could be minimized. In a previous study, we performed a whole genome survey to search for genes differentially expressed in CD133+ GBM cells, as compared with their non-tumorigenic CD133- counterparts, in attempt to identify molecular events associated with tumorigenesis. Sixteen genes, many of which not previously associated with astrocytomas, were found aberrantly expressed in CD133+ cells, but not in CD133-, when compared with corresponding non-neoplastic controls. Now, we propose further functional studies for some of these cancer stem cell-associated genes to determine their value as therapeutic targets. Thus, in this project, we propose to evaluate the relevance of E2F2 and HOXC9 genes to the tumorigenic properties of GBM cells. In particular, loss of function studies will be conducted in human GBM cell lines using the iRNA technique. The effects of E2F2 and HOXC9 silencing on cell proliferation, migration, invasion and resistance to apoptosis will be evaluated in vitro. In addition, the effects on tumor development will be analyzed in vivo using murine models of xenotranplant. (AU)