Growth Factors and Ras Signal Transduction Pathway

Besides loss of tumor suppressor functions, an enhanced signal transduction through the polypeptide growth factors and protein tyrosine kinase (PTK) receptors is the best-characterized group of molecular alterations that are associated with meningioma tumorigenesis. Growth factors and their receptors, which transduce their signals through Ras GTPase proteins, are overexpressed on the same population of tumor cells compared with normal, precursor lep-tomeningeal cells. The Ras proto-oncogene family encodes four closely related plasma membrane proteins of 21 kDa that are essential for entry into the mitotic cell cycle, for maintenance of proliferation, and for regulation of differentiation, adhesion molecule expression and cytoskeletal actin organization. Therefore, overexpression of growth factors and their receptors enhances signal transduction through the Ras pathway with a consequent aberration of cellular functions that are considered critically important in meningioma tumorigenesis.

The list of aberrantly overexpressed molecules is long and includes epidermal, platelet-derived, fibroblastic, insulin-like and vascular endothelial growth factors (EGF, PDGF, FGF, IGF, VEGF, respectively) and their PTK receptors. At present, it is not known which growth factors and/or receptors are the most critical in meningioma tumorigenesis. Nevertheless, the expression of VEGF by tumor cells appears to be prognostically relevant. Elevated expression of VEGF is found in most meningiomas, and it correlates with the development of menin-gioma blood supply from cerebral arteries and emergence of peritumoral brain edema. Further-more, high levels of VEGF expression were recently identified as the most powerful predictor of meningioma recurrence.

The clinical importance of frequent expression of the hepatocyte growth factor (HGF) and c-met, a proto-oncogene that encodes receptor for HGF by meningioma cells, is not known, but HGF and c-met may represent an important link with the NF-2 tumor suppressor pathway. It was recently shown that the HGF-regulated tyrosine kinase substrate physically interacts in vivo and in vitro with NF-2 tumor suppressor protein [45]. At present, it is not clear exactly how the HGF and NF-2 molecular pathways cross-talk. Another line of evidence suggests that the NF-2 protein antiproliferative action may occur downstream of Ras proteins. Overexpression of the NF-2 protein is able to reverse some aspects of the Ras-protein-induced malignant pheno-type, such as anchorage-independent growth in a soft agar, and to restore contact inhibition of cell growth.

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