Src Family Kinases as Regulators of Angiogenesis: Therapeutic Implications

Donald   P.   Lesslie III; Gary   E.   Gallick

Abstract

Despite its discovery nearly a century ago, the functions of the Src family of protein tyrosine kinases (SFKs) remain incompletely understood. While much has been learned regarding the functions of Src family kinases in the last few years, new roles for Src, particularly in promoting the progression of cancer towards the metastatic phenotype, continue to emerge. SFKs, through their functions as kinases and adapter proteins in signaling complexes, regulate such diverse cellular events as proliferation, migration, cell cycle control, and apoptosis. In tumor cells, the kinase activity of Src is frequently activated, with greater increases during progressive stages. Likewise, resistance to chemotherapy also corresponds with Src kinase activity. Thus, Src activation is predictive of poor prognosis in several tumors. Recently, selective SFK inhibitors are showing promise in clinical trials in imatinib mesylate (Gleevec, Novartis) resistant chronic myelogenous leukemia. However, in vitro studies have suggested that Src inhibitors may hold promise in the treatment of solid tumors such as colon and pancreatic cancer in which new therapeutic inhibitors are desperately needed. This review will summarize briefly the structure and function of Src and the evidence for Src in promoting tumor progression and metastasis. As recent work in this laboratory and others has demonstrated that Src is a regulator of expression of diverse pro-angiogenic factors produced by tumor cells, and a regulator of the endothelial cells that respond to these factors, this review will focus on the role of Src in angiogenesis and potential roles of Src inhibitors as antiangiogenic agents.

Keywords: src kinases, angiogenesis, targeted therapy, chemotherapy, metastasis

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