Implication of heat shock protein 90 (HSP90) in tumor angiogenesis: a molecular target for anti-angiogenic therapy?
The inhibition of oncogenic signaling pathways has gained great interest for cancer therapy. In this context, the molecular chaperone heat shock protein 90 (HSP90) has emerged as a promising molecular target, since it is critically involved in maintaining stability, integrity and functions of key oncogenic proteins. A variety of HSP90 inhibitors have been developed in the past decade and have shown convincing anti-neoplastic activity in pre-clinical tumor models. Importantly, HSP90 inhibitors are predominantly being recognized as "tumor cell targeting" agents since cancer cells a) overexpress HSP90 protein, b) highly rely on HSP90 function for maintaining oncogenic signaling, and c) HSP90 inhibitors bind with high affinity to HSP90 in tumor cells. Nevertheless, results from recent studies also suggest that HSP90 inhibitors elicit anti-angiogenic properties by affecting the PI-3K/Akt/eNOS signal transduction pathway in endothelial cells, as well as through down-regulation of VEGFR-2 expression, a crucial component of the angiogenic process. In addition, blocking HSP90 may also diminish the secretion and expression of tumor cell-derived pro-angiogenic growth factors and cytokines, thus leading to "indirect" anti-angiogenic effects. This review article focuses on the role of HSP90 in angiogenesis and on delineating the effects of HSP90 inhibitors on angiogenic signaling pathways involved in tumor vascularization.
Staufer
Katharina
K
Departments of Hepatobiliary and Transplantation Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Stoeltzing
Oliver
O
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy*
D020533:Angiogenesis Inhibitors; D018841:HSP90 Heat-Shock Proteins