Anti-tumoral Properties of Endogenous Angiogenesis Inhibitors: A Case for Continued TIMP-2 Preclinical Development

Dr. Judah Folkman first introduced the concept of anti-angiogenic therapy almost four decades ago. This novel idea has subsequently been supported by extensive research in the multistep process of tumor-associated angiogenesis. As new blood vessels are formed, angiogenesis is switched on within the tumor microenvironment and the physiological balance between endogenous pro-angiogenic and anti-angiogenic factors is disrupted. Since then, angiogenesis inhibitors have been developed as drugs and administered in the clinic as part of anti-cancer therapy. Tissue inhibitor of metalloproteinase 2 (TIMP-2) is an endogenous inhibitor of angiogenesis that was initially discovered through the ability to inhibit matrix metalloproteinase (MMP) activity. Subsequently, TIMP-2 was shown to suppress endothelial cell proliferation and migration through MMP dependent and independent mechanisms. Moreover, recent studies indicate that TIMP-2- mediated inhibition of tumor growth may occur, at least in part, via mechanisms that are distinct from its ability to inhibit MMP activity. TIMP-2 is an essential element of the normal tissue microenvironment in the presence of low levels of MMP expression. However, in tumor tissue TIMP-2 levels are reduced. Recent experiments demonstrate that reconstitution of TIMP-2 expression in tumors not only inhibits tumor angiogenesis, but also acts directly on tumor cells to modulate interactions between the tumor cells and the microenvironment. These recent research findings support the idea that TIMP-2 is an excellent candidate for preclinical development as a novel biological agent for cancer therapy.