Nicole C. Harris and Marc G. Achen Pages 1821 - 1842 ( 22 )
The growth of blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis) in and around solid tumors is central to the growth and metastatic spread of cancer. The therapeutic targeting of angiogenesis has become an established modality of cancer treatment, however, more comprehensive targeting of angiogenic signaling pathways may be required to enhance the clinical benefits of this approach. Angiogenesis and lymphangiogenesis are driven, or modulated, by a range of secreted glycoproteins including vascular endothelial growth factors, platelet-derived growth factors, and transforming growth factor-β. These key regulatory growth factors are subject to proteolytic activation, involving highly specific cleavage events, which can occur at the cell surface or in the extracellular milieu. These cleavage events are catalysed by a variety of enzymes including proprotein convertases. This proteolysis can regulate the activity of these growth factors by enhancing binding affinities for cell surface receptors and co-receptors, or by altering their interactions with heparan sulfate proteoglycans, thereby modulating bioavailability. The proteolytic processing of these growth factors complicates strategies for targeting them for diagnostic and/or therapeutic purposes in cancer, as processing can generate various forms with distinct biological properties. Hence it has been important to determine which forms are biologically active for promoting angiogenesis and lymphangiogenesis in cancer, so as to indicate clinical relevance. Here we review the regulation of tumor angiogenesis and lymphangiogenesis by proteolytic activation of growth factors, and the potential therapeutic and diagnostic strategies arising from our understanding of this process.
Angiogenesis, cancer, lymphangiogenesis, proprotein convertase, proteolytic processing, VEGF.
, Tumour Angiogenesis Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia