Without new blood vessels, neoplasms cannot expand beyond a few millimeters, the point at which the diffusion of nutrients and the disposal of waste products become rate-limiting. Regulation of angiogenesis thus must be controlled at multiple levels. For instance, the VEGF family of heparin-binding proteins and their primary receptors, VEGFR-1 and VEGFR-2 (KDR), products of the flt-1 and the flk-1 gene, respectively, are required for angioblast differentiation and vasculogenesis, and specific VEGF isoforms play distinct roles in promoting endothelial growth and migration during angiogenesis. In addition, angiogenesis is profoundly affected by several members of the FGF family and their four receptors, and indeed, supplementing the media of endothelial cell cultures with basic FGF (FGF2) and heparin is now well established as a means to obtain optimal growth, migration, and capillary morphogenesis. In addition to producing proangiogenic factors, tumor cells also directly or indirectly generate negative angiogenic stimuli. The ultimate growth rate of the tumors is thus a fine balance between positive and negative angiogenic cues.

Heparan sulfate proteoglycans (HSPGs) act in concert with members of the FGF and VEGF families and their receptors to control various aspects of vascular development and tumor angiogenesis. A processed form of the newly discovered HSPG-collagen hybrid molecule collagen type XVIII can exert strong antitumor activity by reversibly blocking tumor angiogenesis. This Perspective will focus primarily on the roles of this and other HSPGs on angiogenesis, with special emphasis on the activity of the protein core, its functional partners, and its processed isoforms.