Basement membranes are specialized sheets of extracellular matrices which are known to play integral roles in cellular functions such as adhesion, migration, and differentiation. The major constituents of these extracellular matrices include type IV collagen, laminin, and proteoglycans, particularly the low density heparan sulfate proteoglycan called perlecan. Proteoglycans consist of a core protein containing covalently attached glycosaminoglycan side chains. Perlecan was originally isolated from the Engelbreth-Holm Swarm (EHS) basement membrane producing mouse tumor, and it has been shown to be synthesized both with and without heparan sulfate side chains. It is a multifaceted gene and, as such, has been the focus of my research. In this work, I have found that perlecan mRNA and protein is localized not only to basement membranes, but is also expressed in tissues as diverse as the kidney, colon, lung, heart, thymus, ovary and testis. High levels of perlecan are also synthesized by developing cartilage, specifically in the proliferating chondrocytes. Through in vivo studies, I have shown that down-regulation of perlecan expression in allografts induced by mouse M2 melanoma cells through the use of an inducible antisense expression system results in a dramatic decrease in the growth rate of these tumors in syngeneic mice and a concurrent inhibition of angioyenesis. This effect is mediated by FGF-2, and these findings suggest a possible therapeutic application for perlecan in human melanoma. Overall, my research work has established a fundamental role for perlecan in vasculogenesis not only during development but also during malignant transformation.
