Perlecan and Tumor Angiogenesis

Abstract

S U M M A R YPerlecan is a major heparan sulfate proteoglycan (HSPG) of basement membranes (BMs) and connective tissues. The core protein of perlecan is divided into five domains based on sequence homology to other known proteins. Commonly, the N-terminal domain I of mammalian perlecan is substituted with three HS chains that can bind a number of matrix molecules, cytokines, and growth factors. Perlecan is essential for metazoan life, as shown by genetic manipulations of nematodes, insects, and mice. There are also known human mutations that can be lethal. In vertebrates, new functions of perlecan emerged with the acquisition of a closed vascular system and skeletal connective tissues. Many of perlecan's functions may be related to the binding and presentation of growth factors to high-affinity tyrosine kinase (TK) receptors. Data are accumulating, as discussed here, that similar growth factor-mediated processes may have unwanted promoting effects on tumor cell proliferation and tumor angiogenesis. Understanding of these attributes at the molecular level may offer opportunities for therapeutic intervention.

Heparan Sulfate of Perlecan Is Involved in Glomerular Filtration

“…Changes in the HS of HSPG have been suggested in proteinuric glomerular diseases (31). Several functions of perlecan HS have been proposed (9,32). HS chains may sequester and trap growth factors, protecting them from proteolytic degradation (33).…”

Basement membranes

“…These results suggest that viable unc-52 mutations effectively increase growth factor signaling, possibly due to failure to sequester/localize the growth factors properly. Evidence for growth factor binding to perlecan and modulation of signaling has been demonstrated in vertebrates (Jiang and Couchman, 2003.…”

The "chemoinvasion assay": a tool to study tumor and endothelial cell invasion of basement membranes

“…Interactions between detached tumor cells and the stromal extracellular matrix occur via fibronectin, collagen, other glycoproteins and proteoglycans (Bogenrieder and Herlyn 2003, Casey et al, 2003, Esparza et al, 1999, Jiang and Couchman, 2003.…”