Basement membrane proteoglycans: modulators Par Excellence of cancer growth and angiogenesis

Abstract

Proteoglycans located in basement membranes, the nanostructures underling epithelial and endothelial layers, are unique in several respects. They are usually large, elongated molecules with a collage of domains that share structural and functional homology with numerous extracellular matrix proteins, growth factors and surface receptors. They mainly carry heparan sulfate side chains and these contribute not only to storing and preserving the biological activity of various heparan sulfate-binding cytokines and growth factors, but also in presenting them in a more "active configuration" to their cognate receptors. Abnormal expression or deregulated function of these proteoglycans affect cancer and angiogenesis, and are critical for the evolution of the tumor microenvironment. This review will focus on the functional roles of the major heparan sulfate proteoglycans from basement membrane zones: perlecan, agrin and collagen XVIII, and on their roles in modulating cancer growth and angiogenesis.

Fig. 1.

Structural domains of human perlecan, agrin and collagen XVIII. The five domains of perlecan are in Roman numerals from the N- to the C-terminus. The other domains of agrin and collagen XVII are listed or detailed in the text.

Fig. 2.

Schematic representation of the C-termini of perlecan, agrin and collagen XVIII (left) and their respective cognate receptors (right). Also annotated are the locations of various protease cleavage sites generating intact modules or fragments thereof from the three polypeptides. For additional details see the text.