Enzymatic remodeling of heparan sulfate proteoglycans within the tumor microenvironment: growth regulation and the prospect of new cancer therapies.
Heparan sulfate proteoglycans (HSPGs), via their interactions with numerous effector molecules such as FGF-2, IL-8, and VEGF, regulate the biological activity of cells by acting as co-receptors that promote signaling. The extent and nature of their role as co-receptors is often misregulated in cancer as manifested by alterations in HSPG structure and expression level. This misregulation of HSPGs can aid in promoting the malignant phenotype. In addition to expression-related changes in HSPGs, recent discoveries indicate that HSPGs localized within the tumor microenvironment can be attacked by enzymes that alter proteoglycan structure resulting in dramatic effects on tumor growth and metastasis. This review focuses on remodeling of HSPGs by three distinct mechanisms that occur in vivo; (i) shedding of proteoglycan extracellular domains from cell surfaces, (ii) fragmentation of heparan sulfate chains by heparanase, and (iii) removal of sulfates from the 6-O position of heparan sulfate chains by extracellular sulfatases. Assessing or monitoring the remodeling of HSPGs has important implications for tumor diagnosis and patient prognosis while therapeutic manipulation of the remodeling process represents an exciting new possibility for treating cancer.
Sanderson
Ralph D
RD
Department of Pathology and the Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. RDSanderson@uams.edu
Yang
Yang
Y
Kelly
Thomas
T
MacLeod
Veronica
V
Dai
Yuemeng
Y
Theus
Allison
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005786:Gene Expression Regulation; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000378:metabolism; D015398:Signal Transduction; D053667:Syndecans; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000970:Antineoplastic Agents; D019812:Heparan Sulfate Proteoglycans; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D053667:Syndecans; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2