Heparan sulfate proteoglycans (HSPGs) are an integral and dynamic part of normal tissue architecture at the cell surface and within the extracellular matrix. The modification of HSPGs in the tumor microenvironment is known to result not just in structural but also functional consequences, which significantly impact
cancer progression. As substrates for the key
enzymes sulfatases and
heparanase, the modification of HSPGs is typically characterized by the degradation of
heparan sulfate (HS) chains/sulfation patterns via the endo-6-O-sulfatases (Sulf1 and Sulf2) or by
heparanase, an endo-
glycosidase that cleaves the HS
polymers releasing smaller fragments from
HSPG complexes. Numerous studies have demonstrated how these
enzymes actively influence
cancer cell proliferation, signaling, invasion, and
metastasis. The activity or expression of these
enzymes has been reported to be modified in a variety of
cancers. Such observations are consistent with the degradation of normal architecture and basement membranes, which are typically compromised in metastatic disease. Moreover, recent studies elucidating the requirements for these
proteins in
tumor initiation and progression exemplify their importance in the development and progression of
cancer. Thus, as the influence of the tumor microenvironment in
cancer progression becomes more apparent, the focus on targeting
enzymes that degrade HSPGs highlights one approach to maintain normal tissue architecture, inhibit
tumor progression, and block
metastasis. This review discusses the role of these
enzymes in the context of the tumor microenvironment and their promise as therapeutic targets for the treatment of
cancer.