The heparanase/heparan sulfate proteoglycan axis: A potential new therapeutic target in sarcomas.
Heparanase, the only known mammalian endoglycosidase degrading heparan sulfate (HS) chains of HS proteoglycans (HSPG), is a highly versatile protein affecting multiple events in tumor cells and their microenvironment. In several malignancies, deregulation of the heparanase/HSPG system has been implicated in tumor progression, hence representing a valuable therapeutic target. Currently, multiple agents interfering with the heparanase/HSPG axis are under clinical investigation. Sarcomas are characterized by a high biomolecular complexity and multiple levels of interconnection with microenvironment sustaining their growth and progression. The clinical management of advanced diseases remains a challenge. In several sarcoma subtypes, high levels of heparanase expression have been correlated with poor prognosis associated factors. On the other hand, expression of cell surface-associated HSPGs (i.e. glypicans and syndecans) has been found altered in specific sarcoma subtypes. Recent studies provided the preclinical proof-of-principle of the role of the heparanase/HSPG axis as therapeutic target in various sarcoma subtypes. Although currently there are no clinical trials evaluating agents targeting heparanase and/or HSPGs in sarcomas, we here provide arguments for this strategy as potentially able to implement the therapeutic options for sarcoma patients.
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Molecular Pharmacology Unit, via Amadeo 42, 20133 Milan, Italy. Electronic address: giuliana.cassinelli@istitutotumori.mi.it.
Giuliana
G
Cassinelli
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Molecular Pharmacology Unit, via Amadeo 42, 20133 Milan, Italy.
Nadia
N
Zaffaroni
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Molecular Pharmacology Unit, via Amadeo 42, 20133 Milan, Italy.
Cinzia
C
Lanzi
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D055808:Drug Discovery / Q000379:methods; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006493:Heparin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D018716:Molecular Mimicry; D058990:Molecular Targeted Therapy; D012509:Sarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D000099175:Heparanase
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005966:Glucuronidase; D019812:Heparan Sulfate Proteoglycans; D006493:Heparin; D000099175:Heparanase; C559639:SST 0001
Heparan sulfate mimetic; Heparan sulfate proteoglycan; Heparanase; Heparanase inhibitor; Sarcoma