Heparanase: A Potential Therapeutic Target in Sarcomas.

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Abstract

Sarcomas comprise a heterogeneous group of rare malignancies of mesenchymal origin including more than 70 subtypes. They may arise in muscle, bone, cartilage and other connective tissues. Their high histological and genetic heterogeneity makes diagnosis and treatment very challenging. Deregulation of heparanase has been found in several sarcoma subtypes and high expression levels have been correlated with poor prognosis in Ewing's sarcoma and osteosarcoma. Altered expression of specific heparan sulfate proteoglycans and heparan sulfate biosynthetic enzymes has also been observed. Advances in molecular pathogenesis of sarcomas have evidenced the critical role of several heparan sulfate binding growth factors and receptor tyrosine kinases, highly interconnected with the microenvironment, in sustaining tumor growth and progression. Interference with heparanase/heparan sulfate functions represents a potential therapeutic approach in sarcoma. In this chapter, we summarize the current knowledge about the biological significance of heparanase expression and its potential as a therapeutic target in subtypes of both soft tissue and bone sarcomas. Particular emphasis is given to the involvement of heparan sulfate proteoglycans and their synthesizing and modifying enzymes in bone physiology and disorders leading up to the pathobiology of bone sarcomas. The chapter also describes the cooperation between exostin loss-of-function and heparanase upregulation in hereditary Multiple Osteochondroma syndrome as a paradigmatic example of constitutive alteration of the heparanase/heparan sulfate proteoglycan system which may contribute to progression to malignant secondary chondrosarcoma. Preclinical evidence of the role of heparanase as a promising therapeutic target in various sarcoma subtypes is finally resumed.
Original languageEnglish
Pages (from-to)405-431
Number of pages27
JournalAdvances in Experimental Medicine and Biology
Volume1221
DOIs
Publication statusPublished - 2020

Keywords

  • Humans
  • Cancer therapy
  • Osteosarcoma
  • Rhabdomyosarcoma
  • Chondrosarcoma
  • Heparan sulfate
  • Heparan sulfate mimetics
  • Heparanase
  • Heparanase inhibitor
  • Multiple Osteochondroma
  • Synovial sarcoma
  • Ewing’s sarcoma
  • Glucuronidase/*antagonists inhibitors/metabolism
  • Heparan Sulfate Proteoglycans
  • Heparitin Sulfate
  • Sarcoma/*drug therapy/enzymology

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