Cancer Microenvironment

, Volume 5, Issue 2, pp 115–132

Significance of Heparanase in Cancer and Inflammation

  • Israel Vlodavsky
  • Phillip Beckhove
  • Immanuel Lerner
  • Claudio Pisano
  • Amichai Meirovitz
  • Neta Ilan
  • Michael Elkin
Review Paper

DOI: 10.1007/s12307-011-0082-7

Cite this article as:
Vlodavsky, I., Beckhove, P., Lerner, I. et al. Cancer Microenvironment (2012) 5: 115. doi:10.1007/s12307-011-0082-7

Abstract

Heparan sulfate proteoglycans (HSPGs) are primary components at the interface between virtually every eukaryotic cell and its extracellular matrix. HSPGs not only provide a storage depot for heparin-binding molecules in the cell microenvironment, but also decisively regulate their accessibility, function and mode of action. As such, they are intimately involved in modulating cell invasion and signaling loops that are critical for tumor growth, inflammation and kidney function. In a series of studies performed since the cloning of the human heparanase gene, we and others have demonstrated that heparanase, the sole heparan sulfate degrading endoglycosidase, is causally involved in cancer progression, inflammation and diabetic nephropathy and hence is a valid target for drug development. Heparanase is causally involved in inflammation and accelerates colon tumorigenesis associated with inflammatory bowel disease. Notably, heparanase stimulates macrophage activation, while macrophages induce production and activation of latent heparanase contributed by the colon epithelium, together generating a vicious cycle that powers colitis and the associated tumorigenesis. Heparanase also plays a decisive role in the pathogenesis of diabetic nephropathy, degrading heparan sulfate in the glomerular basement membrane and ultimately leading to proteinuria and kidney dysfunction. Notably, clinically relevant doses of ionizing radiation (IR) upregulate heparanase expression and thereby augment the metastatic potential of pancreatic carcinoma. Thus, combining radiotherapy with heparanase inhibition is an effective strategy to prevent tumor resistance and dissemination in IR-treated pancreatic cancer patients. Also, accumulating evidence indicate that peptides derived from human heparanase elicit a potent anti-tumor immune response, suggesting that heparanase represents a promising target antigen for immunotherapeutic approaches against a broad variety of tumours. Oligosaccharide-based compounds that inhibit heparanase enzymatic activity were developed, aiming primarily at halting tumor growth, metastasis and angiogenesis. Some of these compounds are being evaluated in clinical trials, targeting both the tumor and tumor microenvironment.

Keywords

Extracellular matrixTumor microenvironmentInflammationTumor associated macrophagesHeparan sulfateHeparanaseMetastasisColitisColon carcinoma

Abbreviations

ECM

Extracellular matrix

HS

Heparan sulfate

HSPGs

Heparan sulfate proteoglycans

GAG

Glycosaminoglycan

MMP

Matrix metalloproteinase

VEGF

Vascular endothelial growth factor

CAF

Cancer-associated fibroblasts

UC

Ulcerative colitis

IBD

Inflammatory bowel disease

AOM

Azoxymethane

DSS

Dextran sodium sulfate

IR

Ionoizing radiation

Egr1

Early growth response 1

CTL

Cytotoxic T lymphocyte

HAT

Histone acetyltransferase

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Israel Vlodavsky
    • 1
  • Phillip Beckhove
    • 2
  • Immanuel Lerner
    • 3
  • Claudio Pisano
    • 4
  • Amichai Meirovitz
    • 3
  • Neta Ilan
    • 1
  • Michael Elkin
    • 3
  1. 1.Cancer and Vascular Biology Research CenterThe Rappaport Faculty of Medicine, TechnionHaifaIsrael
  2. 2.Traslational Immunology Unit, DKFZHeidelbergGermany
  3. 3.Sharett Oncology InstituteHadassah-Hebrew University Medical CenterJerusalemIsrael
  4. 4.Sigma-Tau SpARomeItaly