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Significance of Heparanase in Cancer and Inflammation

  • Review Paper
  • Published:
Cancer Microenvironment

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.

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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

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Acknowledgements

We thank Prof. Benito Casu (‘Ronzoni’ Institute, Milan, Italy) and Prof. Ralph Sanderson (University of Alabama at Birmingham) for their continuous support and active collaboration. This work was supported by National Institutes of Health (NIH) grants CA106456 (IV) and CA138535 (RDS), the Israel Science Foundation (549/06); the Ministry of Science & Technology of the State of Israel and the German Cancer Research Center (DKFZ), the Juvenile Diabetes Research Foundation (JDRF 1-2006-695 and 38-2009-635) and by a research contract from Sigma-Tau Research Switzerland S.A. I. Vlodavsky is a Research Professor of the ICRF. We gratefully acknowledge the contribution, motivation and assistance of the research teams in the Hadassah-Hebrew University Medical Center (Jerusalem, Israel) and the Cancer and Vascular Biology Research Center of the Rappaport Faculty of Medicine (Technion, Haifa).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine, Technion, P. O. Box 9649, Haifa, 31096, Israel

    Israel Vlodavsky & Neta Ilan

  2. Traslational Immunology Unit, DKFZ, Heidelberg, Germany

    Phillip Beckhove

  3. Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Immanuel Lerner, Amichai Meirovitz & Michael Elkin

  4. Sigma-Tau SpA, 00040, Pomezia, Rome, Italy

    Claudio Pisano

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  1. Israel Vlodavsky
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Correspondence to Israel Vlodavsky.

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Vlodavsky, I., Beckhove, P., Lerner, I. et al. Significance of Heparanase in Cancer and Inflammation. Cancer Microenvironment 5, 115–132 (2012). https://doi.org/10.1007/s12307-011-0082-7

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