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A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer

Oncogene volume 24, pages 4037–4051 (2005)Cite this article

A Corrigendum to this article was published on 09 June 2005

Abstract

Heparan sulfate proteoglycans are integral components of the extracellular matrix that surrounds all mammalian cells. In addition to providing structural integrity, they act as a storage depot for a variety of heparan sulfate (HS)-binding proteins, including growth factors and chemokines. Heparanase is a matrix-degrading enzyme that cleaves heparan sulfate side chains from the core proteoglycans, thus liberating such HS-binding proteins, as well as potentially contributing to extracellular matrix degradation. Here, we report that heparanase mRNA and protein expression are increased in the neoplastic stages progressively unfolding in a mouse model of multistage pancreatic islet carcinogenesis. Notably, heparanase is delivered to the neoplastic lesions in large part by infiltrating Gr1+/Mac1+ innate immune cells. A sulfated oligosaccharide mimetic of heparan sulfate, PI-88, was used to inhibit simultaneously both heparanase activity and HS effector functions. PI-88 had significant effects at distinct stages of tumorigenesis, producing a reduction in the number of early progenitor lesions and an impairment of tumor growth at later stages. These responses were associated with decreased cell proliferation, increased apoptosis, impaired angiogenesis, and a substantive reduction in the number of invasive carcinomas. In addition, we show that the reduction in tumor angiogenesis is correlated with a reduced association of VEGF-A with its receptor VEGF-R2 on the tumor endothelium, implicating heparanase in the mobilization of matrix-associated VEGF. These data encourage clinical applications of inhibitors such as PI-88 for the many human cancers where heparanase expression is elevated or mobilization of HS-binding regulatory factors is implicated.

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Acknowledgements

We thank Progen Industries, Australia, for supplying PI-88, and B Creese and D Podger, Progen, Australia, for helpful advice. We thank C Concengco and E Solliven for excellent technical assistance, and D Ginzinger and M Yu, UCSF Cancer Center Genome Facility, for Taqman analysis. We are grateful to K Butterfield and J Folkman, Harvard Medical School, MA, USA, for providing primary bovine endothelial cells, and R Brekken, Hope Heart Institute, WA, USA, for providing the GV39M antibody. We thank Z Werb and O Stevaux for insightful review of the manuscript. JAJ is a Fellow of the Leukemia and Lymphoma Society. This work was supported by the William K Bowes Jr Foundation, the American Cancer Society, and the US National Cancer Institute (DH). CF and CRP are recipients of an Australian National Health and Medical Research Council Program grant.

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  1. Department of Biochemistry and Biophysics, Diabetes and Comprehensive Cancer Centers, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA, 94143-0534, USA

    Johanna A Joyce, Nicole Meyer-Morse & Douglas Hanahan

  2. Division of Immunology and Genetics, The John Curtin School of Medical Research, The Australian National University, PO Box 334, Canberra, ACT, 2601, Australia

    Craig Freeman & Christopher R Parish

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  1. Johanna A Joyce
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Correspondence to Johanna A Joyce or Douglas Hanahan.

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Joyce, J., Freeman, C., Meyer-Morse, N. et al. A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer. Oncogene 24, 4037–4051 (2005). https://doi.org/10.1038/sj.onc.1208602

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