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J. Biol. Chem., Vol. 282, Issue 18, 13326-13333, May 4, 2007

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Heparanase Enhances Syndecan-1 Shedding

A NOVEL MECHANISM FOR STIMULATION OF TUMOR GROWTH AND METASTASIS^*

Yang Yang, Veronica MacLeod, Hua-Quan Miao^¶, Allison Theus, Fenghuang Zhan^||, John D. Shaughnessy, Jr.^||, Jeffrey Sawyer, Jin-Ping Li^**, Eyal Zcharia, Israel Vlodavsky, and Ralph D. Sanderson¹

From the Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, ^¶ImClone Systems, Inc., New York, New York 10014, ^||Myeloma Institute for Research and Therapy and the Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, ^**Department of Medical Biochemistry and Microbiology, Biomedical Center, S-751 23 Uppsala, Sweden, and Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel

When shed from the cell surface, the heparan sulfate proteoglycan syndecan-1 can facilitate the growth, angiogenesis, and metastasis of tumors. Here we report that tumor cell expression of heparanase, an enzyme known to be a potent promoter of tumor progression and metastasis, regulates both the level and location of syndecan-1 within the tumor microenvironment by enhancing its synthesis and subsequent shedding from the tumor cell surface. Heparanase regulation of syndecan-1 is detected in both human myeloma and breast cancer cell lines. This regulation requires the presence of active enzyme, because mutated forms of heparanase lacking heparan sulfate-degrading activity failed to influence syndecan-1 expression or shedding. Removal of heparan sulfate from the cell surface using bacterial heparitinase dramatically accelerated syndecan-1 shedding, suggesting that the effects of heparanase on syndecan-1 expression by tumor cells may be due, at least in part, to enzymatic removal or reduction in the size of heparan sulfate chains. Animals bearing tumors formed from cells expressing high levels of heparanase or animals transgenic for heparanase expression exhibited elevated levels of serum syndecan-1 as compared with controls, indicating that heparanase regulation of syndecan-1 expression and shedding can occur in vivo and impact cancer progression and perhaps other pathological states. These results reveal a new mechanism by which heparanase promotes an aggressive tumor phenotype and suggests that heparanase and syndecan-1 act synergistically to fine tune the tumor microenvironment and ensure robust tumor growth.

Received for publication, December 7, 2006 , and in revised form, March 7, 2007.

^* This work was supported by National Institutes of Health Grants CA 103054 and CA 055819 (to R. D. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

¹ To whom correspondence should be addressed: Dept. of Pathology, University of Alabama at Birmingham, 814 SHEL, 1530 Third Ave. S., Birmingham, AL 35294. Tel.: 205-996-6226; Fax: 205-996-6119; E-mail: sanderson{at}uab.edu.

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