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J. Biol. Chem., Vol. 280, Issue 48, 40066-40073, December 2, 2005

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HSulf-1 and HSulf-2 Are Potent Inhibitors of Myeloma Tumor Growth in Vivo^*

Yuemeng Dai, Yang Yang, Veronica MacLeod, Xinping Yue, Alan C. Rapraeger, Zachary Shriver¶, Ganesh Venkataraman¶, Ram Sasisekharan||, and Ralph D. Sanderson1

From the Department of Pathology and the Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, the Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706, ^¶Momenta Pharmaceuticals, Inc., Cambridge, Massachusetts 02142, and the ^||Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

To participate as co-receptor in growth factor signaling, heparan sulfate must have specific structural features. Recent studies show that when the levels of 6-O-sulfation of heparan sulfate are diminished by the activity of extracellular heparan sulfate 6-O-endosulfatases (Sulfs), fibroblast growth factor 2-, heparin binding epidermal growth factor-, and hepatocyte growth factor-mediated signaling are attenuated. This represents a novel mechanism for regulating cell growth, particularly within the tumor microenvironment where the Sulfs are known to be misregulated. To directly test the role of Sulfs in tumor growth control in vivo, a human myeloma cell line was transfected with cDNAs encoding either of the two known human endosulfatases, HSulf-1 or HSulf-2. When implanted into severe combined immunodeficient (SCID) mice, the growth of these tumors was dramatically reduced on the order of 5- to 10-fold as compared with controls. In addition to an inhibition of tumor growth, these studies revealed the following. (i) HSulf-1 and HSulf-2 have similar functions in vivo. (ii) The extracellular activity of Sulfs is restricted to the local tumor cell surface. (iii) The Sulfs promote a marked increase in extracellular matrix deposition within tumors that may, along with attenuated growth factor signaling, contribute to the reduction in tumor growth. These findings demonstrate that dynamic regulation of heparan sulfate structure by Sulfs present within the tumor microenvironment can have a dramatic impact on the growth and progression of malignant cells in vivo.

Received for publication, July 25, 2005 , and in revised form, September 15, 2005.

^* This work was supported by National Institutes of Health Grants CA68494 and CA55819 (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.

¹ To whom correspondence should be addressed: Dept. of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, AR 72205. Tel.: 501-686-6413; Fax: 501-686-5168; E-mail: RDSanderson{at}uams.edu.

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