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J. Biol. Chem., Vol. 281, Issue 9, 6020-6029, March 3, 2006

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Cathepsin S Controls Angiogenesis and Tumor Growth via Matrix-derived Angiogenic Factors^*

Bing Wang, Jiusong Sun, Shiro Kitamoto, Min Yang, Anders Grubb^¶, Harold A. Chapman^||, Raghu Kalluri^**, and Guo-Ping Shi¹

From the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, the Department of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China, the ^¶Department of Clinical Chemistry, University Hospital, S-22185 Lund, Sweden, the ^||Department of Medicine, University of California, San Francisco, California 94143, and the ^**Center for Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

The cysteine protease cathepsin S is highly expressed in malignant tissues. By using a mouse model of multistage murine pancreatic islet cell carcinogenesis in which cysteine cathepsin activity has been functionally implicated, we demonstrated that selective cathepsin S deficiency impaired angiogenesis and tumor cell proliferation, thereby impairing angiogenic islet formation and the growth of solid tumors, whereas the absence of its endogenous inhibitor cystatin C resulted in opposite phenotypes. Although mitogenic vascular endothelial growth factor, transforming growth factor-1, and the anti-angiogenic endostatin levels in either serum or carcinoma tissue extracts did not change in cathepsin S- or cystatin C-null mice, tumor tissue basic fibroblast growth factor and serum type 1 insulin growth factor levels were higher in cystatin C-null mice, and serum type 1 insulin growth factor levels were also increased in cathepsin S-null mice. Furthermore, cathepsin S affected the production of type IV collagen-derived anti-angiogenic peptides and the generation of bioactive pro-angiogenic 2 fragments from laminin-5, revealing a functional role for cathepsin S in angiogenesis and neoplastic progression.

Received for publication, August 18, 2005 , and in revised form, December 16, 2005.

^* This work was supported by National Institutes of Health Grants HL60942, HL67283 (to G. P. S.), HL48621 (to H. A. C.), and DK62987 (to R. K.). 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: Cardiovascular Medicine, NRB-7, 77Ave. Louis Pasteur, Boston, MA 02115. Tel.: 617-525-4358; Fax: 617-525-4380; E-mail: gshi{at}rics.bwh.harvard.edu.

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