TY - JOUR
T1 - Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors
AU - Wang, Bing
AU - Sun, Jiusong
AU - Kitamoto, Shiro
AU - Yang, Min
AU - Grubb, Anders
AU - Chapman, Harold A.
AU - Kalluri, Raghu
AU - Shi, Guo Ping
PY - 2006/3/3
Y1 - 2006/3/3
N2 - 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-β1, 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 γ2 fragments from laminin-5, revealing a functional role for cathepsin S in angiogenesis and neoplastic progression.
AB - 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-β1, 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 γ2 fragments from laminin-5, revealing a functional role for cathepsin S in angiogenesis and neoplastic progression.
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U2 - 10.1074/jbc.M509134200
DO - 10.1074/jbc.M509134200
M3 - Article
C2 - 16365041
AN - SCOPUS:33646827205
SN - 0021-9258
VL - 281
SP - 6020
EP - 6029
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 9
ER -