Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors.
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-beta1, 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 gamma2 fragments from laminin-5, revealing a functional role for cathepsin S in angiogenesis and neoplastic progression.
Wang
Bing
B
Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 77 Ave. Louis Pasteur, Boston, MA 02115, USA.
Sun
Jiusong
J
Kitamoto
Shiro
S
Yang
Min
M
Grubb
Anders
A
Chapman
Harold A
HA
Kalluri
Raghu
R
Shi
Guo-Ping
GP
D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D020533:Angiogenesis Inhibitors / Q000378:metabolism; D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D049109:Cell Proliferation; D024141:Collagen Type IV / Q000378:metabolism; D055316:Cystatin C; D015891:Cystatins / Q000235:genetics / Q000378:metabolism; D043169:Endostatins / Q000378:metabolism; D005109:Extracellular Matrix / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D000097794:Kalinin
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D001324:Autoantigens; D002403:Cathepsins; D015815:Cell Adhesion Molecules; D024141:Collagen Type IV; D055316:Cystatin C; D015891:Cystatins; D043169:Endostatins; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011993:Recombinant Fusion Proteins; D000097794:Kalinin; C525030:CST3 protein, human; C502624:Col4a2 protein, mouse; C525031:Cst3 protein, mouse; C057112:type IV collagen alpha3 chain; C028217:cathepsin S