Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors
Author
Summary, in English
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-beta 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 gamma 2 fragments from laminin-5, revealing a functional role for cathepsin S in angiogenesis and neoplastic progression.
Department/s
Publishing year
2006
Language
English
Pages
6020-6029
Publication/Series
Journal of Biological Chemistry
Volume
281
Issue
9
Document type
Journal article
Publisher
American Society for Biochemistry and Molecular Biology
Topic
- Medicinal Chemistry
- Pharmacology and Toxicology
Status
Published
ISBN/ISSN/Other
- ISSN: 1083-351X