Wang Bing, Sun Jiusong, Kitamoto Shiro, Yang Min, Grubb Anders, Chapman Harold A, Kalluri Raghu, Shi Guo-Ping
Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 77 Ave. Louis Pasteur, Boston, MA 02115, USA.
J Biol Chem. 2006 Mar 3;281(9):6020-9. doi: 10.1074/jbc.M509134200. Epub 2005 Dec 19.
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.
半胱氨酸蛋白酶组织蛋白酶S在恶性组织中高表达。利用一个多阶段小鼠胰岛细胞癌变的小鼠模型（其中半胱氨酸组织蛋白酶活性在功能上与之相关），我们证明，组织蛋白酶S的选择性缺乏会损害血管生成和肿瘤细胞增殖，从而损害血管生成性胰岛形成和实体瘤生长，而其内源性抑制剂胱抑素C的缺失则导致相反的表型。尽管在组织蛋白酶S基因敲除或胱抑素C基因敲除小鼠中，血清或癌组织提取物中的促有丝分裂血管内皮生长因子、转化生长因子-β1和抗血管生成内皮抑素水平没有变化，但胱抑素C基因敲除小鼠的肿瘤组织碱性成纤维细胞生长因子和血清1型胰岛素生长因子水平较高，组织蛋白酶S基因敲除小鼠的血清1型胰岛素生长因子水平也升高。此外，组织蛋白酶S影响IV型胶原衍生的抗血管生成肽的产生以及层粘连蛋白-5生物活性促血管生成γ2片段的生成，揭示了组织蛋白酶S在血管生成和肿瘤进展中的功能作用。
