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

Abstract

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.Angiogenesis, the development of the microvasculature, is an essential process occurring under many pathological and physiological circumstances and depends on tightly controlled interactions between cells and extracellular matrix (ECM) 2 mediated by integral membrane proteins. These include integrins, which provide a link between ECM and the cytoskeleton, and extracellular proteases and their inhibitors, which mediate focal degradation of ECM components (1, 2), generate cell growth factors (3), and produce angiogenic regulatory factors (4).Lysosomal cysteine protease cathepsins have been shown to be highly expressed in human and murine tumors (5), where angiogenesis plays essential roles. Interruption of their expression either by antisense RNA (6) or RNA interference (7, 8) reduced tumor cell invasion, angiogenesis, and tumor growth. A recent study also demonstrated that inhibition of the activities of cysteine proteases with a broad inhibitor reduced angiogenesis and growth of pancreatic ␤-cell islet carcinoma in mice with an SV40 T antigen (Tag) transgene driven by the rat insulin II promoter (RIP1-Tag2) (9). Administration of JPM-ethyl ester (10), which affects all activities of cysteinyl cathepsins, significantly diminished the angiogenic switch, tumor burden, and tumor cell proliferation (11). However, many important questions are still unanswered; for example, which cathepsin(s) is the most important and by what mechanisms do these cysteinyl cathepsins affect tumor progression? Earlier studies suggested the importance of cathepsin (Cat) B in tumor angiogenesis and growth (6 -8). However, additional studies also demonstrated constitutive expression of Cat B in several cell types or tissues (12, 13). Therefore, cathepsins other than Cat B may also be involved in angiogenesis, tumor growth, cell proliferation, and...

Cysteine Cathepsins S and L Modulate Anti-angiogenic Activities of Human Endostatin

“…Cysteine cathepsins are commonly reported to participate to and enhance cell growth, migration, invasion, angiogenesis, and metastasis, and comprehensible relationships have been established between their deregulation and cancer progression (25,26,38). For instance, cathepsin S, which can degrade anti-angiogenic collagen IV-derived peptides and release proangiogenic fragments from laminin, has been described to favor angiogenesis and microvessel formation in physiological neovascularization (39). Nevertheless, our current perception of the role of cathepsins is evolving.…”

Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia

“…On the other hand, it is well known that, among three glycoprotein subunits of laminin-5 (a3, b3 and g2), g2 chain-derived fragments promote cancer cell migration, invasion and associated vasculogenesis 28,29 . CatS deficiency has been shown to reduce processing of laminin-5 g2-derived fragments in a mouse tumour model 11 . In contrast, a deficiency of its endogenous inhibitor, cystatin C, promotes tumour growth by enhancing g2-derived fragment production 26 .…”

“…In addition, except for Jagged-1, ischaemic injury increased all targeted molecules in CatK þ / þ and CatK À / À mice. Multiple studies have demonstrated that Cats (CatS and CatL) participate in the release of the extracellular matrix and basement membrane-derived growth factors, either by converting them from their latent forms or degrading their associated inhibitors 11,27 . Endostatin is a proteolytic fragment of type XVIII collagen generated by several proteases in vivo, including Cats and MMPs.…”

“…There is growing evidence for specific intra-and extracellular functions for these lysosomal enzymes, which have been shown to participate in numerous cardiovascular pathogeneses and progressions [6][7][8][9][10] . Wang et al 11 reported that CatS activity controlled the production of matrix-derived angiogenic factors (anti-: canstatin, arresten and tumstatin; pro-: g2 fragments), revealing a functional role for CatS in angiogenesis and tumour growth. Moreover, recent findings of a few studies show that CatL plays crucial roles in the invasive and functional capacities of endothelial progenitor cells (EPC) in the EPC-mediated neovascularization process 12,13 .…”

Quantifying Cathepsin S Activity in Antigen Presenting Cells Using a Novel Specific Substrate

“…Furthermore, cathepsin S-deficient mice showed decreased susceptibility to collagen-induced arthritis (14), and rats with adjuvant-induced arthritis displayed significant decreases in inflammation after oral administration of the cathepsin S inhibitor LHVS (16), not only supporting a specific role for CatS in rheumatoid arthritis but also validating CatS as an appropriate drug target in other autoimmune disorders. CatS has recently emerged as an important proteolytic enzyme in cancer development, and CatS inhibitors have been proposed as anticancer agents (17,18). Compounds targeting CatS in rheumatoid arthritis, bronchial asthma, and psoriasis are already undergoing clinical evaluation, and the development of new CatS inhibitors is still a growing field (19).…”