Association of cathepsin E with tumor growth arrest through angiogenesis inhibition and enhanced immune responses

Abstract

Cathepsin E (CE) is an intracellular aspartic proteinase implicated in various physiological and pathological processes, yet its actual roles in vivo remain elusive. To assess the physiological significance of CE expression in tumor cells, human CE was stably expressed in human prostate carcinoma ALVA101 cells expressing very little CE activity. Tumor growth in nude mice with xenografted ALVA101/hCE cells was slower than with control ALVA101/mock cells. Angiogenesis antibody array and ELISA assay showed that this was partly due to the increased expression of some antiangiogenic molecules including interleukin 12 and endostatin in tumors induced by CE expression. In vitro studies also demonstrated that, among the cathepsins tested, CE most efficiently generated endostatin from the non-collagenous fragment of human collagen XVIII at mild acidic pH. Histological examination revealed that tumors formed by ALVA101/hCE cells were partitioned by well-developed membranous structures and covered with thickened, well-stratified hypodermal tissues. In addition, both the number and extent of activation of tumor-infiltrating macrophages were more profound in ALVA101/hCE compared to ALVA101/mock tumors. The chemotactic response of macrophages to ALVA101/hCE cells was also higher than that to ALVA/mock cells. These results thus indicate that CE expression in tumor cells induces tumor growth arrest via inhibition of angiogenesis and enhanced immune responses.

Pericellular proteolysis in cancer

“…Cleavage of plasminogen by MMP2, MMP3, MMP7, MMP9, MMP12, and MMP19 generates angiostatin (Patterson and Sang 1997;Cornelius et al 1998;Lijnen et al 1998;Moses and O'Reilly 2003;Brauer et al 2011), and endostatin is generated through cleavage of collagen XVIII by MMP3, MMP9, and MMP13 (Ma et al 2007;Bendrik et al 2010;Fukuda et al 2011). Besides MMPs, different cathepsin family members, including the cysteine cathepsins L and S (Felbor et al 2000;Veillard et al 2011) and the aspartic cathepsin E (Shin et al 2007), have been shown to generate endostatin from collagen XVIII. Conversely, Wang et al (2006) proposed that cathepsin S promotes angiogenesis by degradation of the anti-angiogenic peptides canstatin and arresten and generation of proangiogenic fragments from laminin 5 in pancreatic neuroendocrine cancer (Fig.…”

Cathepsin E (EC 3.4.23.34) — a review

“…Cathepsin E www.fhc.viamedica.pl inhibits growth of the tumor and inhibits apoptosis in prostate cancer cells by releasing tumor necrosis factor [75]. Furthermore, inhibition of tumor growth by inhibition of angiogenesis, as well as strengthening immunological response, has been found [76]. An increased activity of cathepsin E in tumors causes increased expression of certain anti-angiogenic factors, including interleukin-12 and endostatin.…”

Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice

“…Furthermore, proteolytic events affect tumor biological processes, such as proliferation and angiogenesis, by liberating ECM-bound growth and angiogenic factors or by processing and activating these factors (3,4). Several protease classes, including metallo-, aspartic, serine, and cysteine proteases, are implicated in promoting tumor progression and metastasis (5)(6)(7)(8). The family of lysosomal cysteine proteases, the cysteine cathepsins (clan CA; C1 family), has recently attracted attention as tumor-promoting enzymes (9).…”