Association of cathepsin E with tumor growth arrest through angiogenesis inhibition and enhanced immune responses.
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.
Shin
Masashi
M
Department of Pharmacology, Graduate School of Dental Science, Kyushu University, Fukuoka, Japan.
Kadowaki
Tomoko
T
Iwata
Jun-Ichi
J
Kawakubo
Tomoyo
T
Yamaguchi
Noriko
N
Takii
Ryosuke
R
Tsukuba
Takayuki
T
Yamamoto
Kenji
K
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D020059:Cathepsin E / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D043170:Collagen Type XVIII / Q000378:metabolism; D043169:Endostatins / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology / Q000473:pathology*; D014162:Transfection
D020533:Angiogenesis Inhibitors; D043170:Collagen Type XVIII; D043169:Endostatins; D020059:Cathepsin E