403회 CD99-derived protein and peptide ligands inhibit cancer cell grow…

403회

연사 : 한 장 희, 강원대학교 의과대학 해부학교실

제목:  CD99-derived protein and peptide ligands inhibit cancer cell growth, metastasis and inflammation in mice.

Abstract

The human CD99 protein is a 32kD integral membrane protein expressed in most human cells. Its function is supposed to be involved in controlling cell-cell interaction, T cell activation, and transendothelial migration of leucocytes. In this seminar, the following four issues about the function of CD99 will be presented. The first issue is roles for CD99 in cell-extra cellular matrix adhesion and cell motility. CD99 cross-linking suppressed cell adhesion to fibronectin, collagen type IV and laminin and cell motility by decreasing 1integrin affinity through H-Ras/Raf/MEK/ERK pathway. The second one is the effect of CD99 signaling on angiogenesis and tumor growth. CD99 activation inhibited basic fibroblast growth factor (bFGF)-induced tubular morphogenesis of human umbilical endothelial cells (HUVECs). CD99-derived peptide (11-mer) suppressed the growth of mouse melanoma cells, B16F10, in the nude mouse xenograft model, suggesting that CD99 has anti-tumor effects in vivo through the inhibition of angiogenesis. The third is on the effects of CD99 signaling on extravasation of tumor cells. CD99 peptide treatment prevented human breast carcinoma MCF-7 cells from migrating through HUVECs. In parallel, it suppressed the invasion of MCF-7 cells through extracellular matrix proteins. In addition, the CD99 peptide reduced the metatasis of B16F10 to lung and livers in the nude mouse, suggesting that CD99 has anti-metastasis effects in vivo through the inhibition of extravasation of tumor cells. Finally, we examined the effect of CD99 on transendothelial migration of human monocytic U937 cells and the progression of collagen-induced arthritis (CIA) in mice. CD99 peptide treatment significantly inhibited U937 cells transmigration across HUVEC in a static two-compartment model. Arthritis was induced in DBA/1J mice by subcutaneous immunization with bovine type II collagen on days 0 and 21. The CD99 peptide was administered intraperitoneally for 3 weeks as therapy (40 ㎍/kg) after disease onset. Clinical scores, serum antibody levels, and cytokine levels were measured to evaluate the knee joints of mice with CIA. In therapeutic CD99 dosing models, all clinical scores, and serum levels of interferon- (INF-) and tumor necrosis factor- (TNF-) were reduced. In addition, the number of granulocytes was reduced in the knee joints of CD99 peptide-treated CIA mice. Thus, CD99 significantly suppressed monocyte transendothelial migration and the progression of CIA in mice. Taken together, these results suggest that CD99-derived proteins and peptides have therapeutic potential for cancer and inflammatory diseases.