Abstract C256: New therapeutic modalities by targeting RCAS1 which induces apoptosis via ectodomain shedding mediated by ADAM9

Abstract

Abstract RCAS1, a receptor-binding cancer antigen, is becoming a clinically relevant molecule in cancer biology. First, regarding the clinical significance, RCAS1 expression has been shown to correlate with overall survival in 15 types of cancer derived from brain, oral cavity, lung, pleural mesothelium, esophagus, stomach, bile duct, gallbladder, pancreas, colon, gastrointestinal mesenchyme, kidney, prostate, uterine cervix, and endometrium. RCAS1 expression correlates with other clinicopathological parameters including tumor histology, differentiation, size, stage, the depth of invasion, lymphovascular space involvement, lymph node metastasis, and positive peritoneal cytological results. The concentration of RCAS1 in serum or pleural effusions is significantly higher in patients with cancer as compared to normal controls and its levels are associated with response to treatment, suggesting that RCAS1 has value as a biomarker for monitoring therapeutic efficacy. Second, concerning the biological activity, RCAS1 induces apoptosis in its putative receptor expressing cells including peripheral lymphocytes and NK cells in vitro as well as in tumor-infiltrating lymphocytes in vivo in several malignancies. RCAS1 expression is associated with the expression of MMP-1 and laminin 5 in cervical cancer. Moreover, the number of cells expressing vimentin significantly decreases in relation to the RCAS1 expression level in cervical and ovarian cancer stromal tissues. Vimentin is an intermediate filament protein, and change in its expression correlates with cell behavior alterations in the epithelia-stroma interaction. These findings suggest that RCAS1 may play a role in tumor progression by modifying the characteristics of connective tissue around tumor cells. In addition, enhanced RCAS1 expression in COS-7 cells following introduction of the RCAS1-encoding gene significantly promotes in vivo tumor growth via increased expression of VEGF. In cervical cancer, RCAS1 expression correlates significantly with VEGF expression and microvessel density. We here show the novel intriguing biological characteristics of RCAS1. RCAS1 is secreted by ectodomain shedding via the PKC-δ, Ras-MAPK, and transactivation pathways and ADAM9 is a key protease for RCAS1 secretion. Apoptosis in K562 cells that express the putative RCAS1 receptor is mainly induced by secreted RCAS1 and not by the membranous type. Serum from uterine and ovarian cancer patients induces growth inhibition in K562 cells, and this inhibitory effect is partially reversed after immunodepletion of RCAS1. Shedding of membrane proteins changes their fate, location, and mode of action, thus affecting their biological activities. This shedding process is therefore an important regulatory step in the function of membrane proteins involved in cell-cell communication during development, cell differentiation, and tissue maintenance. Accumulating these evidences, RCAS1 may contribute to tumor progression by the escape from immune surveillance and connective tissue remodeling. Further exploration of the biological function of RCAS1 should help in the development of novel therapeutic strategies against human malignancies that target the RCAS1 expression and its shedding mechanism. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C256.