Cemip, A Secreted Protein Highly Induced In Colon Cancer And Associated With Poor Patient Survival

Background: Colorectal cancer is the second leading cause of cancer death among adult Americans. Tumor stage still remains the clinical standard for determining prognosis of colon cancer patients and for selecting individuals for treatment with adjuvant chemotherapy. Genes induced in colon cancer provide novel candidate biomarkers of tumor phenotype and aggressiveness. The goal of this study was to identify genes whose expression is dramatically up-regulated in colon neoplasia even at the early stages of the disease, and with the potential to be new prognostic markers of patient outcome and/or targets for new therapies. Methods: We used expression microarrays, real-time PCR, Western blot, and immunohistochemistry to identify CEMIP (originally named KIAA1199/CCSP1) induction in colon cancer, and characterized the biological properties of the corresponding protein in cell-line and mouse xenografts. Sandwich ELISA was developed to determine CEMIP plasma levels in patients with colon cancer. Prognostic importance of gene induction was demonstrated by real-time PCR measurement of gene expression in colon cancer cases of known clinical outcome. Results: We originally identified CEMIP as a novel transcript that is induced an average of 54-fold in colon cancer, with a similar increase in protein level. We find that CEMIP is a secreted protein and that plasma levels of CEMIP in colon cancer patients is increased compared to normal subjects (P = 0.05). Knocking out CEMIP in a human colon cancer cell line markedly reduced growth of tumor xenografts implanted in athymic mice. Tumors that did grow had increased deposition of hyaluronan, linking CEMIP participation in hyaluronan degradation to the modulation of tumor phenotype. Human stage III colon cancer cases with greater than average increased tumor CEMIP expression had a median survival time of 37 months, versus greater than 140 months for colon cancer cases with below average CEMIP expression (P = 0.004). Similarly, among combined stage II plus III colon cancer cases, median survival decreased by 92 months for CEMIP high versus low expressing tumors (P = 0.0003). Conclusions: CEMIP is highly expressed in colon neoplasia and is a novel member of the colon cancer secreted proteome making it a candidate serological marker of early human colon neoplasia. CEMIP facilitates tumor growth, and high CEMIP correlates with poor outcome in stage III and in stages II plus III combined cohorts. CEMIP may have utility as both a prognostic marker of colon cancer outcome, and as a potential therapeutic target. Citation Format: Stephen P. Fink, Lois Myeroff, Revital Kariv, Petra Platzer, Baozhong Xin, Debra Mikkola, Earl Lawrence, Nathan Morris, Arman Nosrati, James Willson, Joseph Willis, Martina Veigl, Jill Barnholtz-Sloan, Zhenghe Wang, Sanford Markowitz. CEMIP, a secreted protein highly induced in colon cancer and associated with poor patient survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3126.