Abstract LB-147: Colonic crypt neuroendocrine cells regulate colonic stem cells during colorectal cancer development
Authors: Shirin R. Modarai, Lynn M. Opdenaker, Bruce M. Boman
Journal: Cancer Research (2015)

Abstract Our studies on tissues from colon cancer patients show that in the development of CRC, stem cells (SC) overpopulation underlies tumor initiation and progression. Specifically, we have involved studying patients with Familial Adenomatous Polyposis (FAP) during CRC development, which carry cancer-predisposing germline mutations in the adenomatous polyposis coli (APC) gene. These results indicate that SC overpopulation caused by APC mutations is the driver mechanism. However, how the APC mutations cause SC overpopulation needs clarification. Similar to SCs, Neuroendocrine cells (NECs) comprise ∼1% of the total cells in the colon and both reside in the crypt stem cell niche in the colonic epithelium. NECs are involved in autocrine and paracrine signaling to help regulate the function of surrounding cells. This leads to an overall goal of this project, to study the relationship between NECs and SCs in young-onset CRC, especially those individuals with a genetic predisposition to CRC. Our overall hypothesis is that NECs play a key role in maintaining the SC population in the normal colon and, aberrant signaling from NECs contributes to tumor initiation and increased stemness. To begin to investigate underlying mechanisms, we studied human colon tissues with varying APC genotypes: (i) normal crypts (homozygous-wildtype APC); (ii) normal-appearing FAP crypts (heterozygous-mutant APC); (iii) adenomatous FAP crypts (homozygous-mutant APC); (iv) CRCs (homozygous-mutant APC&amp; other mutations). Preliminary data from our laboratory has shown that in colon cancer progression: (i) there is a decrease in the number of cells that co-express both SC and NEC markers (ii) there is a decrease in the total number of NECs, and (iii) there is an increase in the total number of SCs. Furthermore, we have established an in vitro co-culture model system to study regulation of SCs by NECs. Results from our model show that SSTR1 and GLP-2R NEC signaling plays a role in modulating colonic SC populations. This in vitro model system can help analyze the interaction between SCs and NECs during CRC progression. Taken together, our findings indicate that: (1) NE factors contribute to colonic SC regulation via an autocrine or paracrine mechanism in normal colon, and (2) dysregulation of these mechanisms contributes to colon cancer development. Using our established in vitro model system, we can track the changes in the SC and NEC population size, based on different conditions of anchorage independent growth and presence of potential therapeutic agents. Citation Format: Shirin R. Modarai, Lynn M. Opdenaker, Bruce M. Boman. Colonic crypt neuroendocrine cells regulate colonic stem cells during colorectal cancer development. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-147. doi:10.1158/1538-7445.AM2015-LB-147