Abstract 5019: Stem cell and neuroendocrine cell phenotypes of normal and malignant colonic cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-04, Vol.73 (8_Supplement), p.5019-5019
• Main Authors: Modarai, Shirin R., Opdenaker, Lynn M., Boman, Bruce M.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-5019

In the development of colorectal cancer (CRC), stem cell (SC) overpopulation underlies tumor initiation and progression, but the underlying mechanisms are poorly understood. We hypothesized that neuroendocrine cells (NE) cells play a key role in maintaining the SC population in the normal colon and, aberrant signaling from NE cells contributes to tumor initiation and increased stemness. Indeed, NE cells and SCs reside in close proximity to each other in the SC niche at the bottom of the normal human colonic crypt. Therefore, it seems feasible that the communication between NE cells and SCs is crucial to normal crypt homeostasis and that dysregulation of the interactions between the two cell types could lead to SC overpopulation during cancer progression. Our studies on human colonic tissues show that in normal crypts, most cells (>80%) expressing the colonic SC marker ALDH1 co-express NE markers such as chromogranin-A (CGA). Neither ALDH1+ nor CGA+ cells co-stained for markers for proliferating cells. Thus, in normal crypts, many ALDH1+ cells have NE characteristics (likely representing progenitor NE cells). In APC mutant crypts, the size of the undifferentiated SC population (ALDH+/CGA-) progressively increased relative to the size of the NEC population (both ALDH1+/CGA+ and ALDH1-/CGA+) during the stepwise progression to cancer. The distributions of these populations also extended father up the crypt (outside the normal SC niche). To evaluate how NE factors might regulate SCs, we did further studies to assess how NE factors might be regulating SCs. Because we found, by flow cytometric analysis, that various CRC cell lines (COL0320, DiFi, LoVo, SW480, HCT116 & HT29) each maintains a unique proportion of SCs and NE cells over time, we surmised these proportions are maintained constant through feedback mechanisms involving SC and NEC subpopulations. When these cell lines were induced to differentiate along the NE lineage upon retinoid treatment, they showed a decrease in the proportion of ALDEFLUOR+ cells and an increase in NE cell differentiation and enhanced collagen IV production. Retinoid treatment to induce NE differentiation also decreased the sphere-forming ability in terms of the number and sizes of spheres that were formed from each cell line. 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