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PROGRAM | Biological Sciences

Stem Cell and Neuroendocrine Cell Phenotypes in Normal and Malignant Colonic Cells

By: Shirin Modarai Chair: Bruce Boman Co-Chair: Deni Galileo

ABSTRACT

In the development of colorectal cancer (CRC), stem cell (SC) overpopulation underlies tumor initiation and progression, but the underlying mechanisms are poorly understood. We hypothesize 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 increased “stemness” and tumor growth. 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, ALDH1+,SSTR1+ and GLP-2R+ expressing cells are located in the SC niche and are less than 5% of the total colonic crypt cells. During stepwise progression to cancer there is a progressive increase in the proportion of ALDH+ cells and small decrease in SSTR1 and GLP-2R cells. We did further studies to assess how specific 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 NE cell subpopulations. When these cell lines were induced to differentiate along the NE lineage upon retinoid treatment, they showed a decrease in the proportion of ALDH1+cells and an increase in NE cell differentiation. Retinoid treatment that induces NE differentiation also decreased the sphere-forming ability of cells in terms of the number and sizes of spheres that were formed from each cell line. Furthermore, co-cultures with ALDH1+ and SSTR1+ cells and the addition of exogenous somatostatin to ALDH+ cells resulted in a maintenance of ALDH+ population size in the HT29 cells while in the SW480 cells, the same treatment resulted in the same maintenance of ALDH+ cells, but a decrease in total cell number and cell viability. Interestingly, inhibition of SSTR signalling resulted in a decreased percentage of ALDH+ cells and total cell number. Lastly, co-cultures with ALDH1+ and GLP-2R+ cells with the addition of exogenous glucagon-like peptide 2 to ALDH+ cells resulted in a decrease in the ALDH+ population size in both cell lines and a slight increase in total cell number. Taken together, our findings support the hypothesis that: (1) specific NE factors maintain or decrease the colonic SC population size via a paracrine mechanism in the normal colon, and (2) dysregulation of these mechanisms contributes to increased “stemness” and tumor growth.

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