Abstract
Colorectal cancer is the third leading cause of cancer-related death in the western world. In vitro and in vivo experiments showed that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can attenuate the proliferation of cancer cells, including colon cancer, and increase the efficacy of various anticancer drugs. However, these studies address the effects of n-3 PUFAs on the bulk of the tumor cells and not on the undifferentiated colon cancer stem-like cells (CSLCs) that are responsible for tumor formation and maintenance. CSLCs have also been linked to the acquisition of chemotherapy resistance and to tumor relapse. Colon CSLCs have been immunophenotyped using several antibodies against cellular markers including CD133, CD44, EpCAM, and ALDH. Anti-CD133 has been used to isolate a population of colon cancer cells that retains stem cells properties (CSLCs) from both established cell lines and primary cell cultures. We demonstrated that the n-3 PUFA, eicosapentaenoic acid (EPA), was actively incorporated into the membrane lipids of COLO 320 DM cells. 25 uM EPA decreased the cell number of the overall population of cancer cells, but not of the CD133 (+) CSLCs. Also, we observed that EPA induced down-regulation of CD133 expression and up-regulation of colonic epithelium differentiation markers, Cytokeratin 20 (CK20) and Mucin 2 (MUC2). Finally, we demonstrated that EPA increased the sensitivity of COLO 320 DM cells (total population) to both standard-of-care chemotherapies (5-Fluorouracil and oxaliplatin), whereas EPA increased the sensitivity of the CD133 (+) CSLCs to only 5-Fluorouracil.
Highlights
Colorectal cancer is the third leading cause of death from cancer in the western world and each year is responsible for a half million deaths worldwide [1,2]
These results showed that COLO 320 DM cells incorporated and efficiently metabolized eicosapentaenoic acid (EPA)
In this work we investigated whether pretreatment with EPA increases the chemotherapy response of standard-of-care anticancer drugs in both bulk of tumor cells and cancer stem-like cells (CSLCs) population cultured from COLO 320 DM cells
Summary
Colorectal cancer is the third leading cause of death from cancer in the western world and each year is responsible for a half million deaths worldwide [1,2]. Ricci-Vitiani [4] and O’Brian [7] were the first to provide independent proof of the existence of colon CSLCs. Ricci-Vitiani [4] and O’Brian [7] were the first to provide independent proof of the existence of colon CSLCs They isolated a CD133 (+) population of cells within the tumor that was capable of growing as undifferentiated colon-spheres in a serumfree media, which could be differentiated into the heterogeneous tumor cell population. They demonstrated that only the CD133 (+) subpopulation was tumorigenic in a serial xenograft assay in immunodeficient NOD/SCID mice. Recent evidence from clinical studies showed that CD133 expression was negatively correlated with patient prognosis in advanced colon cancer [10,11]
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