A tumor hypoxic niche protects human colon cancer stem cells from chemotherapy
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Hypoxia has been found to play an important role in regulating the biological characteristics of cancer stem cells (cCSCs). In this study, we tested whether a tumor hypoxic niche serves to the chemotherapeutic resistance of colon cCSCs.
Each of 23 fresh samples of human colon adenocarcinoma was transplanted into nude mice. The tumor-bearing mice randomly and equally received (A) saline, (B) 5-fluorouracil (15 mg/kg), (C) oxaliplatin (10 mg/kg), and (D) oxaliplatin plus 5-fluorouracil when xenografts reached 250 mm3 (n = 10). After 2-week treatment, tumor cells were quantified by flow cytometry for expression of CD133 and the hypoxic proportion of CD133+ and CD133− cells which were also sorted and detected for ki67 and pimonidazole via immunofluorescence.
The hypoxic subpopulation of CD133+ and CD133− cells was 66.5 and 26.4 %, respectively. Although there was no marked change for the hypoxic subpopulation of CD133+ cells after treatment, the hypoxic fraction of proliferative CD133+ cells was increased by 14.62, 16.45, and 20.46 % in groups B, C, and D, respectively. Furthermore, proliferative cells in CD133+ and CD133− cells were reduced by 29.93 and 62.5 % in group C, and by 25.26 and 68.22 % in group D; in group B, however, the proliferative CD133+ cells were increased by 37.09 %; the CD133− cells were unchanged.
Most CD133+ cCSCs are located in a hypoxic niche, where cCSCs are better at retaining proliferating property under chemotherapy. Oxaliplatin, rather than 5-FU, inhibits proliferation of cCSCs, which may be the mechanism underlying a better outcome by oxaliplatin in colon cancer patients.
KeywordsColon cancer stem cells CD133 Hypoxia Chemotherapeutic resistance
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