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A tumor hypoxic niche protects human colon cancer stem cells from chemotherapy

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgments

This work was supported by National Natural Science Fund of China (30870734, 81172131); “The 12th Five-year plan” for Technology Platform Construction of Innovative Drug Research and Development of China (2011ZX09302-001); The National Basic Research 550 Program of China( 2007CB947802).

Conflict of interest

We declare that we have no conflict of interest.

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Authors and Affiliations

  1. Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, 37 Guoxue Lane, Chengdu, 610041, People’s Republic of China

    Qin Mao, Yu Zhang, Xiaoyue Fu, Jianxin Xue, Wenhao Guo, Maobing Meng & You Lu

  2. Institute of Digestive Surgery, West China Hospital, Sichuan University, Chengdu, People’s Republic of China

    Zongguang Zhou

  3. Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, 37 Guoxue Lane, Chengdu, 610041, People’s Republic of China

    Xianming Mo

  4. State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China

    Qin Mao, Yu Zhang, Xiaoyue Fu, Jianxin Xue, Wenhao Guo, Maobing Meng & You Lu

  5. Guizhou People’s Hospital, Guizhou, People’s Republic of China

    Yu Zhang

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  1. Qin Mao
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  2. Yu Zhang
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Correspondence to Xianming Mo or You Lu.

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Qin Mao and Yu Zhang contributed equally to this work.

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Mao, Q., Zhang, Y., Fu, X. et al. A tumor hypoxic niche protects human colon cancer stem cells from chemotherapy. J Cancer Res Clin Oncol 139, 211–222 (2013). https://doi.org/10.1007/s00432-012-1310-3

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  • DOI: https://doi.org/10.1007/s00432-012-1310-3

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