A tumor hypoxic niche protects human colon cancer stem cells from chemotherapy
A tumor hypoxic niche protects human colon cancer stem cells from chemotherapy
复制标题
肿瘤缺氧生态位保护人类结肠癌干细胞免受化疗
DOI：
10.1007/s00432-012-1310-3
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发表时间：
2013-02-01
影响因子：
3.6
通讯作者：
Lu, You
中科院分区：
文献类型：
--
作者：
Mao, Qin;Zhang, Yu;Lu, You
已发现低氧在调节肿瘤干细胞的生物学特性中起着重要作用。在这项研究中，我们测试了肿瘤低氧生态位是否有助于结肠癌的化疗耐药。23例新鲜的人结肠腺癌标本被移植到裸鼠体内。荷瘤小鼠在移植瘤达到250 mm(3)(n=10)时，随机平均接受(A)生理盐水、(B)5-氟尿嘧啶(15 mg/kg)、(C)奥沙利铂(10 mg/kg)和(D)奥沙利铂+5-氟尿嘧啶(n=10)。治疗2周后，流式细胞仪检测肿瘤细胞CD133的表达，免疫荧光法检测CD133(+)和CD133(-)细胞的缺氧率，CD133(+)和CD133(-)细胞的缺氧率分别为66.5%和26.4%。治疗后CD133(+)细胞缺氧亚群无明显变化，但增殖期CD133(+)细胞缺氧百分率B、C、D组分别增加14.62、16.45、20.46%。C组CD133(+)和CD133(-)细胞增殖细胞分别减少29.93%和62.5%，D组分别减少25.26%和68.22%，而B组CD133(+)细胞增加37.09%，CD133(-)细胞无变化。奥沙利铂而不是5-FU抑制肿瘤干细胞的增殖，这可能是奥沙利铂改善结肠癌患者预后的机制。
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 mm(3) (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.