Paschall Amy V, Yang Dafeng, Lu Chunwan, Redd Priscilla S, Choi Jeong-Hyeon, Heaton Christopher M, Lee Jeffrey R, Nayak-Kapoor Asha, Liu Kebin
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
Oncotarget. 2016 Nov 29;7(48):78698-78712. doi: 10.18632/oncotarget.12168.
The chemotherapeutic agent 5-Fluorouracil (5-FU) is the most commonly used drug for patients with advanced colon cancer. However, development of resistance to 5-FU is inevitable in almost all patients. The mechanism by which colon cancer develops 5-FU resistance is still unclear. One recently proposed theory is that cancer stem-like cells underlie colon cancer 5-FU resistance, but the phenotypes of 5-FU-resistant colon cancer stem cells are still controversial. We report here that 5-FU treatment selectively enriches a subset of CD133+ colon cancer cells in vitro. 5-FU chemotherapy also increases CD133+ tumor cells in human colon cancer patients. However, sorted CD133+ colon cancer cells exhibit no increased resistance to 5-FU, and CD133 levels exhibit no correlation with colon cancer patient survival or cancer recurrence. Genome-wide analysis of gene expression between sorted CD133+ colon cancer cells and 5-FU-selected colon cancer cells identifies 207 differentially expressed genes. CD24 is one of the genes whose expression level is lower in the CD133+ and 5-FU-resistant colon cancer cells as compared to CD133+ and 5-FU-sensitive colon cancer cells. Consequently, CD133+CD24lo cells exhibit decreased sensitivity to 5-FU. Therefore, we determine that CD133+CD24lo phenotype defines 5-FU-resistant human colon cancer stem cell-like cells.
化疗药物5-氟尿嘧啶（5-FU）是晚期结肠癌患者最常用的药物。然而，几乎所有患者都会不可避免地产生对5-FU的耐药性。结肠癌产生5-FU耐药性的机制仍不清楚。最近提出的一种理论是，癌症干细胞样细胞是结肠癌5-FU耐药性的基础，但5-FU耐药性结肠癌干细胞的表型仍存在争议。我们在此报告，5-FU处理在体外可选择性地富集CD133+结肠癌细胞亚群。5-FU化疗也会增加人类结肠癌患者体内的CD133+肿瘤细胞。然而，分选得到的CD133+结肠癌细胞对5-FU的耐药性并未增加，且CD133水平与结肠癌患者的生存率或癌症复发无相关性。对分选得到的CD133+结肠癌细胞和5-FU筛选的结肠癌细胞之间的基因表达进行全基因组分析，鉴定出207个差异表达基因。CD24是其中一个基因，与CD133+和5-FU敏感的结肠癌细胞相比，其在CD133+和5-FU耐药的结肠癌细胞中的表达水平较低。因此，CD133+CD24lo细胞对5-FU的敏感性降低。所以，我们确定CD133+CD24lo表型定义了5-FU耐药的人类结肠癌干细胞样细胞。
