Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition.
Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition.
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DOI：
10.1158/0008-5472.can-08-2023
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发表时间：
2009-03-01
期刊：
影响因子：
11.2
通讯作者：
Ellis LM
中科院分区：
文献类型：
--
作者：
Dallas NA;Xia L;Fan F;Gray MJ;Gaur P;van Buren G 2nd;Samuel S;Kim MP;Lim SJ;Ellis LM
5-氟尿嘧啶（5 FU）和奥沙利铂是转移性结直肠癌（CRC）的标准治疗，但耐药性的发展是不可避免的。由于癌症干细胞（CSC）被假设为耐药，我们研究了新开发的耐药CRC细胞系中的CSC特性，并试图确定治疗靶点。将人CRC细胞系HT 29暴露于增加剂量的5 FU（HT 29/5 FU-R）或奥沙利铂（HT 29/Ox）以在临床相关剂量下实现抗性。Western blotting和流式细胞术用于确定分子改变。使用胰岛素样生长因子1受体（IGF-1 R）单克隆抗体（MoAb）AVE-1642在体外和体内使用鼠异种移植模型抑制信号传导。HT 29/5 FU-R和HT 29/OxR表现出16- 30倍的CD 133+细胞富集和2倍的CD 44+细胞富集（推定的CRC CSC标志物）。耐药细胞富集5- 22倍的双阳性（CD 133 +/CD 44+）细胞。与CSC表型一致，抗性细胞表现出体外细胞增殖的降低（47-59%; p<0.05）。在耐药细胞系中，磷酸化和总IGF-1 R水平增加。在体外，相对于亲本细胞，HT 29/5 FU-R和HT 29/OxR细胞对IGF-1 R抑制的响应性高约5倍（p<0.01）。与亲本细胞相比，源自HT 29/OxR细胞的肿瘤显示出响应于IGF-1 R MoAB的显著更大的生长抑制（p<0.05）。化学抗性CRC细胞富集CSC标志物和CSC表型。化疗诱导的IGF-1 R活化提供了对IGF-1 R靶向治疗的增强的敏感性。CSC靶点的识别为这种疾病提供了一种新的治疗方法。
5-fluorouracil (5FU) and oxaliplatin are standard therapy for metastatic colorectal cancer (CRC), but the development of chemoresistance is inevitable. Since cancer stem cells (CSCs) are hypothesized to be chemoresistant, we investigated CSC properties in newly developed chemoresistant CRC cell lines and sought to identify targets for therapy. The human CRC cell line HT29 was exposed to increasing doses of 5FU (HT29/5FU-R) or oxaliplatin (HT29/Ox) to achieve resistance at clinically relevant doses. Western blotting and flow cytometry were done to determine molecular alterations. The insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibody (MoAb) AVE-1642 was used to inhibit signaling in vitro and in vivo using murine xenograft models. HT29/5FU-R and HT29/OxR demonstrated 16- to 30-fold enrichment of CD133+ cells and 2-fold enrichment of CD44+ cells (putative CRC CSC markers). Resistant cells were enriched 5- to 22-fold for double-positive (CD133+/CD44+) cells. Consistent with the CSC phenotype, resistant cells exhibited a decrease in cellular proliferation in vitro (47–59%; p<0.05). Phosphorylated and total IGF-1R levels were increased in resistant cell lines. HT29/5FU-R and HT29/OxR cells were ~5-fold more responsive to IGF-1R inhibition relative to parental cells (p<0.01) in vitro. Tumors derived from HT29/OxR cells demonstrated significantly greater growth inhibition in response to an IGF-1R MoAB than did parental cells (p<0.05). Chemoresistant CRC cells are enriched for CSC markers and the CSC phenotype. Chemotherapy-induced IGF-1R activation provided for enhanced sensitivity to IGF-1R targeted therapy. Identification of CSC targets presents a novel therapeutic approach in this disease.