Telang Nitin
Cancer Prevention Research Program, Palindrome Liaisons Consultants, Montvale, NJ 07645-1559, USA.
Oncol Lett. 2018 Jan;15(1):642-648. doi: 10.3892/ol.2017.7147. Epub 2017 Oct 6.
Mutations in the adenomatous polyposis coli (Apc) tumor suppressor gene represent the primary genetic defect in colon carcinogenesis. Apc mouse models exhibit pre-invasive small intestinal adenomas. Cell culture models exhibiting Apc defects in the colon and quantifiable cancer risk provide a novel clinically relevant approach. The tumor-derived Apc colonic epithelial cell line 1638N COL-Pr represented the experimental model. The anti-inflammatory drugs sulindac (SUL) and celecoxib (CLX) represented the test compounds. Compared with non-tumorigenic Apc C57COL cells, the Apc 1638N COL cells and Apc 1638N COL-Pr cells exhibited progressive loss of homeostatic growth control. Compared with Apc cells, Apc cells displayed increased expression of biomarkers specific for hyper-proliferation. Treatment of Apc cells with SUL and CLX resulted in inhibition of anchorage-independent colony formation , which is indicative of reduced cancer risk . Mechanistically, SUL and CLX suppressed the expression of the Apc target genes β-catenin, cyclin D1, c-Myc and cyclooxygenase-2. Long-term treatment with high concentrations of SUL and CLX led to the selection of hyper-proliferative drug-resistant phenotypes. The Apc SUL-resistant phenotype displayed spheroid formation and enhanced the expression of the stem cell-specific molecular markers CD44, CD133 and c-Myc. These data demonstrated the growth-inhibitory efficacy of SUL and CLX and indicated that drug resistance leads to the selection of a putative cancer stem cell phenotype. The study outcome validates a stem cell-targeted mechanistic approach to identify testable alternative leads for chemotherapy-resistant colon cancer.
腺瘤性息肉病大肠杆菌（Apc）肿瘤抑制基因的突变是结肠癌发生的主要遗传缺陷。Apc小鼠模型表现出侵袭前的小肠腺瘤。在结肠中表现出Apc缺陷且具有可量化癌症风险的细胞培养模型提供了一种新的临床相关方法。肿瘤来源的Apc结肠上皮细胞系1638N COL-Pr代表实验模型。抗炎药物舒林酸（SUL）和塞来昔布（CLX）代表测试化合物。与非致瘤性Apc C57COL细胞相比，Apc 1638N COL细胞和Apc 1638N COL-Pr细胞表现出稳态生长控制的逐渐丧失。与Apc细胞相比，Apc细胞中与过度增殖相关的生物标志物表达增加。用SUL和CLX处理Apc细胞导致非锚定依赖性集落形成受到抑制，这表明癌症风险降低。从机制上讲，SUL和CLX抑制了Apc靶基因β-连环蛋白、细胞周期蛋白D1、c-Myc和环氧化酶-2的表达。长期用高浓度的SUL和CLX处理导致选择了过度增殖的耐药表型。Apc SUL耐药表型表现出球体形成并增强了干细胞特异性分子标志物CD44、CD133和c-Myc的表达。这些数据证明了SUL和CLX的生长抑制功效，并表明耐药性导致选择了一种假定的癌症干细胞表型。该研究结果验证了一种针对干细胞的机制方法，以识别对化疗耐药的结肠癌的可测试替代线索。
