Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, Malmo¨, Sweden.
Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Center, Skåne University Hospital, Malmo¨, Sweden.
Cancer Lett. 2018 Nov 28;437:13-24. doi: 10.1016/j.canlet.2018.08.019. Epub 2018 Aug 23.
Inflammation is implicated in the etiology of sporadic colon cancer (CC), which is one of the leading causes of cancer-related deaths worldwide. Here, we report that inhibition of the inflammatory receptor CysLT through its antagonist, montelukast, is beneficial in minimizing stemness in CC and thereby minimizing tumor growth in a mouse xenograft model of human colon cancer. Upon treatment with montelukast, colonospheres derived from HT-29 and SW-480 human colon cancer cells exhibited a significant phenotypic change coupled with the downregulation of mRNA and protein expression of cancer stem cell (CSC) markers ALDH1 and DCLK1. Moreover, montelukast reduced the size of HT-29 cell-derived tumors in mice. The reduction in tumor size was associated with decreased levels of ALDH1A1, DCLK1, BCL2 mRNA and macrophage infiltration into the tumor tissue. Interestingly, this treatment elevated levels of the tumor suppressor 15-PGDH while reducing COX-2 expression. Our data highlight the association of CysLTR with CSCs and demonstrate that inhibition of CysLTR could prove beneficial in minimizing CSC-induced tumor growth. This work advances the notion that targeting CSCs is a promising approach to improve outcomes in those afflicted with colon cancer.
炎症与散发性结肠癌（CC）的病因有关，CC 是全球癌症相关死亡的主要原因之一。在这里，我们报告称，通过其拮抗剂孟鲁司特抑制炎症受体 CysLT 有利于最大限度地减少 CC 中的干性，从而最大限度地减少人结肠癌小鼠异种移植模型中的肿瘤生长。在用孟鲁司特治疗后，源自 HT-29 和 SW-480 人结肠癌细胞的结肠球体表现出显著的表型变化，并伴随着癌症干细胞（CSC）标志物 ALDH1 和 DCLK1 的 mRNA 和蛋白表达下调。此外，孟鲁司特减少了小鼠中 HT-29 细胞来源肿瘤的大小。肿瘤大小的减少与 ALDH1A1、DCLK1、BCL2 mRNA 水平降低以及巨噬细胞浸润肿瘤组织有关。有趣的是，这种治疗方法提高了肿瘤抑制因子 15-PGDH 的水平，同时降低了 COX-2 的表达。我们的数据强调了 CysLTR 与 CSCs 的关联，并表明抑制 CysLTR 可能有助于最大限度地减少 CSC 诱导的肿瘤生长。这项工作提出了靶向 CSCs 是改善结肠癌患者预后的一种有前途的方法的观点。
