Proliferation State and Polo-Like Kinase1 Dependence of Tumorigenic Colon Cancer Cells
Proliferation State and Polo-Like Kinase1 Dependence of Tumorigenic Colon Cancer Cells
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DOI：
10.1002/stem.1163
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发表时间：
2012-09-01
期刊：
影响因子：
5.2
通讯作者：
Zeuner, Ann
中科院分区：
文献类型：
--
作者：
Francescangeli, Federica;Patrizii, Michele;Zeuner, Ann
肿瘤起始细胞负责实体癌和血液癌中的肿瘤维持和复发。虽然最初认为肿瘤起始细胞主要是静止的，但在乳腺癌中发现了快速增殖的致瘤细胞。在结肠癌中，致瘤群体的增殖活性尚未确定，尽管它代表了开发更有效的治疗策略的重要参数。在这里，我们表明，致瘤性结肠癌细胞可以发现在一个快速增殖的状态在体外和体内，无论是在人类肿瘤和小鼠异种移植。Polo样激酶1（Plk 1）是一种细胞增殖所必需的有丝分裂激酶，其抑制剂在体外诱导结肠癌起始细胞死亡方面表现出比其他靶向化合物和化疗药物更高的效率。在体内，Plk 1抑制剂杀死CD 133（+）结肠癌细胞，导致结肠癌干细胞衍生的异种移植物完全生长停滞，而化疗药物仅减缓肿瘤进展。虽然化疗治疗增加了CD 133（+）细胞增殖，但Plk 1抑制剂治疗消除了所有增殖的肿瘤起始细胞。在Plk 1抑制剂处理后存活的静止CD 133（+）细胞在从静止状态退出时可被随后的Plk 1抑制杀死。总之，这些结果提供了一个新的见解，无论是在基础条件下，并在治疗反应的结肠肿瘤起始细胞的增殖状态，并表明Plk 1抑制剂作为潜在的有用的治疗结直肠癌。干细胞2012;30：1819-1830
Tumor-initiating cells are responsible for tumor maintenance and relapse in solid and hematologic cancers. Although tumor-initiating cells were initially believed to be mainly quiescent, rapidly proliferating tumorigenic cells were found in breast cancer. In colon cancer, the proliferative activity of the tumorigenic population has not been defined, although it represents an essential parameter for the development of more effective therapeutic strategies. Here, we show that tumorigenic colon cancer cells can be found in a rapidly proliferating state in vitro and in vivo, both in human tumors and mouse xenografts. Inhibitors of polo-like kinase1 (Plk1), a mitotic kinase essential for cell proliferation, demonstrated maximal efficiency over other targeted compounds and chemotherapeutic agents in inducing death of colon cancer-initiating cells in vitro. In vivo, Plk1 inhibitors killed CD133(+) colon cancer cells leading to complete growth arrest of colon cancer stem cell-derived xenografts, whereas chemotherapeutic agents only slowed tumor progression. While chemotherapy treatment increased CD133(+) cell proliferation, treatment with Plk1 inhibitors eliminated all proliferating tumor-initiating cells. Quiescent CD133(+) cells that survived the treatment with Plk1 inhibitors could be killed by subsequent Plk1 inhibition when they exited from quiescence. Altogether, these results provide a new insight into the proliferative status of colon tumor-initiating cells both in basal conditions and in response to therapy and indicate Plk1 inhibitors as potentially useful in the treatment of colorectal cancer. STEM CELLS 2012;30:1819-1830