Self-renewal as a therapeutic target in human colorectal cancer
Self-renewal as a therapeutic target in human colorectal cancer
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DOI：
10.1038/nm.3418
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发表时间：
2014-01-01
期刊：
影响因子：
82.9
通讯作者：
O'Brien, Catherine A.
中科院分区：
文献类型：
--
作者：
Kreso, Antonija;van Galen, Peter;O'Brien, Catherine A.
治疗后的肿瘤复发仍然是一个主要的临床挑战。来自异种移植模型和人体试验的证据表明，在治疗后存活的肿瘤中选择性富集癌症起始细胞（CIC）。结合最近的报告显示CIC基因特征影响患者生存，这些研究预测，靶向自我更新，CIC独特的关键“干性”特性，可能代表癌症治疗的新范式。在这里，我们证明了肿瘤的形成，更具体地说，人类结直肠CIC功能依赖于典型的自我更新调节剂BMI-1。BMI-1的下调抑制结直肠CIC自我更新的能力，导致其致瘤潜力的消除。用小分子BMI-1抑制剂治疗原发性结直肠癌异种移植物导致结直肠CIC丧失，并对肿瘤生长造成长期和不可逆的损害。靶向BMI-1相关的自我更新机制为治疗结直肠癌的新治疗方法提供了基础。
Tumor recurrence following treatment remains a major clinical challenge. Evidence from xenograft models and human trials indicates selective enrichment of cancer-initiating cells (CICs) in tumors that survive therapy. Together with recent reports showing that CIC gene signatures influence patient survival, these studies predict that targeting self-renewal, the key 'stemness' property unique to CICs, may represent a new paradigm in cancer therapy. Here we demonstrate that tumor formation and, more specifically, human colorectal CIC function are dependent on the canonical self-renewal regulator BMI-1. Downregulation of BMI-1 inhibits the ability of colorectal CICs to self-renew, resulting in the abrogation of their tumorigenic potential. Treatment of primary colorectal cancer xenografts with a small-molecule BMI-1 inhibitor resulted in colorectal CIC loss with long-term and irreversible impairment of tumor growth. Targeting the BMI-1-related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer.