Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment
Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment
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DOI：
10.1073/pnas.0908682107
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发表时间：
2010-01-26
影响因子：
11.1
通讯作者：
Kucherlapati, Raju
中科院分区：
文献类型：
--
作者：
Hung, Kenneth E.;Maricevich, Marco A.;Kucherlapati, Raju
大多数用于结肠癌的基因工程小鼠（GEM）模型基于组织范围或生殖系基因修饰，导致肿瘤主要发生在小肠。这些模型中有几个涉及腺瘤性结肠息肉病（APC）基因的修饰，是家族性癌症易感综合征的极好模型。我们已经开发了一种散发性结肠癌的随机体细胞突变模型，该模型表现为远端结肠中的孤立原发性肿瘤，并概括了在人类结肠癌中观察到的整个腺瘤-癌-转移轴。使用该模型，我们分析了Apc基因单独突变或与另一种结肠癌相关突变基因Kras G12 D等位基因组合的肿瘤。由于局限于远端结肠，肿瘤的自然病程可以通过连续结肠镜检查进行分析。由于哺乳动物雷帕霉素靶蛋白（mTOR）通路是结肠癌中复杂信号网络的关键组成部分，因此我们使用该模型来评估通过雷帕霉素治疗已建立肿瘤的小鼠来阻断mTOR的功效。治疗后，Apc突变肿瘤比对照肿瘤小80%以上。然而，具有Apc和Kras突变的肿瘤对雷帕霉素治疗没有反应。这些研究表明，mTOR抑制剂应进一步探索作为肿瘤中没有KRAS激活突变的患者的潜在结直肠癌治疗方法。
Most genetically engineered mouse (GEM) models for colon cancer are based on tissuewide or germline gene modification, resulting in tumors predominantly of the small intestine. Several of these models involve modification of the adenomatous polyposis coli (Apc) gene and are excellent models for familial cancer predisposition syndromes. We have developed a stochastic somatic mutation model for sporadic colon cancer that presents with isolated primary tumors in the distal colon and recapitulates the entire adenoma-carcinoma-metastasis axis seen in human colon cancer. Using this model, we have analyzed tumors that are either solely mutant in the Apc gene or in combination with another colon cancer-associated mutant gene, the Kras G12D allele. Because of the restricted location in the distal colon, the natural history of the tumors can be analyzed by serial colonoscopy. As the mammalian target of rapamycin (mTOR) pathway is a critical component of the complex signaling network in colon cancer, we used this model to assess the efficacy of mTOR blockade through rapamycin treatment of mice with established tumors. After treatment, Apc mutant tumors were more than 80% smaller than control tumors. However, tumors that possessed both Apc and Kras mutations did not respond to rapamycin treatment. These studies suggest that mTOR inhibitors should be further explored as potential colorectal cancer therapies in patients whose tumors do not have activating mutations in KRAS.