The neurotensin receptor-1 promotes tumor development in a sporadic but not an inflammation-associated mouse model of colon cancer
The neurotensin receptor-1 promotes tumor development in a sporadic but not an inflammation-associated mouse model of colon cancer
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DOI：
10.1002/ijc.26208
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发表时间：
2012-04-15
影响因子：
6.4
通讯作者：
Pothoulakis, Charalabos
中科院分区：
文献类型：
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作者：
Bugni, James M.;Al-Rabadi, Leina;Pothoulakis, Charalabos
神经降压素受体-1（NTR-1）在结肠癌和结肠癌细胞系中过表达。通过该受体的信号传导刺激结肠细胞衍生的细胞系的增殖，并促进结肠炎动物模型中的炎症和粘膜愈合。鉴于这种信号通路在介导结肠炎中的因果作用以及炎症在癌症发展中的重要性，我们使用NTR-1缺陷（Ntsr 1（-/-））和野生型（Ntsr 1（+/+））小鼠测试了NTR-1在炎症相关和散发性结肠癌小鼠模型中的作用。在用氧化偶氮甲烷（AOM）处理以模拟散发性癌症的小鼠中，NTR-1对肿瘤发展具有显著影响，其中Ntsr 1（+/+）小鼠比Ntsr 1（-/-）小鼠发展两倍以上的肿瘤（p = 0.04）。NTR-1对异常隐窝病灶的数量或肿瘤大小没有影响，表明NT/NTR-1信号传导促进癌前细胞向腺瘤的转化。有趣的是，NTR-1状态不影响炎症相关癌症模型中的肿瘤发展，其中小鼠用AOM治疗，然后用两个周期的5%葡聚糖硫酸钠（DSS）治疗。此外，结肠分子和组织病理学分析进行后不久，一个周期的DSS。NTR-1状态不影响结肠髓过氧化物酶活性或损伤和炎症的组织病理学评分。然而，Ntsr 1（-/-）小鼠对DSS诱导的死亡率更有抵抗力（p = 0.01），并且具有超过两倍的IL 6和Cxcl 2（已知促进肿瘤发展的细胞因子）的结肠表达水平（p < 0.04）。这些结果代表了第一次直接证明，有针对性地破坏Ntsr 1基因降低了对结肠肿瘤发生的易感性。
Neurotensin receptor-1 (NTR-1) is overexpressed in colon cancers and colon cancer cell lines. Signaling through this receptor stimulates proliferation of colonocyte-derived cell lines and promotes inflammation and mucosal healing in animal models of colitis. Given the causal role of this signaling pathway in mediating colitis and the importance of inflammation in cancer development, we tested the effects of NTR-1 in mouse models of inflammation-associated and sporadic colon cancer using NTR-1-deficient (Ntsr1(-/-)) and wild-type (Ntsr1(+/+)) mice. In mice treated with azoxymethane (AOM) to model sporadic cancer, NTR-1 had a significant effect on tumor development with Ntsr1(+/+) mice developing over twofold more tumors than Ntsr1(-/-) mice (p = 0.04). There was no effect of NTR-1 on the number of aberrant crypt foci or tumor size, suggesting that NT/NTR-1 signaling promotes the conversion of precancerous cells to adenomas. Interestingly, NTR-1 status did not affect tumor development in an inflammation-associated cancer model where mice were treated with AOM followed by two cycles of 5% dextran sulfate sodium (DSS). In addition, colonic molecular and histopathologic analyses were performed shortly after a single cycle of DSS. NTR-1 status did not affect colonic myeloperoxidase activity or histopathologic scores for damage and inflammation. However, Ntsr1(-/-) mice were more resistant to DSS-induced mortality (p = 0.01) and had over twofold higher colonic expression levels of Il6 and Cxcl2 (p < 0.04), cytokines known to promote tumor development. These results represent the first direct demonstration that targeted disruption of the Ntsr1 gene reduces susceptibility to colon tumorigenesis.