K-ras activation generates an inflammatory response in lung tumors
K-ras activation generates an inflammatory response in lung tumors
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DOI：
10.1038/sj.onc.1209237
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发表时间：
2006-03-01
期刊：
影响因子：
8
通讯作者：
Wong, KK
中科院分区：
文献类型：
--
作者：
Ji, H;Houghton, AM;Wong, KK
K-ras的激活突变是人类肺癌中最常见的遗传改变之一。为了分析K-ras在支气管上皮细胞中的激活在肺肿瘤发生中的作用，我们通过产生具有Clara细胞分泌蛋白（CC 10）-Cre重组酶和Lox-Stop-Lox K-ras（G12 D）等位基因的条件突变小鼠来建立肺腺癌模型。在CC 10阳性细胞中，K-ras突变等位基因的激活导致以细胞性腺瘤、腺瘤和最终腺癌为特征的进行性表型。令人惊讶的是，K-ras在细支气管上皮细胞中的活化与以肺泡巨噬细胞和中性粒细胞的大量浸润为特征的强烈炎症反应相关。这些小鼠在这种肺部炎症反应的情况下显示出早期死亡率，中位生存期为8周。来自这些突变小鼠的支气管肺泡灌洗液含有MIP-2、KC、MCP-1和LIX趋化因子，这些趋化因子随年龄显著增加。来源于这些肿瘤的细胞系直接产生MIP-2、LIX和KC。该模型表明，肺中的K-ras激活诱导炎症趋化因子的产生，并为进一步研究炎症细胞、趋化因子和肿瘤进展之间的复杂相互作用提供了极好的手段。
Activating mutations in K-ras are one of the most common genetic alterations in human lung cancer. To dissect the role of K-ras activation in bronchial epithelial cells during lung tumorigenesis, we created a model of lung adenocarcinoma by generating a conditional mutant mouse with both Clara cell secretory protein (CC10)-Cre recombinase and the Lox-Stop-Lox K-ras(G12D) alleles. The activation of K-ras mutant allele in CC10 positive cells resulted in a progressive phenotype characterized by cellular atypia, adenoma and ultimately adenocarcinoma. Surprisingly, K-ras activation in the bronchiolar epithelium is associated with a robust inflammatory response characterized by an abundant infiltration of alveolar macrophages and neutrophils. These mice displayed early mortality in the setting of this pulmonary inflammatory response with a median survival of 8 weeks. Bronchoalveolar lavage fluid from these mutant mice contained the MIP-2, KC, MCP-1 and LIX chemokines that increased significantly with age. Cell lines derived from these tumors directly produced MIP-2, LIX and KC. This model demonstrates that K-ras activation in the lung induces the elaboration of inflammatory chemokines and provides an excellent means to further study the complex interactions between inflammatory cells, chemokines and tumor progression.