Intratumoral Localization of Aromatase and Interaction between Stromal and Parenchymal Cells in the Non-Small Cell Lung Carcinoma Microenvironment
Intratumoral Localization of Aromatase and Interaction between Stromal and Parenchymal Cells in the Non-Small Cell Lung Carcinoma Microenvironment
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DOI：
10.1158/0008-5472.can-09-4653
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发表时间：
2010-08-15
期刊：
影响因子：
11.2
通讯作者：
Sasano, Hironobu
中科院分区：
文献类型：
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作者：
Miki, Yasuhiro;Suzuki, Takashi;Sasano, Hironobu
近年来，由于瘤内芳构化产生的雌激素在人类非小细胞肺癌(NSCLC)的增殖中起着重要作用，但其细节仍不清楚。因此，在这项研究中，我们评估了芳香酶在非小细胞肺癌中的可能作用如下：(A)使用激光捕获显微切割结合定量逆转录-聚合酶链式反应和免疫组织化学方法，评估六例肺腺癌病例中芳香化酶mRNA/蛋白的瘤内定位；(B)通过共培养系统检测从肺癌组织分离的间质细胞对肺癌细胞株(A549和LK87)芳香酶mRNA转录表达的可能影响；以及(C)使用细胞因子抗体阵列筛选来自间质细胞LK001S和LK002S的细胞因子，并随后评估这些细胞因子对A549和LK87芳香化酶表达的影响。芳香酶的mRNA和蛋白主要在瘤内癌细胞中表达，而在间质细胞中不表达。LK001S或LK002S细胞可上调A549和LK87芳香酶的表达。在LK001S和LK002S细胞的条件培养液中检测到多种细胞因子，如白介素6(IL-6)、抑瘤素M和肿瘤坏死因子-α，它们都是芳香酶基因的诱导因子。抑瘤素M和IL-6分别诱导A549和LK87芳香酶基因表达。这些结果都表明，肿瘤内微环境，特别是癌细胞与间质细胞的相互作用，通过芳香化酶的表达，在调节肿瘤内雌激素合成方面起着关键作用。癌症资源；70(16)；6659-69。(C)2010年AACR。
Estrogens produced as a result of intratumoral aromatization has been recently shown to play important roles in proliferation of human non-small cell lung carcinomas (NSCLC), but the details have remained largely unknown. Therefore, in this study, we evaluated the possible roles of intratumoral aromatase in NSCLCs as follows: (a) evaluation of intratumoral localization of aromatase mRNA/protein in six lung adenocarcinoma cases using laser capture microdissection combined with quantitative reverse transcriptase-PCR and immunohistochemistry; (b) examination of the possible effects of isolated stromal cells from lung carcinoma tissues on aromatase mRNA transcript expression in lung carcinoma cell lines (A549 and LK87) through a coculture system; and (c) screening of cytokines derived from stromal LK001S and LK002S cells using cytokine antibody arrays and subsequent evaluation of effects of these cytokines on aromatase expression in A549 and LK87. Both aromatase mRNA and protein were mainly detected in intratumoral carcinoma cells but not in stromal cells. Aromatase expression of A549 and LK87 was upregulated in the presence of LK001S or LK002S cells. Several cytokines such as interleukin-6 (IL-6), oncostatin M, and tumor necrosis factor-alpha, all known as inducible factors of aromatase gene, were detected in conditioned media of LK001S and LK002S cells. Treatment of both oncostatin M and IL-6 induced aromatase gene expression in A549 an LK87, respectively. These results all indicated that intratumoral microenvironments, especially carcinoma-stromal cell interactions, play a pivotal role in the regulation of intratumoral estrogen synthesis through aromatase expression in human lung adenocarcinomas. Cancer Res; 70(16); 6659-69. (C) 2010 AACR.