Intratumoral estrogens and estrogen receptors in human non-small cell lung carcinoma
Intratumoral estrogens and estrogen receptors in human non-small cell lung carcinoma
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DOI：
10.1158/1078-0432.ccr-07-1950
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发表时间：
2008-07-15
影响因子：
11.5
通讯作者：
Sasano, Hironobu
中科院分区：
文献类型：
--
作者：
Niikawa, Hiromichi;Suzuki, Takashi;Sasano, Hironobu
目的：在人类非小细胞肺癌（NSCLC）中可能存在性别依赖性因素，但其确切作用仍不清楚。因此，我们检测了NSCLC肿瘤内雌二醇浓度，以研究雌激素在NSCLC中的局部作用。实验设计：59例NSCLC冷冻标本可用于液相色谱/电喷雾串联质谱法研究瘤内雌二醇浓度。此外，稳定表达雌激素受体（ER）α的A549 NSCLC细胞（A549 + ER α）或ER β（A549 + ER）用于体外研究。在59例NSCLC患者中，43例（73%）癌组织中雌二醇浓度高于相应的非肿瘤肺组织，肿瘤内雌二醇浓度显著高于相应的非肿瘤性肺（P = 0.0002和2.2倍）。在ER α或ER β阳性病例中，雌二醇的瘤内浓度与芳香化酶表达、肿瘤大小和Ki-67状态呈正相关。在体外研究中，雌二醇显著增加了A549 + ER α或A549 + ER β的细胞增殖，而选择性ER调节剂他莫昔芬或雷洛昔芬显著抑制了这一增殖。A549 + EF α和A549 + ER β细胞均表达芳香化酶。在这些细胞中的细胞增殖水平显着增加睾酮治疗下，它被抑制，除了芳香化酶抑制剂来曲唑。结论：这些结果表明，雌二醇是本地产生的NSCLC主要由芳香化酶和ER α或ER β阳性NSCLC的生长中起着重要的作用。因此，使用选择性ER调节剂和/或芳香酶抑制剂可能在ER和芳香酶均阳性的NSCLC中具有临床有效性。
Purpose: The possible involvement of gender-dependent factors has been suggested in human non-small cell lung carcinomas (NSCLC), but their precise roles remain largely unclear. Therefore, we examined intratumoral estradiol concentrations in NSCLC to examine local actions of estrogens in NSCLC.Experimental Design: Fifty-nine frozen specimens of NSCLC were available for liquid chromatography/electrospray tandem mass spectrometry to study intratumoral estradiol concentrations, In addition, A549 NSCLC cells stably expressing estrogen receptor (ER) alpha (A549 + ER alpha) or ER beta (A549 + ER) were used in vitro studies.Results: Forty-three (73%) of 59 NSCLC showed higher concentration of estradiol in carcinoma tissues than the corresponding nonneoplastic lung tissues from the same patient, and intratumoral estradiol concentrations were significantly (P = 0.0002 and 2.2-fold) higher than the corresponding nonneoplastic lungs. The intratumoral concentration of estradiol was positively correlated with aromatase expression, tumor size, and Ki-67 status in ER alpha- or ER beta-positive cases. In in vitro studies, estradiol significantly increased cell proliferation of A549 + ER alpha or A549 + ER beta, which was significantly suppressed by selective ER modulators, tamoxifen or raloxifene. Both A549 + EF alpha and A549 + ER beta cells expressed aromatase. The cell proliferation level in these cells was significantly increased under treatment with testosterone, and it was inhibited by addition of the aromatase inhibitor letrozole.Conclusions: These results suggest that estradiol is locally produced in NSCLC mainly by aromatase and plays an important role in the growth of ER alpha- or ER beta-positive NSCLC. Therefore use of selective ER modulators and/or aromatase inhibitors may be clinically effective in NSCLC that are positive for both ER and aromatase.