2011-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/655381摘要：肺癌是台灣以及世界各國最嚴重的癌症死亡原因。表皮生長素受體(EGFR) 是ErbB 受體家族的一員。EGFR 受到活化，可促進細胞增生、抗凋亡、血管新生、侵襲及轉移。近年來EGFR 抑制劑，尤其是小分子tyrosine kinase inhibitor (TKI)對某些肺癌病人有明顯的療效。最近有研究發現EGFR kinase domain 突變與非小細胞肺癌對EGFR TKI 之敏感性有關。EGFR 突變發生於 exon 18 到 exon 21 ，好發於女性、不抽煙、東亞裔及腺癌之肺癌患者。臨床上可以利用偵測 EGFR kinase domain突變來預測肺癌病人使用EGFR TKI 之治療效果及存活期間。肺癌病人約 15%以惡性肋膜積液表現，而最終有50%之肺癌病患會產生惡性肋膜積液。肋膜積液抽取及引流是臨床上常用來診斷及治療之方法。它相當簡便且可以多次抽取，是獲取肺癌細胞的好方法。之前我们利用惡性肋膜積液研究，發現惡性肋膜積液之EGFR 突變率較開刀切除之肺癌檢體之EGFR 突變率為高(Eur Respir J 2008)。此差異之原因值得進一步研究。SDF-1 是一種chemokine，可活化CXCR4 此受體。肋膜之間皮細胞會分泌SDF-1，吸引表現CXCR4 之細胞。SDF-1/CXCR4 是肺癌細胞引起惡性肋膜積液及癌轉移之重要機轉。我们利用各別EGFR mutants andwild type 殖體轉殖之癌細胞，以in vitro invasion assay 發現 mutantEGFR 轉殖之細胞，表現大量CXCR4，而被間皮細胞condition medium及SDF-1 吸引。本計劃希望可以釐清 mutant EGFR 與CXCR4 之關係，mutantEGFR 如何調控CXCR4 之表現，具mutant EGFR 之肺癌細胞如何引起惡性肋膜積液，利用惡性肋膜積液之老鼠model 研究藥物抑制CXCR4 可否抑制mutant EGFR 造成惡性肋膜積液。並以肺癌病患之肺癌組織及惡性肋膜積液研究mutant EGFR 與CXCR4 之關聯性。<br> Abstract: Lung cancer is the leading cause of cancer mortality in most countries, includingTaiwan. Activation of EGFR stimulates cell proliferation, anti-apoptosis, angiogenesisand metastasis. Several EGFR molecular tyrosine kinase inhibitors (TKIs), such asgefitinib and erlotinib, have been developed in recent years. The clinical response ofnon-small cell lung cancer (NSCLC) to EGFR TKI therapy was dramatic in somepatients, especially in East Asian people. Studies have identified mutations of theEGFR catalytic domain that predict the response to TKIs of NSCLC. In East Asia,around 30-40% of NSCLC patients has EGFR mutations and has good response toEGFR TKIs.Pleural effusion sampling is easy, relatively non-invasive and repeatable, cancercells in the effusion will be a useful source of information on the mutation status ofEGFR. Our recent study disclosed that the patients with MPEs of lungadenocarcinoma had a higher EGFR mutation rate than the patients with surgicallyresected lung adenocarcinoma (68.4% vs. 50.5%, p=0.007) (Eur Respir J 2008).But, the mechanism of higher EGFR mutation rate in malignant pleural effusion is notclear.Stromal-derived factor-1 (SDF-1) is a chemokine of the CXC family and exerts itsactivity by interacting with CXCR4 receptor. Mesothelial cells can express a lot of SDF-1.Oonakahara et al. found an elevated SDF-1 level in malignant pleural effusions. Recentevidences suggested that SDF-1/CXCR4 axis involves in the formation of MPEs of lungcancer. Therefore, we examined the expression of CXCR4 in mutant EGFR lung cancercells. We found that, indeed, lung cancer cell line with mutant EGFR expressed moreCXCR4 and attracted by SDF-1 or condition medium of mesothelial cells then wild typelung cancer cells.Mutant EGFR lung adenocarcinoma could upregulate IL-6 and activate the stat3pathway. Furthermore, autocrine IL-6 activation of Stat3 in adenocarcinoma was involvedin the formation of malignant pleural effusion by upregulating VEGF. Our hypothesis isthat mutant EGFR lung adenocarcinomas have higher CXCR4 expression and themutant EGFR cancer cells are attracted to the pleura by the SDF-1 secreted by pleuralmesothelial cells. After pleural metastasis, the mutant EGFR lung cancer cells (throughthe high expression of CXCR4) can upregulate IL-6, then activate stat3 and increaseexpression of VEGF. The increased VEGF play a role in the production of malignantpleural effusion.From this project, we will accomplish these following aims:1. To verify that lung cancer cells with mutant EGFR have higher chemotaxis tomesothelial cells and SDF-1 through the higher expression of CXCR4.2. To disclose the pathway and mechanism that mutant EGFR regulates the CXCR4expression in lung cancer cells.3. To explore the role of the mutant EGFR lung cancer cells in the inducing of malignantpleural effusion.4. Use Animal model to study the role of mutant EGFR in formation of malignant pleuraleffusion and use CXCR4 inhibitor to inhibit the formation of malignant pleuraleffusion5. Use lung cancer specimens and clinical pleural effusion specimen to study theEGFR 突變癌轉移惡性肋膜積液肺癌EGFR mutationcancer metastasismalignant pleural effusionlung cancer