癌相關纖維母細胞調控肺癌幹性可塑性之研究

Cancer-associated fibroblasts regulate the plasticity for lung cancer stemness

陳菀均(Wan-Jiun Chen)

指導教授 ： 楊泮池

共同指導教授 ： 陳惠文(Huei-Wen Chen)

國立臺灣大學/醫學院/腫瘤醫學研究所/博士(2014年)

https://doi.org/10.6342/NTU.2014.00956

摘要

無論在台灣或全世界，肺癌是占癌症死亡的首位。縱使許多治療方法以及新藥的出現能夠提高肺癌病人之存活率，然而其病人的癒後仍是相當不好。近年來研究指出癌症幹細胞被認為是腫瘤在經過化學治療後具有藥物抗藥性以及具有復發成為新的腫瘤之細胞群。癌症被認為像是一個器官，其組成包含不同種類之細胞群起源自其幹細胞，此幹細胞被稱為癌症幹細胞。癌症幹細胞被認為類似幹細胞具有幹性(stemness)，意指其具有維持自我更新和分化為不同特異種類細胞之能力。此概念源自於惡性血液疾病但最近也被落實於固態腫瘤當中，其中也包括我們所研究的主題-肺癌。
癌症幹細胞被認為是治療癌症重要的標靶細胞，然而在腫瘤微環境中癌症幹細胞如何維持其幹性目前仍然不清楚。因此找出維持癌症幹細胞能力以及建立體外培養系統是極需研究之課題。本研究結果證明藉由腫瘤的微環境中的癌相關纖維母細胞(cancer-associated fibroblasts, CAFs)，透過旁泌素(paracrine)機制分泌IGF-II、HGF及SDF1作用於癌症幹細胞相對應之接受體IGF1R、Met及CXCR4可以維持癌症幹細胞特性及促進癌症幹細胞生長。有趣且其具應用價值的是藉由標靶之抗體或抑制劑阻斷旁泌素(paracrine)機制之訊息傳遞路徑可以有效抑制肺癌幹細胞之能力阻止腫瘤之生長。本研究也進一步利用臨床檢體分析發現其中癌相關纖維母細胞之IGF-II和表現於肺癌細胞之IGF1R、Nanog與病人癒後及復發有顯著之相關。本研究發現癌相關纖維母細胞為支持細胞幹性之利基(Niche)，阻斷癌症幹細胞以及癌相關纖維母細胞之旁泌素(paracrine)機制可作為臨床治療肺癌幹細胞的方法。

關鍵字

肺癌 ； 肺癌幹細胞 ； 腫瘤微環境 ； 癌相關纖維母細胞

並列摘要

Lung cancer is the leading cause of cancer death in Taiwan and worldwide. After a lot of efforts for improving the survival, the prognosis remained bad. Recently, cancer stem cells (CSCs) theory is proposed for an intrinsic resistance of tumor to chemotherapy. Cancer is regarded as an organ because of hierarchically organized heterogeneous populations of cells and possible originate from its stem cells “cancer stem cells”. CSCs can be viewed to have the ability “stemness” as stem cells with true multipotency and asymmetric division that maintain self-renewal and differentiate to specialized cell types. It is becoming increasingly clear that CSCs not only exist in hematologic malignancy but also in solid tumor including lung cancer. Cancer stem cells (CSCs) are the key target to cure cancer; however, how the CSCs subpopulation could be maintained and preserving their stemness in the tumorous microenvironment remains unknown. To establish a culture system for maintaining cancer stemness is urgently needed. Here, we demonstrated that cancer-associated fibroblasts (CAFs) can play as feeders with exhibiting significantly elevated paracrine IGF-II, HGF and SDF1 to enrich and maintain the cancer stemness and tumorigenecity of lung cancer cells synergistically through IGF1R, Met and CXCR4 that expressed in cancer cells. Interestingly and applicability, blockage of the paracrine signaling with specific antibody or inhibitors could inhibit Nanog expression, cancer stemness and tumor growth. The Cox regression analysis was performed to evaluate whether the IGF-II in CAFs; IGF1R and Nanog in cancer cells are independent prognostic factors. The Kaplan–Meier survival analysis was conducted to determine the association of the IGF-II, IGF1R and Nanog with overall survival and relapse-free survival. Our data demonstrate CAFs constitute the supporting niche for cancer stemness, and targeting this paracrine signaling may present a new therapeutic strategy for NSCLC.

並列關鍵字

lung cancer ； cancer stem cell (CSC) ； tumor microenvironment ； cancer associated fibroblasts (CAFs)

參考文獻

1. Jemal, A. et al. Global cancer statistics. CA Cancer J Clin 61, 69-90 (2011).

2. Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2013. CA Cancer J Clin 63, 11-30 (2013).

3. Herbst, R.S., Heymach, J.V. & Lippman, S.M. Lung cancer. N Engl J Med 359, 1367-1380 (2008).

4. McErlean, A. & Ginsberg, M.S. Epidemiology of lung cancer. Semin Roentgenol 46, 173-177 (2011).

5. Vineis, P. et al. Tobacco and cancer: recent epidemiological evidence. J Natl Cancer Inst 96, 99-106 (2004).