In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line.
In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line.
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DOI：
10.1111/cas.12600
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发表时间：
2015-03
期刊：
影响因子：
5.7
通讯作者：
Yano S
中科院分区：
文献类型：
--
作者：
Nanjo S;Nakagawa T;Takeuchi S;Kita K;Fukuda K;Nakada M;Uehara H;Nishihara H;Hara E;Uramoto H;Tanaka F;Yano S
EML4-ALK肺癌约占非小细胞肺癌病例的3-7%。研究EML4-ALK肺癌肿瘤进展及靶向药敏/耐药的分子机制，临床相关的动物模型必不可少。本研究发现肺腺癌细胞系A925L表达EML4-ALK基因融合（变体5a， E2:A20），对ALK抑制剂克唑替尼和阿勒替尼敏感。我们进一步建立了高度致瘤性的A925LPE3细胞，该细胞也具有EML4-ALK基因融合（变体5a），并且对ALK抑制剂敏感。通过转染荧光素酶基因的A925LPE3细胞，我们建立了晚期EML4-ALK肺癌重要临床关注的胸膜癌、骨转移和脑转移的体内成像模型。有趣的是，克唑替尼在胸膜癌模型中引起肿瘤缩小，但在骨和脑转移模型中没有引起肿瘤缩小，而阿勒替尼在所有三种模型中都表现出显著的疗效，表明这些ALK抑制剂的临床疗效。我们的多器官部位体内成像模型可为进一步分析EML4-ALK肺癌的发病机制及其在不同器官微环境下对ALK抑制剂的反应和耐药提供有用的资源。
EML4-ALK lung cancer accounts for approximately 3–7% of non-small-cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.
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影响因子：
8.8
作者：
Tanizaki, J.;Okamoto, I.;Takezawa, K.;Sakai, K.;Azuma, K.;Kuwata, K.;Yamaguchi, H.;Hatashita, E.;Nishio, K.;Janne, P. A.;Nakagawa, K.
通讯作者：
Nakagawa, K.
影响因子：
2.2
作者：
GREEN, LM;READE, JL;WARE, CF
通讯作者：
WARE, CF
DOI：
10.1093/jnci/95.6.458
发表时间：
2003-03-19
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Uehara, H;Kim, SJ;Fidler, IJ
通讯作者：
Fidler, IJ
影响因子：
20.4
作者：
Gainor, Justin F.;Ou, Sai-Hong Ignatius;Shaw, Alice T.
通讯作者：
Shaw, Alice T.
影响因子：
51.1
作者：
Gadgeel, Shirish M.;Gandhi, Leena;Ou, Sai-Hong Ignatius
通讯作者：
Ou, Sai-Hong Ignatius