Microenvironment-Modulated Metastatic CD133+/CXCR4+/EpCAM- Lung Cancer-Initiating Cells Sustain Tumor Dissemination and Correlate with Poor Prognosis
Microenvironment-Modulated Metastatic CD133+/CXCR4+/EpCAM- Lung Cancer-Initiating Cells Sustain Tumor Dissemination and Correlate with Poor Prognosis
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DOI：
10.1158/0008-5472.can-14-3781
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发表时间：
2015-09-01
期刊：
影响因子：
11.2
通讯作者：
Roz, Luca
中科院分区：
文献类型：
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作者：
Bertolini, Giulia;D'Amico, Lucia;Roz, Luca
转移是肺癌相关死亡的主要原因，但对于原发肿瘤成功扩散和转移起始的具体决定因素知之甚少。在这里，我们证明直接从非小细胞肺癌患者来源的异种移植物（PDX）中分离的CD133（+）/CXCR4（+）癌症起始细胞（CIC）具有优异的在远处器官播种和启动转移的能力。我们还报告说，CXCR4 抑制成功地阻止了残留肿瘤中顺铂耐药的 CD133(+)/CXCR4(+) 细胞的增加及其转移。对静脉注射或自发播散至小鼠肺部的肺肿瘤细胞进行的免疫表型分析表明，CD133(+)/CXCR4(+)特定亚群具有生存优势和增强的定植能力，同时上皮细胞粘附分子(EpCAM(-))的表达降低，这也显示出最大的体外侵袭潜力。接下来我们证明，从携带 PDX 的小鼠肺部回收的富含 CD133(+)/CXCR4(+)/EpCAM(-) CIC 的播散细胞具有高度致瘤性和转移性。重要的是，引发上皮间质转化的微环境刺激，包括来自癌症相关成纤维细胞的信号，能够通过产生CD133(+)/CXCR4(+)/EpCAM(-)子集来增加肺癌细胞的传播潜力。这些发现在患者样本中也具有相关性，其中播散性 CIC 在转移性淋巴结中富集（20 倍，P = 0.006），并且在原发性肿瘤中检测到它们与不良临床结果相关（无病生存：P = 0.03；总生存：P = 0.05）。总的来说，这些结果强调了特定细胞亚群在转移过程中的重要性、对播散性肿瘤细胞进行深入表征的必要性，以及针对原发性肿瘤和肿瘤-微环境相互作用的治疗策略的潜力。 (C) 2015 年 AACR。
Metastasis is the main reason for lung cancer-related mortality, but little is known about specific determinants of successful dissemination from primary tumors and metastasis initiation. Here, we show that CD133(+)/CXCR4(+) cancer-initiating cells (CIC) directly isolated from patient-derived xenografts (PDX) of non-small cell lung cancer are endowed with superior ability to seed and initiate metastasis at distant organs. We additionally report that CXCR4 inhibition successfully prevents the increase of cisplatin-resistant CD133(+)/CXCR4(+) cells in residual tumors and their metastatization. Immunophenotypic analysis of lung tumor cells intravenously injected or spontaneously disseminated to murine lungs demonstrated the survival advantage and increased colonization ability of a specific subset of CD133(+)/CXCR4(+) with reduced expression of epithelial cell adhesion molecule (EpCAM(-)), which also shows the greatest in vitro invasive potential. We next prove that recovered disseminated cells from lungs of PDX-bearing mice enriched for CD133(+)/CXCR4(+)/EpCAM(-) CICs are highly tumorigenic and metastatic. Importantly, microenvironment stimuli eliciting epithelial-to-mesenchymal transition, including signals from cancer-associated fibroblasts, are able to increase the dissemination potential of lung cancer cells through the generation of the CD133(+)/CXCR4(+)/EpCAM(-) subset. These findings also have correlates in patient samples where disseminating CICs are enriched in metastatic lymph nodes (20-fold, P = 0.006) and their detection in primary tumors is correlated with poor clinical outcome (disease-free survival: P = 0.03; overall survival: P = 0.05). Overall, these results highlight the importance of specific cellular subsets in the metastatic process, the need for in-depth characterization of disseminating tumor cells, and the potential of therapeutic strategies targeting both primary tumor and tumor-microenvironment interactions. (C) 2015 AACR.