RANKL expression specifically observed in vivo promotes epithelial mesenchymal transition and tumor progression.
RANKL expression specifically observed in vivo promotes epithelial mesenchymal transition and tumor progression.
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DOI：
10.1016/j.ajpath.2011.02.003
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发表时间：
2011-06
期刊：
影响因子：
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通讯作者：
Tamaki Yamada;M. Tsuda;Tomomi Takahashi;Y. Totsuka;M. Shindoh;Y. Ohba
中科院分区：
文献类型：
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作者：
Tamaki Yamada;M. Tsuda;Tomomi Takahashi;Y. Totsuka;M. Shindoh;Y. Ohba
最近的发现将注意力集中在微环境在肿瘤进展中的分子后果上，但癌细胞本身对环境条件的反应事件仍然不清楚。在这里，我们以头颈部鳞状细胞癌为模型，确定核因子受体激活剂κB配体(RANKL)是体内肿瘤发生所必需的微环境特异性因子。在人类HNSCC组织中，RANKL大量表达，其表达水平与组织分化程度有关。RANKL在低分化鳞癌中的表达水平显著高于高分化和中分化鳞癌。相反，所有被测试的HNSCC细胞系都显示出极低的RANKL表达；然而，当这些细胞系被接种到小鼠头颈部时，RANKL的表达有效地上调。RANKL的表达以微环境特有的方式恢复，当细胞接种到后肢时，无法观察到RANKL的表达。RANKL的强制表达以一种不依赖血管内皮生长因子的方式补偿后肢环境中的肿瘤生长，促进上皮间充质转化，并诱导肿瘤血管生成。这些结果提示RANKL在HNSCC体内的表达与肿瘤的生长和发展有关。RANKL可能为生物恶性肿瘤提供一种新的功能标记物和基于微环境的特殊性质的治疗靶点。
Recent findings have focused attention on the molecular consequences of the microenvironment in tumor progression, but events occurring in cancer cells themselves in response to their ambient conditions remain obscure. Here, we identify receptor activator of nuclear factor κB ligand (RANKL) as a microenvironment-specific factor essential for tumorigenesisin vivo, using head and neck squamous cell carcinoma (HNSCC) as a model. In human HNSCC tissues, RANKL is abundantly expressed, and its expression level correlates with the histological grade of differentiation. RANKL levels are significantly higher in poorly differentiated SCCs than in well or moderately differentiated SCCs. In contrast, all HNSCC cell lines tested displayed extremely low RANKL expression; however, RANKL is efficiently up-regulated when these cell lines are inoculated in the head and neck region of mice. RANKL expression is restored in a microenvironment-specific manner, and cannot be observed when the cells are inoculated in the hindlimbs. Forced expression of RANKL compensates for tumor growth in the hindlimb milieu, promotes epithelial mesenchymal transition, and induces tumor angiogenesis, in a manner independent of vascular endothelial growth factor (VEGF). These results implicate RANKL expression causatively in tumor growth and progression in HNSCCin vivo. RANKL may provide a novel functional marker for biological malignancy and a therapeutic target based on the specific nature of the microenvironment.