Laboratory of Pathophysiology and Signal Transduction, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Am J Pathol. 2011 Jun;178(6):2845-56. doi: 10.1016/j.ajpath.2011.02.003. Epub 2011 May 10.
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 tumorigenesis in 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 HNSCC in vivo. RANKL may provide a novel functional marker for biological malignancy and a therapeutic target based on the specific nature of the microenvironment.
最近的研究结果集中于肿瘤进展中微环境的分子后果，但肿瘤细胞自身对周围环境做出反应的过程仍不清楚。在这里，我们以头颈部鳞状细胞癌（HNSCC）为模型，鉴定核因子κB 受体激活物配体（RANKL）为体内肿瘤发生所必需的特定微环境因子。在人 HNSCC 组织中，RANKL 大量表达，其表达水平与组织学分化程度相关。RANKL 在低分化 SCC 中显著高于高分化或中分化 SCC。相比之下，所有测试的 HNSCC 细胞系均显示极低的 RANKL 表达；然而，当这些细胞系接种到小鼠的头颈部时，RANKL 会被高效地上调。RANKL 以特定于微环境的方式恢复表达，而当细胞接种到后肢时则无法观察到。强制表达 RANKL 可以补偿后肢环境中的肿瘤生长，促进上皮间质转化，并诱导肿瘤血管生成，这与血管内皮生长因子（VEGF）无关。这些结果表明，RANKL 表达在体内 HNSCC 的肿瘤生长和进展中具有因果关系。RANKL 可能为 HNSCC 的生物学恶性提供了一个新的功能标志物，以及一个基于微环境特异性的治疗靶点。
