Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
Cancer Res. 2011 Feb 1;71(3):758-67. doi: 10.1158/0008-5472.CAN-10-2756. Epub 2010 Dec 15.
A large body of evidence has shown that stromal cells play a significant role in determining the fate of neighboring tumor cells through the secretion of various cytokines. How cytokine secretion by stromal cells is regulated in this context is poorly understood. In this study, we used a bioengineered human tissue model of skin squamous cell carcinoma progression to reveal that RalA function in dermal fibroblasts is required for tumor progression of neighboring neoplastic keratinocytes. This conclusion is based on the observations that suppression of RalA expression in dermal fibroblasts blocked tumorigenic keratinocytes from invading into the dermal compartment of engineered tissues and suppressed more advanced tumor progression after these tissues were transplanted onto the dorsum of mice. RalA executes this tumor-promoting function of dermal fibroblasts, at least in part, by mediating hepatocyte growth factor (HGF) secretion through its effector proteins, the Sec5 and Exo84 subunits of the exocyst complex. These findings reveal a new level of HGF regulation and highlight the RalA signaling cascade in dermal fibroblasts as a potential anticancer target.
大量证据表明，基质细胞通过分泌各种细胞因子在决定邻近肿瘤细胞的命运方面发挥着重要作用。在这种情况下，基质细胞中细胞因子分泌是如何调节的还知之甚少。在这项研究中，我们使用了一种经过生物工程改造的人类皮肤鳞状细胞癌进展模型，揭示了真皮成纤维细胞中的 RalA 功能对于邻近肿瘤性角质形成细胞的肿瘤进展是必需的。这一结论基于以下观察结果：抑制真皮成纤维细胞中的 RalA 表达可阻止致瘤性角质形成细胞侵入工程组织的真皮区，并在这些组织移植到小鼠背部后抑制更晚期的肿瘤进展。RalA 通过其效应蛋白 Sec5 和外泌体复合物的 Exo84 亚基来介导肝细胞生长因子 (HGF) 的分泌，从而执行真皮成纤维细胞的这种促进肿瘤的功能。这些发现揭示了 HGF 调节的新水平，并强调了真皮成纤维细胞中的 RalA 信号级联作为一种潜在的抗癌靶点。
