Akt-Girdin Signaling in Cancer-Associated Fibroblasts Contributes to Tumor Progression
Akt-Girdin Signaling in Cancer-Associated Fibroblasts Contributes to Tumor Progression
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DOI：
10.1158/0008-5472.can-14-1317
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发表时间：
2015-03-01
期刊：
影响因子：
11.2
通讯作者：
Takahashi, Masahide
中科院分区：
文献类型：
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作者：
Yamamura, Yumiko;Asai, Naoya;Takahashi, Masahide
PI3K-Akt信号传导对于恶性肿瘤的发生、进展和转移至关重要，但其在肿瘤微环境中的作用研究相对较少。在此，我们报道 Akt 底物 Girdin（一种调节细胞迁移的肌动蛋白结合蛋白）在肿瘤微环境中的癌症相关成纤维细胞 (CAF) 和血管中通过 Akt 磷酸化表达和激活。与野生型 (WT) 宿主对照动物相比，Lewis 肺肿瘤移植到 Akt 介导的 Girdin 磷酸化缺陷的小鼠（SA 转基因小鼠）中，表现出 CAF 浸润和肿瘤生长的减少。与其他研究结果相比，我们发现 Girdin 的 Akt 依赖性磷酸化并不是内皮细胞生长的限速步骤。此外，与来自荷瘤WT小鼠的CAF相比，当与来自荷瘤SA转基因小鼠的CAF共移植时，Lewis肺肿瘤表现出有限的生长。总的来说，我们的结果揭示了在肿瘤进展过程中 CAF 中 Akt 介导的 Girdin 磷酸化的作用，强调需要抑制肿瘤细胞和构成肿瘤微环境的细胞中的 Akt 功能。 (C)2015 AACR。
PI3K-Akt signaling is critical for the development, progression, and metastasis of malignant tumors, but its role in the tumor microenvironment has been relatively little studied. Here, we report that the Akt substrate Girdin, an actin-binding protein that regulates cell migration, is expressed and activated by Akt phosphorylation in cancer-associated fibroblasts (CAF) and blood vessels within the tumor microenvironment. Lewis lung tumors grafted into mice defective in Akt-mediated Girdin phosphorylation (SA transgenic mice) exhibited a decrease in both CAF infiltration and tumor growth, compared with wild-type (WT) host control animals. Contrasting with the findings of other studies, we found that Akt-dependent phosphorylation of Girdin was not a rate-limiting step in the growth of endothelial cells. In addition, Lewis lung tumors displayed limited outgrowth when cotransplanted with CAF derived from tumor-bearing SA transgenic mice, compared with CAF derived from tumor-bearing WT mice. Collectively, our results revealed a role for Akt-mediated Girdin phosphorylation in CAF during tumor progression, highlighting the need to inhibit Akt function in both tumor cells and cells that comprise the tumor microenvironment. (C)2015 AACR.