Department of Pathology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan. Department of Cardiology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Department of Pathology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Cancer Res. 2015 Mar 1;75(5):813-23. doi: 10.1158/0008-5472.CAN-14-1317.
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.
PI3K-Akt 信号通路对于恶性肿瘤的发生、发展和转移至关重要，但它在肿瘤微环境中的作用相对较少被研究。在这里，我们报告 Akt 的底物 Girdin，一种调节细胞迁移的肌动蛋白结合蛋白，在肿瘤微环境中的肿瘤相关成纤维细胞 (CAF) 和血管中通过 Akt 磷酸化而表达和激活。与野生型（WT）宿主对照动物相比，植入 Akt 介导的 Girdin 磷酸化缺陷（SA 转基因）小鼠中的 Lewis 肺癌肿瘤显示 CAF 浸润和肿瘤生长均减少。与其他研究的结果相反，我们发现 Girdin 的 Akt 依赖性磷酸化不是内皮细胞生长的限速步骤。此外，与源自携带肿瘤的 WT 小鼠的 CAF 相比，源自携带肿瘤的 SA 转基因小鼠的 CAF 共同移植时，Lewis 肺癌肿瘤的生长受到限制。总之，我们的结果揭示了 Akt 介导的 Girdin 磷酸化在肿瘤进展过程中对 CAF 的作用，突出了需要抑制肿瘤细胞和构成肿瘤微环境的细胞中的 Akt 功能。
