Clear cell renal cell carcinoma (ccRCC) remains a common cause of cancer mortality. Better understanding of ccRCC molecular drivers resulted in the development of antiangiogenic therapies that block the blood vessels that supply tumors with nutrients for growth and metastasis. Unfortunately, most ccRCC patients eventually become resistant to initial treatments, creating a need for alternative treatment options. We investigated the role of the small GTPase Rac1 in ccRCC. Analysis of ccRCC clinical samples indicates that Rac signaling drives disease progression and predicts patients with poorer outcomes. Investigation of Rac1 identifies multiple roles for Rac1 in the pathogenesis of ccRCC. Rac1 is overexpressed in RCC cell lines and drives proliferation and migratory/metastatic potential. Rac1 is also critical for endothelial cells to grow and form endothelial tubular networks potentiated by angiogenic factors. Importantly, Rac1 controls paracrine signaling of angiogenic factors including VEGF from renal carcinoma cells to surrounding blood vessels. A novel Rac1 inhibitor impaired the growth and migratory potential of both renal carcinoma cells and endothelial cells and reduced VEGF production by RCC cells, thereby limiting paracrine signaling both in vitro and in vivo. Lastly, Rac1 was shown to be downstream of VEGF receptor (VEGFR) signaling and required for activation of MAPK signaling. In combination with VEGFR2 inhibitors, Rac inhibition provides enhanced suppression of angiogenesis. Therefore, targeting Rac in ccRCC has the potential to block the growth of tumor cells, endothelial cell recruitment, and paracrine signaling from tumor cells to other cells in the tumor microenvironment.

中文翻译：

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Rac 信号通过启动肿瘤微环境的血管生成开关来驱动透明细胞肾癌肿瘤生长

透明细胞肾细胞癌 (ccRCC) 仍然是癌症死亡的常见原因。对 ccRCC 分子驱动因素的更好理解导致了抗血管生成疗法的发展，这些疗法阻断了为肿瘤提供营养以促进生长和转移的血管。不幸的是，大多数 ccRCC 患者最终会对初始治疗产生抗药性，从而需要替代治疗方案。我们研究了小 GTPase Rac1 在 ccRCC 中的作用。ccRCC 临床样本的分析表明，Rac 信号驱动疾病进展并预测患者预后较差。Rac1 的研究确定了 Rac1 在 ccRCC 发病机制中的多种作用。Rac1 在 RCC 细胞系中过表达并驱动增殖和迁移/转移潜能。Rac1 对于内皮细胞的生长和形成血管生成因子增强的内皮管状网络也至关重要。重要的是，Rac1 控制血管生成因子（包括 VEGF）从肾癌细胞到周围血管的旁分泌信号传导。一种新型的 Rac1 抑制剂损害了肾癌细胞和内皮细胞的生长和迁移潜力，并减少了 RCC 细胞产生的 VEGF，从而限制了体外和体内的旁分泌信号传导。最后，Rac1 被证明是 VEGF 受体 (VEGFR) 信号的下游，并且是激活 MAPK 信号所必需的。与 VEGFR2 抑制剂联合使用，Rac 抑制可增强对血管生成的抑制。因此，在 ccRCC 中靶向 Rac 具有阻断肿瘤细胞生长、内皮细胞募集、