Rac Signaling Drives Clear Cell Renal Carcinoma Tumor Growth by Priming the Tumor Microenvironment for an Angiogenic Switch

Abstract

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.

Heterogeneity of Platelet Derived Growth Factor Pathway Gene Expression Profile Defines Three Distinct Subgroups of Renal Cell Carcinomas

“…This suggests a direct correlation between vascularity and tumor cells in ccRCC (27). Following this report, one of the first to suggest the interrelation between tumor cell behavior and renal tumor vascularization, several studies have confirmed that tumor cell aggressiveness and their response to therapy are closely related to tumor vascularization (27)(28)(29)(30). As evidence of the essential involvement of blood vessels in the behavior of tumor cells, most targeted therapies used in the treatment of ccRCC, target tyrosine kinases and their receptors (31,32).…”

DNMT3A/miR-129-2-5p/Rac1 Is an Effector Pathway for SNHG1 to Drive Stem-Cell-like and Invasive Behaviors of Advanced Bladder Cancer Cells

“…These inhibitors, such as MBQ-167, have shown impressive effects in reducing tumor burden and metastasis in triple-negative breast cancer [ 53 ]. Finally, preliminary evidence suggests that Rac1 inhibitors could be combined with other target-based inhibitors to achieve synergistic effects [ 54 ]. Our search of the Human Protein Atlas database for muscle-invasive bladder cancer showed that patients with high levels of Rac1 expression faired significantly worse than patients with low levels of Rac1 expression ( p = 0.0087; Figure S3 ).…”

Identification of key genes of the ccRCC subtype with poor prognosis

“…In this work, a correlation was revealed between the hub genes of the ccRCC subtype with poor prognosis and the immune cell infiltration cells. Negative correlation of MFI2 , FGA, and FGG with endothelial cells and hematopoietic cells, which contribute to angiogenesis 15 , 16 . Apparently, this explains the poorer response to TKIs in samples with higher expression of MFI2 , CP , FGA , FGG, and APOB (Fig.…”