Captopril, a Renin-Angiotensin System Inhibitor, Attenuates Features of Tumor Invasion and Down-Regulates C-Myc Expression in a Mouse Model of Colorectal Cancer Liver Metastasis

SIMPLE SUMMARY: Approximately 25% of patients with colorectal cancer will present with or develop colorectal liver metastasis (CRLM). Surgical resection of CRLM offers these patients the best chance of a cure. However, liver resection and the subsequent regenerative response has been linked to tumor recurrence in the liver remnant. The Wnt/β-catenin pathway is one of many pathways common to both post-hepatectomy liver regeneration and tumorigenesis. Wnt signaling modulates multiple genes of the renin-angiotensin system (RAS), and Wnt inhibition can attenuate fibrotic responses and improve cancer outcomes via diverse mechanisms. In this study, we investigate the effects of captopril, a RAS inhibitor (RASi), on the Wnt/β-catenin pathway and phenotypic changes associated with tumor progression in the context of the regenerating liver. We show that RASi induced increased Wnt signaling whilst downregulating features of epithelial-to-mesenchymal transition (EMT). Furthermore, RASi induced significant down-regulation of Wnt target genes, c-myc and cyclin D1, indicating that expression of these genes can be down-regulated by RASi despite the accumulation of stabilized β-catenin. ABSTRACT: (1) Background: Recent clinical and experimental data suggests that the liver’s regenerative response following partial hepatectomy can stimulate tumor recurrence in the liver remnant. The Wnt/β-catenin pathway plays important roles in both colorectal cancer carcinogenesis and liver regeneration. Studies have shown that the Wnt/β-catenin pathway regulates multiple renin-angiotensin system (RAS) genes, whilst RAS inhibition (RASi) reduces tumor burden and progression. This study explores whether RASi attenuates features of tumor progression in the regenerating liver post-hepatectomy by modulating Wnt/β-catenin signaling. (2) Methods: Male CBA mice underwent CRLM induction, followed one week later by 70% partial hepatectomy. Mice were treated daily with captopril, a RASi, at 250 mg/kg/day or vehicle control from experimental Day 4. Tumor and liver samples were analyzed for RAS and Wnt signaling markers using qRT-PCR and immunohistochemistry. (3) Results: Treatment with captopril reduced the expression of down-stream Wnt target genes, including a significant reduction in both c-myc and cyclin-D1, despite activating Wnt signaling. This was a tumor-specific response that was not elicited in corresponding liver samples. (4) Conclusions: We report for the first time decreased c-myc expression in colorectal tumors following RASi treatment in vivo. Decreased c-myc expression was accompanied by an attenuated invasive phenotype, despite increased Wnt signaling.