Blockade of the renin–angiotensin system inhibits growth of colorectal cancer liver metastases in the regenerating liver

Abstract

Partial hepatectomy (PH), the preferred option for selected patients with colorectal cancer liver metastases (CRCLM), is associated with 40%-80% tumor recurrence rates. Renin-angiotensin system (RAS) blockade inhibits tumor growth and has been suggested to improve liver regeneration. We documented the effect of RAS blockade on tumor growth and liver regeneration in a murine model. CRCLM induction followed by 70% PH was performed on 78 CBA mice. Liver regeneration (days 2, 6) and CRCLM tumor load were measured by liver (and tumor) weights, percentage of CRCLM burden and tumor nodule count (days 16, 21). mRNA expression of the RAS components was characterised. Statistical analysis was performed using 2-independent sample T-test or Mann-Whitney test (SPSS). Captopril did not impair liver regeneration. By day 21, Captopril decreased tumor burden (percentage of CRCLM in the liver) (48.7 ± 4.7% control, 24.4 ± 6.2 Captopril; p = 0.008), tumor volume (1046.2 ± 200.2 mm 3 , 388.3 ± 150.4; p = 0.02), tumor nodule count per image field (181.1 ± 28.5, 68 ± 17.6; p = 0.005) and tumor angiogenesis (71.8 ± 6.4 vessels/mm 2 , 43.1 ± 7.6; p =0.015) compared to controls. Captopril enhanced tumor apoptosis (1 ± 0.2%, 2.5 ± 0.7; p = 0.028). Liver regeneration and tumor development increased liver ACE levels. Blockade of the RAS effectively retarded CRCLM tumor growth at the late stage of tumor development within the regenerating liver without impeding liver regeneration following PH, via anti-angiogenesis and pro-tumor apoptosis. Captopril may be of therapeutic benefit in patients undergoing PH for CRCLM.

Renin-angiotensin system (RAS) blockade attenuates growth and metastatic potential of renal cell carcinoma in mice

“…Chen et al [31] used an experimental model of breast cancer to show that treatment with candesartan inhibited tumor growth and angiogenesis. Koh et al [33], in a murine model of metastatic colorectal cancer, showed that captopril decreased tumor load and volume, as well as the number of tumor nodules and angiogenesis, suggesting that captopril could inhibit the development of this type of tumor via antiangiogenic actions. In a murine xenograft model of RCC, Hii et al [34] showed that captopril administered in the drinking water significantly reduced the tumor volume.…”

Searching for the link; mechanisms underlying liver regeneration and recurrence of colorectal liver metastasis post partial hepatectomy

“…Additionally, it has been demonstrated in the regenerating liver that ACE inhibition, while reducing the tumor burden of CRLM, does not impede LR. 77 By day 21, treated mice had a significant reduction in tumor load and angiogenesis, alongside a significant increase in tumor cell apoptosis while the number of proliferating hepatocytes was unchanged and the overall percentage of regenerated liver did not differ significantly from controls. 77 Furthermore, studies in breast and prostate cancer have shown that ANG1-7 counteracts the pro-neoplastic effects of classical ANGII.…”

“…77 By day 21, treated mice had a significant reduction in tumor load and angiogenesis, alongside a significant increase in tumor cell apoptosis while the number of proliferating hepatocytes was unchanged and the overall percentage of regenerated liver did not differ significantly from controls. 77 Furthermore, studies in breast and prostate cancer have shown that ANG1-7 counteracts the pro-neoplastic effects of classical ANGII. 78,79 Cambados et al demonstrated that activation of MasR by ANG1-7 eliminated ANGII-induced pro-neoplastic processes including migration and invasion 79 supporting the notion that RAS plays an important role in mediating EMT and ECM remodeling.…”

“…Conversely, CRC cells treated with ANGII also produced significantly more MMP9, which has important roles in angiogenesis and ECM remodeling. Additionally, it has been demonstrated in the regenerating liver that ACE inhibition, while reducing the tumor burden of CRLM, does not impede LR . By day 21, treated mice had a significant reduction in tumor load and angiogenesis, alongside a significant increase in tumor cell apoptosis while the number of proliferating hepatocytes was unchanged and the overall percentage of regenerated liver did not differ significantly from controls …”

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

“…Growth of murine colon cancer metastases to liver [104] and a xenografted non-small cell lung cancer cell line [105] were inhibited by captopril. Of particular importance and interest to the CUSP9* protocol, another CUSP9* drug, artesunate, when added to captopril yielded a synergistic inhibition of angiogenesis in an ovine allantoic membrane angiogenesis model [39].…”