We examined the effects of hyperglycemic conditions on liver metastasis of colorectal cancer (CRC). Angiotensin (AT)-II increased growth, invasion, and anti-apoptotic survival in HT29 and CT26 cells. In contrast, angiotensinogen (ATG) increased these features in HT29 cells but not in CT26 cells. HT29 cells expressed AT-II type 1 receptor, chymase, and rennin, whereas CT26 cells did not express renin. Renin expression and ATG-induced cell growth, invasion, and survival induced and increased as glucose concentration increased in HT29 cells and also CT26 cells. An inhibitor of renin or chymase abrogated A-II production in both cells. Reduction of hepatic ATG production by knockdown suppressed liver metastasis of HT29 cells. An examination of 121 CRC patients showed that diabetes in CRC cases was associated with higher blood HbA1c, higher renin and AT-II concentrations in the primary tumors, and higher incidence of liver metastasis than in nondiabetic cases. These results suggest that diabetes-associated AT activation enhances liver metastasis of CRC. We then examined an antimetastatic therapy by anti-AT treatments in CRC. In a streptozotocin-induced BALB/c mouse diabetes model that was fed a high-calorie diet, the blood sugar level increased and was associated with enhanced CT26 liver metastases. In this diabetic mouse model, liver metastasis of CT26 cells was suppressed by anti-AT treatment with a chymase inhibitor, a renin inhibitor, and an AT-II receptor blocker. Moreover, concurrent hypoglycemic and anti-AT treatments showed a synergistic inhibitory effect on CT26 cell liver metastasis. These results suggest that AT activation ability associated with diabetic conditions enhances liver metastasis of colon cancer. Therefore, treatment with anti-AT and hypoglycemic agents might be relevant for suppressing liver metastasis. This scheme should be examined in a clinical setting.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 457. doi:1538-7445.AM2012-457