Key result
AT1a knockout significantly reduced liver weight and liver metastatic rate compared to wild-type mice in a model of colorectal cancer metastasis.
Why the study?
Does AT1a receptor signaling promote liver metastasis formation in a mouse model of colorectal cancer?
Does AT1a receptor signaling promote liver metastasis formation in a mouse model of colorectal cancer?
Resident hepatic macrophages induce liver metastasis formation from colorectal cancer by induction of TGF-β1 through AT1a signaling.
AT1a signaling may promote colorectal cancer liver metastasis in mice; hypothesis-generating for AT1a blockade in patients.
Liver metastases from colorectal cancer ( CRC ) are a clinically significant problem. The renin–angiotensin system is involved in tumor growth and metastases. This study was designed to evaluate the role of angiotensin II subtype receptor 1a ( AT 1a) in the formation of liver metastasis in CRC . A model of liver metastasis was developed by intrasplenic injection of mouse colon cancer ( CMT ‐93) into AT 1a knockout mice ( AT 1a KO ) and wild‐type (C57 BL /6) mice ( WT ). Compared with WT mice, the liver weight and liver metastatic rate were significantly lower in AT 1a KO . The mRNA levels of CD 31, transforming growth factor‐ β1 ( TGF ‐β1), and F4/80 were suppressed in AT 1a KO compared with WT . Double immunofluorescence analysis showed that the number of accumulated F4/80 + cells expressing TGF ‐β1 in metastatic areas was higher in WT than in AT 1a KO . The AT 1a KO bone marrow ( BM ) ( AT 1a KO ‐ BM )→ WT showed suppressed formation of liver metastasis compared with WT ‐ BM → WT . However, the formation of metastasis was further suppressed in WT ‐ BM → AT 1a KO compared with AT 1a KO ‐ BM → WT . In addition, accumulated F4/80 + cells in the liver metastasis were not BM ‐derived F4/80 + cells, but mainly resident hepatic F4/80 + cells, and these resident hepatic F4/80 + cells were positive for TGF ‐β1. Angiotensin II enhanced TGF ‐β1 expression in Kupffer cells. Treatment of WT with clodronate liposomes suppressed liver metastasis by diminishing TGF ‐β1 + F4/80 + cells accumulation. The formation of liver metastasis correlated with collagen deposition in the metastatic area, which was dependent on AT 1a signaling. These results suggested that resident hepatic macrophages induced liver metastasis formation by induction of TGF ‐β1 through AT 1a signaling.
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Shimizu et al. (2017) studied Liver metastasis from colorectal cancer. AT1a knockout vs. Wild-type mice was evaluated on Liver weight and liver metastatic rate. AT1a knockout significantly reduced liver weight and liver metastatic rate compared to wild-type mice in a model of colorectal cancer metastasis.
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