Abstract 1162: Amelioration of the pathologic changes in the hepatocyte-specific BRAF V600E mutated mice by administration of aspirin

Abstract

Abstract We previously reported that the BrafV637E mutation, corresponding to the human BRAFV600E mutation, plays a pivotal role in hepatocarcinogenesis induced by diethylnitrosamine (DEN) in B6C3F1 mice (Mol Carcinog 2017;56:478-488). The livers of transgenic mice with a hepatocyte-specific human BRAFV600E mutation weighed 4.5 times greater than that of normal mice and was entirely consisted of hepatocytes resembling the DEN-induced neoplastic hepatocytes. However, these transgenic mice spontaneously died seven weeks after birth due to thrombotic microangiopathy accompanying interstitial pneumonia, glomerulonephropathy and erythrocyte dyscrasia (Cancer Sci 2019; 110:2748-2759). The hepatocytes of the transgenic mice showed thrombopoietin (TPO) overexpression which is associated with eventual megakaryocytosis and thrombocytosis, and activated platelets were deposited in various tissues including hepatic sinudoids, pulmonary septa and renal glomeruli. Particularly, platelets were sparsely adhered to the sinusoidal endothelial cells (LSEC) and densely adhered to the cell surface and incorporated into the cytoplasm of Kupffer cells in the liver sinusoids. TPO was also overexpressed in the DEN-induced hepatic tumors, and sinusoidal platelet deposition was observed in hepatic tumors of humans and mice, indicating that the hepatic microenvironment of the transgenic mice mimics that of the hepatic tumors. In the transgenic mice, Aspirin (Asp) administration prevented platelet activation, reduced the liver vs body weight ratio, decreased the platelet deposition in the liver, kidney and lung, prevented the erythrocyte dyscrasia and ameliorated the renal and pulmonary changes. In particular, Asp administration turned the neoplastic hepatocyte morphology to the normal morphology in the peripheral part of hepatic lobules, where the sinusoidal platelet deposition was diminished. The platelet factors are necessary for hepatic regeneration, and the interaction of platelets to sinusoidal cells can trigger the production of cytokines that are necessary for hepatocyte proliferation by LSEC and Kupffer cells. Therefore, the macroenvironmental changes including the TPO overproduction by the neoplastic hepatocytes, the eventual megakaryocytosis/thrombocytosis, the platelet activation, and platelet interaction with hepatic sinusoidal cells may contribute to hepatocarcinogenesis from a very early stage. Also, inhibition of platelet activation by Asp may have a preventive effect on hepatocarcinogenesis. Citation Format: Hiroki Tanaka, Kie Horioka, Masahiro Yamamoto, Kosuke Yamazaki, Katsuhiro Ogawa. Amelioration of the pathologic changes in the hepatocyte-specific BRAF V600E mutated mice by administration of aspirin [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1162.