Abstract 4803: Over-production of thrombopoietin in the liver of transgenic mice with liver-specific human BrafV600E expression

Abstract

Abstract The BrafV637E mutation, which corresponds to the human BRAFV600E mutation, plays a pivotal role in mouse hepatic carcinogenesis induced by neonatal treatment with diethylnitrosamine in B6C3F1 mice. We previously established the transgenic mice that express the human BRAFV600E mutation in the liver (Mol Carcinog 2016. doi:10.1002/mc22510). The transgenic mice showed 5 folds increase in liver/body weight as compared to normal mice, and their liver was entirely consisted of small basophilic hepatocytes resembling DEN-induced preneoplastic hepatocytes. The transgenic mice were normally born, but most of them spontaneously died during 2-3 months after birth. In this study, we investigated the reason for spontaneous death in the liver-specific BRAFV600E transgenic mice. The numbers of platelets and megakaryocytes were remarkably increased respectively in peripheral blood and bone marrow in the transgenic mice. Furthermore, fragmented red blood cells and activated platelets with enlarged size were frequently observed in the peripheral blood smear of the transgenic mice. Thrombopoietin mRNA was abundantly expressed in the liver of transgenic mice, and the conditioned-medium of the cultured hepatocytes from the transgenic mice contained increased amount of thrombopoietin as compared with that of normal mouse hepatocytes. Histopathological analysis revealed that many platelets were adhered to the sinusoidal walls in the liver of the transgenic mice. Furthermore, glomerulonephritis associating with platelet deposition in glomerular capillaries and interstitial pneumonia accompanying microthrombosis in alveolar capillaries were also observed. Because platelets have been shown to promote liver regeneration through interaction with various hepatic cell components such as hepatocytes, endothelial cells and Kupffer cells, the platelet accumulation in the liver of the transgenic mice may represent the stimulation for growth and proliferation of hepatocytes by platelets. On the other hand, the platelets might cause the renal and pulmonary diseases which might cause spontaneous death in these mice. Our results indicate that over-production of thrombopoietin by the BRAF-mutated hepatocytes may create the macroenvironment that may favor the growth and proliferation of neoplastic hepatocytes.(Supported by the grant from Japanese Ministry of Education, Culture, Sports, Science and Technology.) Citation Format: Hiroki Tanaka, Kie Horioka, Masahiro Yamamoto, Katsuhiro Okuda, Masaru Asari, Katsuhiro Okuda, Seiji Ohtani, Kosuke Yamazaki, Keiko Shimizu, Katsuhiro Ogawa. Over-production of thrombopoietin in the liver of transgenic mice with liver-specific human BrafV600E expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4803. doi:10.1158/1538-7445.AM2017-4803