Liver Endothelial Cells Induce Hepatocellular Carcinoma via HGF Secretion

Abstract

Introduction: Liver sinusoidal endothelial cells (LSEC) control organ functions, metabolism and development. LSEC express hepatocyte growth factor (HGF), which is involved in prenatal development, metabolic homeostasis and liver regeneration. This study aimed to elucidate the precise contribution of LSEC-derived HGF in liver cancer. Method: Stab2-iCretg/wt;Hgffl/fl (HgfΔLSEC) mice and Hgffl/fl control mice were used to investigate the role of HGF in HCC development. Mice were injected with DEN to induce liver cancer. Liver changes in DEN-treated mice closely resemble chronic liver disease in humans, up to progression to HCC. After 12 months, macroscopic cancer development was assessed by magnetic resonance imaging (MRI). In addition, histopathologic and molecular examination of liver specimens was performed. Results: Magnetic resonance imaging and histologic evaluation showed significantly fewer malignant lesions in the HgfΔLSEC mice. Additionally, these lesions were found to be significantly smaller. On average, the tumors of Hgffl/fl were 1.5 cm and those of HgfΔLSEC were only 0.5cm in diameter. Further histological workup revealed a higher grade of proliferation in HgfΔLSEC mice compared to wildtypes. This was further confirmed by analysis for DNA damage pathways. Conclusion: In summary, our results indicate that LSECs may play a central role in HCC development through the production of HGF. Loss of HGF production in LSECs reduced the number of tumors as well as the size and progression of tumors. Further evaluation is needed to elucidate the complete role of LSECs in liver cancer development to find new therapeutic targets.