OncoTargets and Therapy (Oct 2019)
The Roles Of Angiogenesis And Cancer Stem Cells In Sorafenib Drug Resistance In Hepatocellular Carcinoma
Abstract
Chiung-Chi Cheng,1,2 Wei-Ting Chao,3 Chen-Chun Liao,3 Jing-Hao Shih,3 Yih-Shyong Lai,1 Yung-Hsiang Hsu,4 Yi-Hsiang Liu1,4 1Department of Pathology, Chang Bing Show-Chwan Memorial Hospital, Changhua 505, Taiwan; 2Center for General Education, Providence University, Taichung City 433, Taiwan; 3Department of Life Science, Tunghai University, Taichung City 407, Taiwan; 4Department of Pathology, Tzu Chi University, Hualien 97004, TaiwanCorrespondence: Yi-Hsiang LiuDepartment of Pathology, Chang Bing Show-Chwan Memorial Hospital, 6 Lugong Road, Lukang Zhen, Changhua County 505, TaiwanTel +886 4 7813888 ext. 71181Fax +886 4 7073235Email [email protected]: An increasing number of studies support cancer stem cells as the reason for chemoresistance to sorafenib therapy in hepatocellular carcinoma (HCC), but the mechanism is still unclear. In this study, the mechanism of sorafenib resistance in cancer stem cells was examined by in vitro experiments and xenograft mouse model.Methods: The expression of cancer stem cell markers in the Chang liver cell line and PLC/PRF/5 and HepG2 hepatoma cell lines were compared by immunoblot assay before and after sorafenib treatment in vitro. As a xenograft mouse model, subcutaneous injection of hepatoma cells followed by sorafenib therapy was performed in NU/NU mice. The effects of sorafenib therapy on tumor growth and cancer stem cell markers were studied. Angiogenesis associated with cancer stem cells was studied by immunoblot and immunohistochemistry assay.Results: The expression of cancer stem cell markers was higher in PLC/PRF/5 and HepG2 cells than Chang liver cells, indicating that these hepatoma cells had more stemness-related characteristics. The cancer stem cell markers were upregulated in the hepatoma cell lines following sorafenib treatment in vitro. In the xenograft model, tumors from PLC/PRF/5 and HepG2 cells with high E-cadherin expression were more resistance to sorafenib therapy. However, the expression of cancer stem cell markers was not significantly different after sorafenib therapy in these tumors. Furthermore, we found that sorafenib therapy induced angiogenesis within tumors from high E-cadherin expressing hepatoma cells.Conclusion: The mechanism of chemoresistance in sorafenib therapy in HCC may be the tumor angiogenesis associated with high E-cadherin expression in cancer stem cells.Keywords: angiogenesis, cancer stem cells, cytokeratin, E-cadherin, hepatocellular carcinoma, sorafenib
