Macrovascular Endothelial Cells Enhance the Motility of Liver Cancer Cells by Up-regulation of MMP-3, Activation of Integrin/FAK Signaling Pathway and Induction of Non-classical Epithelial-mesenchymal Transition

Song-Ming Ding; Ai-Li Lu; Jian-Fang Lu; Xu-Liang Chen; Muhammad Ibrahim Alhadi Edoo; Lin Zhou; Hai-Yang Xie; Shu-Sen Zheng; Qi-Yong Li

doi:10.7150/jca.38209

Macrovascular Endothelial Cells Enhance the Motility of Liver Cancer Cells by Up-regulation of MMP-3, Activation of Integrin/FAK Signaling Pathway and Induction of Non-classical Epithelial-mesenchymal Transition

J Cancer. 2020 Feb 3;11(8):2044-2059. doi: 10.7150/jca.38209. eCollection 2020.

Authors

Song-Ming Ding¹, Ai-Li Lu², Jian-Fang Lu¹, Xu-Liang Chen¹, Muhammad Ibrahim Alhadi Edoo^{3

4}, Lin Zhou³, Hai-Yang Xie³, Shu-Sen Zheng^{1

3

4}, Qi-Yong Li¹

Affiliations

¹ Division of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, Zhejiang, P.R. China.
² Division of oncology department, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China.
³ Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; Key Laboratory of Organ Trans-plantation, Zhejiang Province; Hangzhou, Zhejiang, China.
⁴ Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China.

Abstract

Background: Liver cancer with portal vein tumor thrombus (PVTT) indicates a serious prognosis. The molecular mechanism of PVTT formation is not totally clarified, the invasion of blood vessels by liver cancer cells is the key step and portal vein endothelial cells plays critical role. Methods: Conditioned medium (CM) of human umbilical vein endothelial cells (HUVEC) were used to culture liver cancer cells and prostate cancer cells for cell motility and viability analysis for the purpose of simulating the role of macrovascular endothelial cells in the development of liver cancer. Results: HUVEC-CM caused long spindle-shaped changes in liver cancer cells; the invasion and migration ability of Bel-7402 and MHCC-LM3 (cultured in HUVEC-CM) increased significantly. Integrins/FAK (focal adhesion kinase) signaling pathway was activated and MMP-3 was up-regulated. However, classical epithelial-mesenchymal transition (EMT) did not involve. HUVEC-CM caused a decrease of cell population in G1- and S-phase of Bel-7402, it also caused an accumulation of cell population in G1 phase and a decrease of cell population in S-phase of MHCC-LM3, MHCC-97L and DU-145. HUVEC-CM promotes apoptosis of Bel-7402 and MHCC-97L and the nude mouse tumorigenic experiment did not find that the HUVEC-CM increase the tumorigenic ability of liver cancer cells. Conclusion: HUVEC may provide an easy-to-adhere roadbed for liver cancer cells invasion of blood vessels by altering extracellular matrix (ECM), activating integrins/FAK pathway and inducing non-classical EMT. The effect of HUVEC-CM on cell viability was cancer cell type dependent. It is a meaningful glance at the mechsanism of PVTT.

Keywords: epithelial-mesenchymal transition (EMT); human umbilical vein endothelial cell (HUVEC); integrins; liver cancer; portal vein tumor thrombus (PVTT); tumor microenvironment (TME).