MIF, secreted by human hepatic sinusoidal endothelial cells, promotes chemotaxis and outgrowth of colorectal cancer in liver prometastasis.

Chun-Ting Hu,Li-Li Guo,Lei Zhang,Shi-Jie Zhu,Lan Shen,Na Zhou,Yong-Jian Deng,Mao-De Lai,Yan-Qing Ding,Qian-Wen Yan,Na Feng,Gui-Hui Tong,Xiu-Wu Bian,Li-Li Ma

doi:10.18632/oncotarget.4198

Abstract

Growth and invasion of metastatic colorectal cancer (CRC) cells in the liver depend on microenvironment. Here, we showed that human hepatic sinusoidal endothelial cells (HHSECs) induce chemotaxis and outgrowth of CRC cells. Macrophage migration inhibitory factor (MIF), released by HHSECs, stimulated chemotaxis of CRC cells. MIF secreted by HHSECs, but not by CRC cells themselves, promoted migration and epithelial-mesenchymal transition (EMT) and facilitated proliferation and apoptotic resistance of CRC cells. In orthotopic implantation models in nude mice, exogenous MIF stimulated growth of CRC cells and metastasis. Furthermore, MIF accelerated mobility of CRC cells by suppressing F-actin depolymerization and phosphorylating cofilin. Noteworthy, MIF levels were correlated with the size of hepatic metastases. We suggest that HHSECs and paracrine MIF promote initial migration and proliferation of CRC cells in the hepatic sinusoids to generate liver metastases.

Highlights

Hepatic metastasis is the leading cause of death in patients with colorectal cancer (CRC), and approximately one-third of CRC patients will develop liver metastases within 3 years after diagnosis [1]
The normal cells of the liver included human hepatic sinusoidal endothelial cells (HHSECs), HL7702s, and LX-2s, and corresponding cells including HUVECs, 293As, and BJs were compared as analog-control cells originating from non-specific target organs of CRC metastasis
The results showed that HHSECs were 3 to 14 times more active than HUVECs in stimulation of CRC cells migration (Figure 1A)

Summary

Introduction

Hepatic metastasis is the leading cause of death in patients with colorectal cancer (CRC), and approximately one-third of CRC patients will develop liver metastases within 3 years after diagnosis [1]. 25% of patients have isolated hepatic metastases that can be resected curatively, and 21–48% survive more than 5 years with low mortality [2,3,4]. Cancer cells get arrested in capillaries of a similar diameter to that of the cells, and extravasation typically occurs in small capillaries [7,8,9]. They can roll on the endothelium under flow conditions in vitro. The rolling has not yet been described in vivo in capillaries in the liver [9,10,11,12]

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