Metastasis-associated in colon cancer-1 promotes vasculogenic mimicry in gastric cancer by upregulating TWIST1/2.

Lin Wang,Na Huang,Yulin Liao,Xi Chen,Wangjun Liao,Li Sun,Li Lin

doi:10.18632/oncotarget.3416

Abstract

Vasculogenic mimicry (VM) is a blood supply modality that is strongly associated with the epithelial-mesenchymal transition (EMT), TWIST1 activation and tumor progression. We previously reported that metastasis-associated in colon cancer-1 (MACC1) induced the EMT and was associated with a poor prognosis of patients with gastric cancer (GC), but it remains unknown whether MACC1 promotes VM and regulates the TWIST signaling pathway in GC. In this study, we investigated MACC1 expression and VM by immunohistochemistry in 88 patients with stage IV GC, and also investigated the role of TWIST1 and TWIST2 in MACC1-induced VM by using nude mice with GC xenografts and GC cell lines. We found that the VM density was significantly increased in the tumors of patients who died of GC and was positively correlated with MACC1 immunoreactivity (p < 0.05). The 3-year survival rate was only 8.6% in patients whose tumors showed double positive staining for MACC1 and VM, whereas it was 41.7% in patients whose tumors were negative for both MACC1 and VM. Moreover, nuclear expression of MACC1, TWIST1, and TWIST2 was upregulated in GC tissues compared with matched adjacent non-tumorous tissues (p < 0.05). Overexpression of MACC1 increased TWIST1/2 expression and induced typical VM in the GC xenografts of nude mice and in GC cell lines. MACC1 enhanced TWIST1/2 promoter activity and facilitated VM, while silencing of TWIST1 or TWIST2 inhibited VM. Hepatocyte growth factor (HGF) increased the nuclear translocation of MACC1, TWIST1, and TWIST2, while a c-Met inhibitor reduced these effects. These findings indicate that MACC1 promotes VM in GC by regulating the HGF/c-Met-TWIST1/2 signaling pathway, which means that MACC1 and this pathway are potential new therapeutic targets for GC.

Highlights

Cancer requires an adequate blood supply to sustain rapid growth [1]
We previously reported that upregulation of metastasis-associated in colon cancer-1 (MACC1) predicts a poor clinical outcome for patients with gastric cancer (GC), and that MACC1 promotes GC cell proliferation and invasion by inducing the epithelial-mesenchymal transition (EMT) through activation of the hepatocyte growth factor (HGF)/ c-Met signaling pathway [14]
To confirm whether vasculogenic mimicry (VM) could be detected in tumor tissues obtained from 88 patients with stage IV GC, we used staining for platelet endothelial cell adhesion molecule-1 (CD31) to identify the endothelium in GC tissue sections, as well as periodic acid-Schiff (PAS) stain to identify extracellular matrix-rich channels between tumor cells

Summary

Introduction

Cancer requires an adequate blood supply to sustain rapid growth [1]. VM is the dominant method that provides the blood supply in the early stage of cancer and is an important route of metastasis [3]. A recent study showed that VM was still markedly increased in the tumors of patients receiving anti-angiogenesis treatment for ovarian carcinoma [11], indicating that VM is a potential alternative for providing the blood supply to maintain tumor growth when endothelium-dependent angiogenesis is inhibited. It was reported that VM occurs in poorly differentiated human GC [5] and that the anti-VM effect of the IRX1 tumor suppressor gene contributes to inhibition of metastasis in animals with GC xenografts [13]. Evidence is limited with regard to whether VM has any influence on the prognosis of GC patients and the underlying mechanisms remain unclear

Methods

Results

Conclusion