Abstract
Genetically deregulated tumor cells generate vascular channels by vasculogenic mimicry (VM) that is independent of endothelial blood vessels. The morphological characteristics of VM and the role of EphA2 in the formation of VM were evaluated in 144 clinical samples of gastric adenocarcinoma and AGS gastric cancer cell line. It has long been believed that VM consists of PAS-positive basement membrane and CD31/CD34-negative cells. Interestingly, we found that the luminal surface of gastric tumor cells that form VM channels showed PAS-positive reaction, and that the involvement of CD31/CD34-positive tumor cells in the formation of VM channels. Highly aggressive tumor cells that formed VM were found to express CD31 or CD34, implicating the angiogenic and vasculogenic potential of the genetically deregulated tumor cells. VM occurrence was positively correlated with high expression of EphA2 in our patient cohort, and the indispensable role of EphA2 in VM formation was identified by gene silencing in AGS cells. We also report that Epstein–Barr virus (EBV)-positive tumor cells were involved in the formation of VM channels in EBV-associated gastric cancer samples. Overall, our results suggest that EphA2 signaling promotes tumor metastasis by inducing VM formation during gastric tumorigenesis.
Highlights
Vasculogenic mimicry (VM), in which tumor cells create their own fluid-conducting channels without the involvement of endothelial cells[1], was first described in human uveal melanomas as periodic acid-Schiff (PAS)-positive patterned vascular channel networks[2]
Our study aimed to examine the morphological characteristics of vasculogenic mimicry (VM) structure and tumor neo-vascularization in human gastric adenocarcinoma tissues, and to evaluate the correlation of EphA2 expression with VM formation, in order to explore the role of EphA2 signaling in the acquisition of VM structures in gastric cancer microenvironment
The three erythrocytes (Fig. 1F, asterisks) enclosed by PASpositive cuboidal tumor cells (Fig. 1F, blue arrows) were found. We considered all these cases in which the erythrocytes were encircled by CD31-positive or PAS-positive cuboidal cancer cells, but not by attenuated endothelial cells, as VM-positive
Summary
Vasculogenic mimicry (VM), in which tumor cells create their own fluid-conducting channels without the involvement of endothelial cells[1], was first described in human uveal melanomas as periodic acid-Schiff (PAS)-positive patterned vascular channel networks[2]. Www.nature.com/scientificreports implication of tumor vascularization in tumor growth and metastatic dissemination[11,17], little is known about the formation of VM in tissue samples from patients with gastric adenocarcinoma. Our study aimed to examine the morphological characteristics of VM structure and tumor neo-vascularization in human gastric adenocarcinoma tissues, and to evaluate the correlation of EphA2 expression with VM formation, in order to explore the role of EphA2 signaling in the acquisition of VM structures in gastric cancer microenvironment
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