Epithelial‐mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1

Abstract

Background:Increasing numbers of studies have demonstrated that circulating tumor cells (CTCs) undergo a phenotypic change termed epithelial-mesenchymal transition (EMT), and researchers have proposed that EMT might provide CTCs with increased potential to survive in the different microenvironments encountered during metastasis through various ways, such as by increasing cell survival and early colonization. However, the exact role of EMT in CTCs remains unclear. Methods: In this study, we identified CTCs of 41 patients with gastric cancer using Cyttel-CTC and im-FISH (immune-fluorescence in situ hybridization) methods, and tested the expression of EMT markers and ULBP1 (a major member of the NKG2Dnatural killer [NK] group 2 member D-ligand family) on CTCs. Moreover, we investigated the relationship between the expression of EMT markers and ULBP1 on CTCs and gastric cancer cell lines. Results: Our results showed that the CTCs of gastric cancer patients exhibited three EMT marker subtypes, and that the expression of ULBP1 was significantly lower on mesenchymal phenotypic CTCs (M + CTCs) than on epithelial phenotypic CTCs (E + CTCs). EMT induced by TGF-β in vitro produced a similar phenomenon, and we therefore proposed that EMT might be involved in the immune evasion of CTCs from NK cells by altering the expression of ULBP1. Conclusions: Our study indicated that EMT might play a vital role in the immune invasion of CTCs by regulating the expression of ULBP1 on CTCs. These findings could provide potential strategies for targeting the immune evasion capacity of CTCs.

A clinical scoring system for predicting tumor recurrence after percutaneous radiofrequency ablation for 3 cm or less hepatocellular carcinoma

“…8. Finally, 4-diamidine-2-phenylindole (DAPI) staining was added to seal the samples, and the circulating tumor cells were observed and counted under fluorescence microscope 15 , 16 .…”

EMT-Associated Heterogeneity in Circulating Tumor Cells: Sticky Friends on the Road to Metastasis

“…Mechanisms induced by EMT such as increased expression of immune checkpoint proteins, altered autophagy, immunoproteasome deficiency and dysfunction of immunological synapses have been implicated and reviewed elsewhere [276,277]. More particularly in the context of CTCs, a reduced expression of ULBP1 (a major ligand of NKG2D) has been reported in EMT-shifted CTCs isolated from gastric cancer patients (Table 1) and in TGF-β-induced cells in vitro, and a mechanism has been proposed by which EMT-shifted CTC resistance to NK cells is increased [134]. In contrast, López-Soto and coworkers reported an enhanced susceptibility to NK cells and an increased expression of different NKG2D ligands in colorectal cancer cells induced to EMT by several means (TGF-β stimulation, inhibition of glycogen synthase kinase-3β, or Snail overexpression) [278].…”

Minimal Residual Disease, Metastasis and Immunity

“…Consequently, SOX9-expressing dormant cancer cells impair NK cytotoxic activity by downregulating ULBP activators of NKG2D receptors on NK cells [120,157]. In a clinical study, downregulation of ULBP1 was detected in CTCs and might be a result of EMT [158]. Alternatively, CD8+ T cell recognition could be avoided by masking antigenic presentation.…”