Role of EphA2‑PI3K signaling in vasculogenic mimicry induced by cancer‑associated fibroblasts in gastric cancer cells

Kim, Hee Sung; Won, You Jin; Shim, Ju Hee; Kim, Hyun Ji; Kim, Byung Sik; Hong, Hea Nam

doi:10.3892/ol.2019.10677

Cited by 23 publications

(34 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the relationship between CAFs and VM formation has rarely been reported. Recently, some studies have con rmed that CAFs can promote VM formation in some tumors, such as HCC [30] and gastric cancer [31,32]. In this study, we observed that GCAFs can promote VM formation and tumor growth of GBC in vitro and in vivo.…”

Section: Discussionsupporting

confidence: 62%

See 1 more Smart Citation

Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth in gallbladder cancer via upregulating the expression of NOX4, a poor prognosis factor, through IL-6-JAK-STAT3 signal pathway

Pan

Wang

Ansari

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Cancer-associated fibroblasts (CAFs) and vasculogenic mimicry (VM) play important roles in the occurrence and development of tumors. However, the relationship between CAFs and VM formation, especially in gallbladder cancer (GBC) has not been clarified. In this study, we investigated whether gallbladder CAFs (GCAFs) can promote VM formation and tumor growth and explored the underlying molecular mechanism.Methods: A co-culture system of human GBC cells and fibroblasts or HUVECs was established. VM formation, proliferation, invasion, migration, tube formation assays, CD31-PAS double staining, optic/electron microscopy and tumor xenograft assay were used to detect VM formation and malignant phenotypes of 3-D co-culture matrices in vitro, as well as the VM formation and tumor growth of xenografts in vivo, respectively. Microarray analysis was used to analyze gene expression profile in GCAFs/NFs and VM (+)/VM (-) in vitro. QRT-PCR, western blotting, IHC and CIF were used to detected NOX4 expression in GCAFs/NFs, 3-D culture/co-culture matrices in vitro, the xenografts in vivo and human gallbladder tissue/stroma samples. The correlation between NOX4 expression and clinicopathological and prognostic factors of GBC patients was analyzed. And, the underlying molecular mechanism of GCAFs promoting VM formation and tumor growth in GBC was explored. Results: GCAFs promote VM formation and tumor growth in GBC; and the finding was confirmed by facts that GCAFs induced proliferation, invasion, migration and tube formation of GBC cells in vitro, and promoted VM formation and tumor growth of xenografts in vivo. NOX4 is highly expressed in GBC and its stroma, which is the key gene for VM formation, and is correlated with tumor aggression and survival of GBC patients. The GBC patients with high NOX4 expression in tumor cells and stroma have a poor prognosis. The underlying molecular mechanism may be related to the upregulation of NOX4 expression through paracrine IL-6 mediated IL-6/JAK/STAT3 signaling pathway.Conclusions: GCAFs promote VM formation and tumor growth in GBC via upregulating NOX4 expression through the activation of IL-6-JAK-STAT3 signal pathway. NOX4, as a VM-related gene in GBC, is overexpressed in GBC cells and GCAFs, which is related to aggression and unfavorable prognosis of GBC patients.

show abstract

Section: Discussionsupporting

confidence: 62%

“…Recently, it was reported that CAFs can promote VM formation in some malignant tumors, such as hepatocellular cancer (HCC) [30] and gastric cancer [31,32]. However, so far, the mechanism of VM formation is not clear, and the relationship between gallbladder cancer-associated broblasts (GCAFs) and VM formation in GBC has not been reported.…”

Section: Introductionmentioning

confidence: 99%

Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth in gallbladder cancer via upregulating the expression of NOX4, a poor prognosis factor, through IL-6-JAK-STAT3 signal pathway

Pan

Wang

Ansari

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…However, the relationship between CAFs and VM formation has rarely been reported. Recently, some studies have con rmed that CAFs can promote VM formation in some tumors, such as HCC [21] and gastric cancer [41,42]. In this study, we observed that GCAFs can promote VM formation and tumor growth of GBCs in vitro and in vivo.…”

Section: Discussionsupporting

confidence: 61%

“…At present, the mechanism of CAFs promoting tumor VM formation is not clear. It was reported that CAFs promoted VM formation in HCC by paracrine TGF-β and SDF1 [21]; CAFs-derived HGF promoted vascularization in gastric cancer via PI3K/AKT and ERK1/2 signaling [41]; CAFs induced vasculogenic mimicry in gastric cancer cells through the role of EphA2-PI3K signaling [42]. In order to explore the underlying molecular mechanism of GCAFs promoting VM formation in GBC, in view of aforementioned microarray analysis results, we found that among 154 VM-related genes, NOX4, JAK and STAT3 are involved in VM formation of GBC.…”

Section: Discussionmentioning

confidence: 99%

Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth of gallbladder cancers via upregulating the expression of NOX4, a poor prognosis factor, through activating IL-6-JAK-STAT3 signal pathway

Pan

Wang

Ansari

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Cancer-associated fibroblasts (CAFs) and vasculogenic mimicry (VM) play important roles in the occurrence and development of tumors. However, the relationship between CAFs and VM formation, especially in gallbladder cancer (GBC) has not been clarified. In this study, we investigated whether gallbladder CAFs (GCAFs) can promote VM formation and tumor growth and explored the underlying molecular mechanism.Methods A co-culture system of human GBC cells and fibroblasts or HUVECs was established. VM formation, proliferation, invasion, migration, tube formation assays, CD31-PAS double staining, optic/electron microscopy and tumor xenograft assay were used to detect VM formation and malignant phenotypes of 3-D co-culture matrices in vitro, as well as the VM formation and tumor growth of xenografts in vivo, respectively. Microarray analysis was used to analyze gene expression profile in GCAFs/NFs and VM (+)/VM (-) in vitro. QRT-PCR, western blotting, IHC and CIF were used to detected NOX4 expression in GCAFs/NFs, 3-D culture/co-culture matrices in vitro, the xenografts in vivo and human gallbladder tissue/stroma samples. The correlation between NOX4 expression and clinicopathological and prognostic factors of GBC patients was analyzed. And, the underlying molecular mechanism of GCAFs promoting VM formation and tumor growth in GBC was explored.Results GCAFs promote VM formation and tumor growth in GBC; and the finding was confirmed by facts that GCAFs induced proliferation, invasion, migration and tube formation of GBC cells in vitro, and promoted VM formation and tumor growth of xenografts in vivo. NOX4 is highly expressed in GBC and its stroma, which is the key gene for VM formation, and is correlated with tumor aggression and survival of GBC patients. The GBC patients with high NOX4 expression in tumor cells and stroma have a poor prognosis. The underlying molecular mechanism may be related to the up-regulation of NOX4 expression through paracrine IL-6 mediated IL-6/JAK/STAT3 signaling pathway.Conclusions GCAFs promote VM formation and tumor growth in GBC via upregulating NOX4 expression through the activation of IL-6-JAK-STAT3 signal pathway. NOX4, as a VM-related gene in GBC, is over-expressed in GBC cells and GCAFs, which is related to aggression and unfavorable prognosis of GBC patients.

show abstract

“…They revealed that CAF-CM-induced VM formation was blocked by EphA2inhibitor and PI3K-inhibitor. In conclusion, CAFs regulate VM formation via EphA2-PI3K signaling in gastric cancer cells [79] (Fig. 2).…”

Section: Tumor-associated Fibroblastsmentioning

confidence: 80%

Vasculogenic mimicry in carcinogenesis and clinical applications

et al. 2020

View full text Add to dashboard Cite

Distinct from classical tumor angiogenesis, vasculogenic mimicry (VM) provides a blood supply for tumor cells independent of endothelial cells. VM has two distinct types, namely tubular type and patterned matrix type. VM is associated with high tumor grade, tumor progression, invasion, metastasis, and poor prognosis in patients with malignant tumors. Herein, we discuss the recent studies on the role of VM in tumor progression and the diverse mechanisms and signaling pathways that regulate VM in tumors. Furthermore, we also summarize the latest findings of non-coding RNAs, such as lncRNAs and miRNAs in VM formation. In addition, we review application of molecular imaging technologies in detection of VM in malignant tumors. Increasing evidence suggests that VM is significantly associated with poor overall survival in patients with malignant tumors and could be a potential therapeutic target.

show abstract

Role of EphA2‑PI3K signaling in vasculogenic mimicry induced by cancer‑associated fibroblasts in gastric cancer cells

Cited by 23 publications

References 38 publications

Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth in gallbladder cancer via upregulating the expression of NOX4, a poor prognosis factor, through IL-6-JAK-STAT3 signal pathway

Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth in gallbladder cancer via upregulating the expression of NOX4, a poor prognosis factor, through IL-6-JAK-STAT3 signal pathway

Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth of gallbladder cancers via upregulating the expression of NOX4, a poor prognosis factor, through activating IL-6-JAK-STAT3 signal pathway

Vasculogenic mimicry in carcinogenesis and clinical applications

Contact Info

Product

Resources

About