HGF derived from cancer‑associated fibroblasts promotes vascularization in gastric cancer via PI3K/AKT and ERK1/2 signaling

Ding, Xusheng; Wu, Xi; Ji, Jun; Cai, Qing; Jiang, Jinling; Shi, Min; Yu, Yingyan; Zhu, Zhenggang; Zhang, Jun

doi:10.3892/or.2018.6500

Cited by 38 publications

(56 citation statements)

References 44 publications

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“…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: 62%

“…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%

“…Recently, it was reported that CAFs promote VM formation in HCC cells by secreting TGF-β and SDF1 [21]; CAFs-derived HGF promote vascularization in gastric cancer [41]. So whether there are speci c genes regulation in the process of GCAFs-triggered VM formation in GBC?…”

Section: Discussionmentioning

confidence: 99%

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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

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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.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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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

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“…TAFs are important factors in tumor growth and VM formation [73][74][75]. Some studies have demonstrated that TAFs are required for tumor vascularization via various signaling pathways in malignant tumors [76][77][78]. In 2016, Yang et al showed that the conditioned medium of tumor-associated fibroblasts (CM-TAMs) could promote VM formation in vitro through secreting TGF-β and SDF1, and the expression of VE-cadherin, MMP-2, and laminin5γ2 was increased by TGF-β and SDF1 in hepatocellular carcinoma [73].…”

Section: Tumor-associated Fibroblastsmentioning

confidence: 99%

Vasculogenic mimicry in carcinogenesis and clinical applications

et al. 2020

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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.

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“…It is reported that, in breast cancer, P2RX7 promoted malignant behaviors of cancer cells via activating ERK1/2 and Akt pathways. 13 Considering the ERK1/2 and Akt pathways are crucial modulator of proliferation and apoptosis, 14 we examined that whether P2RX7 had this mechanism by which it promoted gastric cancer progression. As expected, P2RX7 knockdown inhibited the phosphorylated levels of ERK1/2 and Akt, while P2RX7 overexpression activated the phosphorylation of them (Figure 4(a) and (b)).…”

Section: P2rx7 May Increase the Proliferation Of Gastric Cancer Cellsmentioning

confidence: 99%

P2RX7 functions as a putative biomarker of gastric cancer and contributes to worse prognosis

Wang

Tingran

et al. 2019

Exp Biol Med (Maywood)

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P2RX7 has a vital role in promoting proliferation and metastasis and is relevant to worse prognosis in multiple tumors. Nevertheless, P2RX7’s prognostic value and unambiguous effect in gastric cancer remain to be further explored. Our study showed that the expression of P2RX7 in human gastric tumor tissue ( n = 80) was significantly higher than that in normal human gastric tissue ( n = 20, different cohort). Abnormally high expression of P2RX7 was related to larger tumor size ( P = 0.0473), higher T stage ( P = 0.0367), and lymphatic metastasis ( P = 0.0056). Kaplan–Meier analysis showed that higher expression of P2RX7 was associated with worse overall survival and disease-free survival in gastric cancer patients. Additionally, downregulation of P2RX7 by a specific shRNA suppressed the proliferation and metastasis of gastric cancer cells, while ectopic overexpression P2RX7 had opposite effects. P2RX7 modulated ERK1/2 and Akt pathways and epithelial–mesenchymal transition markers such as E-cadherin, N-cadherin, vimentin, and snail. All in all, our results suggest that P2RX7 represents a prognostic biomarker of patients with gastric cancer and show the importance of P2RX7 as a putative biomarker in gastric cancer. Impact statement The mechanism of gastric cancer is highly complex, accompanied by a variety of genetic abnormalities. It is of great significance to elucidate the pathogenesis of gastric cancer, find its markers and therapeutic targets in the fight against this fatal disease. In this study, we identified P2RX7 as a putative target of gastric cancer, which was overexpressed in gastric cancer tissues and had relationship with worse prognosis. We also elucidated the roles of P2RX7 on the growth and metastasis of gastric cancer cells, and explored the relationship between it and ERK1/2 pathway, Akt pathway, and epithelial–mesenchymal transition. Our findings begin to offer useful insights into the mechanism of gastric cancer progression and provide clues to novel therapy strategies.

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HGF derived from cancer‑associated fibroblasts promotes vascularization in gastric cancer via PI3K/AKT and ERK1/2 signaling

Cited by 38 publications

References 44 publications

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

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

P2RX7 functions as a putative biomarker of gastric cancer and contributes to worse prognosis

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