Hypoxia-Autophagy Axis Induces VEGFA by Peritoneal Mesothelial Cells to Promote Gastric Cancer Peritoneal Metastasis Through an Integrin α5-Fibronectin Pathway

Abstract

Background: Peritoneal metastasis (PM) is an important pathological process in the progression of gastric cancer (GC). The metastatic potential of tumor and stromal cells is governed by hypoxia, which is a key molecular feature of the tumor microenvironment. Mesothelial cells also participate in this complex and dynamic process. However, the molecular mechanisms underlying the hypoxia-driven mesothelial-tumor interactions that promote peritoneal metastasis of GC remain unclear.Methods: We determined the hypoxic microenvironment in PM of nude mice by immunohistochemical analysis and screened VEGFA by human growth factor array kit. The crosstalk mediated by VEGFA between peritoneal mesothelial cells (PMCs) and GC cells was determined in GC cells incubated with conditioned medium prepared from hypoxia-treated PMCs. The association between VEGFR1 and integrin α5 and fibronectin in GC cells was enriched using Gene Set Enrichment Analysis and KEGG pathway enrichment analysis. In vitro and xenograft mouse models were used to evaluate the impact of VEGFA/VEGFR1 on gastric cancer peritoneal metastasis. Confocal microscopy and immunoprecipitation were performed to determine the effect of hypoxia-induced autophagy.Results: Here we report that in the PMCs of the hypoxic microenvironment, SIRT1 is degraded via the autophagic lysosomal pathway, leading to increased acetylation of HIF-1α and secretion of VEGFA. Under hypoxic conditions, VEGFA derived from PMCs acts on VEGFR1 of GC cells, resulting in p-ERK/p-JNK pathway activation, increased integrin α5 and fibronectin expression, and promotion of PM.Conclusions: Our findings have elucidated the mechanisms by which PMCs promote PM in GC in hypoxic environments. This study also provides a theoretical basis for considering autophagic pathways or VEGFA as potential therapeutic targets to treat PM in GC.

LncRNA NEAT1 Enhances Glioma Progression via Regulating the miR-128-3p/ITGA5 Axis

“…An important subtype of the integrin α chain family, ITGA5, forms heterodimers together with integrin β1 (ITGB1). Previous studies have shown that ITGA5 is overexpressed in various cancer types, where it is involved in tumor progression [ 25 – 28 ]. Although its role in glioma has also been reported [ 29 – 31 ], the corresponding upstream and downstream mechanisms of action have not been fully clarified.…”

Alteration and dysfunction of ion channels/transporters in a hypoxic microenvironment results in the development and progression of gastric cancer

“…The levels of ROS have been found to be significantly increased in patients with GC, and abnormally high levels of ROS to induce oxidative stress, which can damage the gastric mucosa and be an important factor in the development of GC [29]. In addition, hypoxia can induce autophagy and an acidic extracellular pH through intermediate components or modes, which are also associated with GC progression and chemoresistance [30][31][32][33][34].…”

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

“…Both HIF-1ɑ and HIF-2ɑ promote a more invasive phenotype [33], by activating the epithelial-mesenchymal transition (EMT) program [34][35][36] or cooperating with other strong pro-invasive factors such as Met receptor and soluble hepatocyte growth factor (HGF) [37], or VEGF receptor (VEGFR)/VEGF [38]. Notably, in triple negative breast cancer (TNBC) HIF-1ɑ stimulates the relase of the typical pro-inflammatory cytokine IL-1β that induces a metastatic attitude in both tumor cells and cancer associated fibroblasts (CAFs), creating a TME that strongly favors metastatization [39].…”