Gastric cancer (GC) remains the world’s fifth most common cancer and third leading cause of cancer-related deaths in 2018 [
1]. Although perioperative or postoperative adjuvant therapies based on gastrectomy have been used, the prognosis is still not ideal [
2]. Peritoneal metastasis (PM) is the most common cause of tumor progression in advanced gastric cancer and is associated with a median patient survival time of only 4 months [
3]. At present, the mechanisms underlying peritoneal metastasis in GC are not fully understood. Accurate diagnostic biomarkers for PM or effective therapeutic targets remain to be further explored.
Hypoxia, or low oxygen tension, is a key molecular feature of the tumor microenvironment that governs the metastatic potential of tumor and stromal cells. Consistently, it was identified that a common site of ovarian cancer metastasis, the omental metastatic microenvironment is indeed hypoxic [
4]. Moreover, the metastatic microenvironment in GC is complex and dynamic, involving multiple cell types that support gastric cancer metastasis. Among these cell types, peritoneal mesothelial cells (PMCs) play a vital role in PM. When establishing peritoneal implants, intraperitoneal injection of primary human PMCs along with ovarian cancer cells increases PM in immunodeficient mice, compared to injection of tumor cells alone [
5]. However, little is known about the molecular mechanisms of hypoxia-driven mesothelial-tumor interactions that underlie PM in GC.
Peritoneal metastasis in GC progresses through a multistep process involving the detachment of cancer cells from the primary tumor, their attachment to the distant peritoneum, invasion into the subperitoneal space, proliferation, and angiogenesis [
6,
7] Angiogenesis is considered a key step in the development and dissemination of human cancer. Previous studies indicate that the presence of angiogenic factors is a necessary event in the progression of PM [
8‐
10] Moreover it was reported that vascular endothelial growth factor (VEGF) is associated with PM in GC and that VEGF is a significant indicator of peritoneal recurrence [
11,
12] Bevacizumab, a monoclonal antibody that recognizes the VEGF-A isoform, inhibits tumor growth by blocking angiogenesis. Anti-angiogenic therapy was shown to normalize tumor vessels and reduce interstitial fluid pressure, ultimately decreasing malignant ascites [
13]. Some studies showed that bevacizumab suppresses cell proliferative activity by inhibiting VEGF-induced angiogenesis, thus decreasing tumor size [
12]. However, a subgroup analysis of one study indicated that patients with PM did not benefit from an available third line therapy, including Ramucirumab, a VEGFR2 antagonist. VEGFR2 is a major receptor tyrosine kinase in endothelial cells that regulates VEGF signaling and drives VEGF-mediated angiogenesis [
14]. Therefore, we hypothesized that in addition to normalizing tumor vessels, VEGF might act directly on tumor cells. Previous studies have shown that VEGFR1, which is a decoy receptor incapable of producing intracellular signals, is a positive regulatory molecule for the migration of monocytes and macrophages. VEGFR1 shows high VEGF affinity but weak tyrosine phosphorylation levels compared to VEGFR2 [
15]. VEGFR1 is widely expressed in various tumor cells and contributes significantly to cancer growth and metastasis. At present, VEGFR1 is emerging as a predictive biomarker for anti-VEGF therapy in cancer [
16,
17] Given this evidence, it is reasonable to believe that VEGFR1 must have a prominent signaling role, even though its signal transduction mechanism and functions are still not fully determined. Moreover, the involvement of VEGFR1 in PM of GC is ambiguous.
Here we report that PMCs in the hypoxic microenvironment degrade SIRT1 via the autophagic lysosomal pathway. This in turn regulates the acetylation level of HIF-1α and promotes the secretion of VEGFA. VEGFA derived from PMCs acts on VEGFR1 in GC cells under hypoxic conditions, thereby activating the p-ERK/p-JNK pathway and increasing the expression of integrin α5 and fibronectin, which are key factors that promote PM of GC. Our study has elucidated the involvement of PMCs in the promotion of PM in GC in a hypoxic environment, and provides evidence for the benefit of targeting autophagic pathways or VEGFA as therapeutic targets for PM in GC.