Omental adipocytes promote peritoneal metastasis of gastric cancer through the CXCL2-VEGFA axis

Br J Cancer. 2020 Aug;123(3):459-470. doi: 10.1038/s41416-020-0898-3. Epub 2020 May 22.

Abstract

Background: Gastric cancer (GC) patients frequently develop peritoneal metastasis; however, the underlying mechanism remains unknown. We hypothesised that omental adipocytes (OmAd) trigger GC cells towards malignant activity to induce peritoneal metastasis.

Methods: We analysed interactions among human GC cells, endothelial cells and OmAd using a 3D co-culture system. We also employed a multipronged animal study, including subcutaneous and orthotopic tumours, and humanised omental adipose tissue models. Urinary levels of CXCL2 were analysed in human GC patients with and without peritoneal metastasis.

Results: Conditioned media derived from OmAd (OmAd-CM) promoted the proliferation, migration and capacity to induce angiogenesis of GC cells through AKT phosphorylation and VEGFA overexpression, whereas silencing CXCL2 in OmAd cancelled OmAd-induced effects. In an orthotopic tumour model using SCID mice, omentectomy suppressed GC growth and peritoneal dissemination, and reduced serum levels of CXCL2. OmAd promoted GC growth in a humanised omental adipose tissue model using NSG mice, but silencing CXCL2 in OmAd cancelled OmAd-induced tumour growth. Finally, urinary levels of CXCL2 were significantly higher in GC patients with peritoneal metastasis than in those without.

Conclusion: Omental adipocytes trigger GC cells to an aggressive phenotype through CXCL2 secretion, which induces angiogenesis followed by cell growth and peritoneal metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / metabolism
  • Animals
  • Cell Line, Tumor
  • Chemokine CXCL2 / genetics
  • Chemokine CXCL2 / urine*
  • Coculture Techniques / methods*
  • Culture Media, Conditioned / chemistry
  • Female
  • Humans
  • Mice
  • Mice, SCID
  • Omentum / cytology*
  • Omentum / metabolism
  • Peritoneal Neoplasms / metabolism
  • Peritoneal Neoplasms / pathology
  • Peritoneal Neoplasms / secondary*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology*
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • CXCL2 protein, human
  • Chemokine CXCL2
  • Culture Media, Conditioned
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Proto-Oncogene Proteins c-akt