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

• Published in: British journal of cancer 2020-08, Vol.123 (3), p.459-470
• Main Authors: Natsume, Makoto, Shimura, Takaya, Iwasaki, Hiroyasu, Okuda, Yusuke, Hayashi, Kazuki, Takahashi, Satoru, Kataoka, Hiromi
• Format: Article
• Language: English
• Subjects: 631/67/1504/1829; 631/67/327; Adipocytes; Adipocytes - cytology; Adipocytes - metabolism; Adipose tissue; AKT protein; Angiogenesis; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell culture; Cell Line, Tumor; Cell proliferation; Chemokine CXCL2 - genetics; Chemokine CXCL2 - urine; Coculture Techniques - methods; Culture media; Culture Media, Conditioned - chemistry; Drug Resistance; Endothelial cells; Epidemiology; Female; Gastric cancer; Humans; Metastases; Metastasis; Mice; Mice, SCID; Molecular Medicine; Omentum - cytology; Omentum - metabolism; Oncology; Peritoneal Neoplasms - metabolism; Peritoneal Neoplasms - pathology; Peritoneal Neoplasms - secondary; Peritoneum; Phenotypes; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Serum levels; Signal Transduction; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Tumors; Up-Regulation; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-0898-3

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.