Omental Tissue-Mediated Tumorigenesis of Gastric Cancer Peritoneal Metastases

Abstract

The peritoneal cavity, especially the omentum, is a common site for gastric cancer metastasis, representing advanced disease stage and poor prognosis. Here, we studied the effects of omental tissue on gastric cancer tumor progression in vitro and in vivo. Utilizing in vitro models, we found that omental tissue secreted factors increased gastric cancer cellular growth (by 30–67%, P < 0.05), motility (>8-fold, P < 0.05), invasiveness (>7-fold, P < 0.05) and chemoresistance to platinum-based chemotherapeutic agents (>1.2-fold for oxaliplatin and >1.6-fold for cisplatin, P < 0.05). Using a robust proteomic approach, we identified numerous molecules secreted into the omental tissue conditioned medium (CM) which may promote gastric cancer cellular aggressiveness (i.e., IL-6, IL-8, MMP9, FN1, and CXCL-5). Next, an in vivo xenograft mouse model showed an increased human gastric adenocarcinoma tumor volume of cells co-cultured with human omental tissue secreted factors; 1.6 ± 0.55 vs. 0.3 ± 0.19 cm3 (P < 0.001), as well as increased angiogenesis. Finally, exosomes were isolated from human omental tissue CM of gastric cancer patients. These exosomes were taken up by gastric cancer cells enhancing their growth (>8-fold, P < 0.01) and invasiveness (>8-fold, P < 0.001). Proteomic analysis of the content of these exosomes identified several established cancer- related proteins (i.e., IL-6, IL-8, ICAM-1, CCl2, and OSM). Taken together, our findings imply that the omentum play an active role in gastric cancer metastasis. The data also describe specific cytokines that are involved in this cross talk, and that omental tissue- derived exosomes may contribute to these unique cellular interactions with gastric cancer cells. Further studies aimed at understanding the biology of gastric cancer intra peritoneal spread are warranted. Hopefully, such data will enable to develop future novel therapeutic strategies for the treatment of metastatic gastric cancer.

YB-1 transferred by gastric cancer exosomes promotes angiogenesis via enhancing the expression of angiogenic factors in vascular endothelial cells

“…Although GC-derived exosomes have been largely studied since the first characterization decades ago [20], the publications on the regulation of GC angiogenesis are limited. So far, a few of cargoes including CD44, CCR6, HER-2/neu [21] and several cytokines [22] were identified in GC-derived exosomes, and miR-130a/C-MYB [23], miR-135b/FOXO1 [24], miR-155/FOXO3 [25] and HGF [26] were, respectively, uncovered to be potential signals for exosome-HUVEC interactions. Given that the complex compositions including receptors, transcription factors, enzymes, extracellular matrix proteins, lipids, nucleic acids (DNA, mRNA, and miRNA) constitute exosomes, far further declarations on the complex working mechanisms of exosomes in GC angiogenesis are needed.…”

Molecular mediators of peritoneal metastasis in pancreatic cancer

“…Several miRNAs are dysregulated and play a role in the peritoneal metastasis of gastric cancer [188]. Mechanisms of interaction between peritoneally metastasizing cancer cells and the omentum seem to be common in ovarian and gastric cancers, as well as in PDA [127,189,190]. This convergence attests to a conserved symbiotic relation between cancer cells and mesothelium.…”

The Emerging Role of Liquid Biopsy in Gastric Cancer

“…In addition to exosomal information transfer from tumor cells, there is also crosstalk between healthy tissues and tumor cells. A proteomic study confirmed the role of omental exosomes in the growth of gastric cancer and the development of peritoneal metastases [ 69 ]. In the circulation, microRNAs can not only be found in exosomes or microvesicles, but also in a protein-bound state.…”