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.
Highlights
Gastric adenocarcinoma is the fourth most common cancer and the second leading cause of cancer-related mortality worldwide [1]
AGS derived from primary gastric adenocarcinoma, N-87 derived from liver metastasis, and SNU16 derived from gastric cancer malignant ascites were incubated with conditioned medium (CM) or regular medium (RM)
We demonstrated that omental tissue CM significantly increased the proliferation of all gastric cancer cell lines compared to RM using an XTT proliferation assay (P < 0.05; Figure 1A)
Summary
Gastric adenocarcinoma is the fourth most common cancer and the second leading cause of cancer-related mortality worldwide [1] This high mortality rate is mainly a result of late diagnosis and limited therapeutic options despite considerable improvements in surgical capabilities and multidisciplinary care [2, 3]. The omentum is composed of adipocytes, endothelial cells, immune cells, stromal cells and aggregates of well-vascularized immune cells called “milky spots” [11] These cells secrete various adipokines which may play a role in gastric cancer tumor progression. Exosomes are 50–140 nm extracellular vesicles that can be released into the extracellular space from many cell types, including the omentum [12, 13]. Little is known about the involvement of adipose tissue-derived exosomes in tumorigenesis and, to the best of our knowledge, there are no data on the role of exosomes in the interaction between the omentum and metastatic epithelial cancer cells
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