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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.01267

Omental Tissue-Mediated Tumorigenesis of Gastric Cancer Peritoneal Metastases

Olga Kersy1, 2, 3,  Shelly Loewenstein2, 3, 4*, Nir Lubezky1, 3, 5, Osnat Sher3, 6,  Natalie B. Simon7, Joseph M. Klausner3, 5, 8 and  Guy Lahat3, 4, 5
  • 1Institute Oncology, Tel Aviv Sourasky Medical Center, Israel
  • 2Tel-Aviv Sourasky Medical Center, Other, Israel
  • 3Sackler Faculty of Medicine, Tel Aviv University, Israel
  • 4Tel-Aviv Sourasky Medical Center, Tel Aviv Sourasky Medical Center, Israel
  • 5Department of Surgery, Tel Aviv Sourasky Medical Center, Israel
  • 6Institute of Pathology, Tel Aviv Sourasky Medical Center, Israel
  • 7College and Graduate School of Arts and Sciences, University of Virginia, United States
  • 8Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv Sourasky Medical Center, Israel

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 cm3 versus 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.

Keywords: Omental tissue, gastric cacner, tumor micoenvironment, Peritoneal metastases, exosoems

Received: 20 Jun 2019; Accepted: 01 Nov 2019.

Copyright: © 2019 Kersy, Loewenstein, Lubezky, Sher, Simon, Klausner and Lahat. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Shelly Loewenstein, Tel Aviv Sourasky Medical Center, Tel-Aviv Sourasky Medical Center, Tel Aviv, 6997801, Tel Aviv, Israel,