Adenocarcinoma of the proximal stomach is the fastest rising malignancy in North America, and is associated with a high rate of recurrence to the peritoneum. As part of cancer treatment, the majority of patients undergo at least one invasive surgical procedure. Recent clinical data has linked postoperative infection complications with adverse oncologic outcomes; however, the underlying mechanisms are unclear. Emerging evidence suggests that the release of TNFa, a key inflammatory cytokine during infection facilitates cancer progression. The role and mechanisms the gram-negative bacterial infections play in facilitating the metastatic potential of gastric cancer to the peritoneum is entirely unknown. We hypothesized that incubation of gastric cancer cells and MC with heat-inactivated E. Coli or LPS can augment gastric cancer cell adhesion and invasion via TNFR1 signaling and increase the potential of peritoneal metastasis. Incubation of human gastric cancer cells or/and MC with heat inactivated E. coli, LPS or TNFa significantly increased in vitro adhesion 3-4 folds to MC and enhanced in vitro invasion. These enhanced cell adhesion and invasion phenotypes following incubation with LPS or E. coli were attenuated at three levels: inhibition of TLR4 (Eritoran), inhibition of TNFR1 (anti-TNFR1/isotype control antibodies) or p38 MAPK inhibitor (BIRB0796). TNFa treatment also increases CD54, CD44 and CD29 expression on cancer cells and MC. To further validate in vitro results, a novel ex-vivo murine peritoneal metastasis model is developed. We report that ex vivo gastric cancer cells adhesion to murine peritoneum is augmented by overnight LPS, E. Coli and TNFa treatments and this effect was abrogated when TNFR1-/- mouse peritoneum is used or in the presence of TNFR1 monoclonal or isotype control antibodies. These findings implicate TNFa in the process of gastric cancer metastasis to peritoneum in the context of systemic infection and identify TNFa as potential therapeutic targets.
Citation Format: Malak Alzahrani, Betty Giannias, France Bourdeau, Rafael Kayano, Lorenzo Ferri. Gram-negative bacterial infection enhances the potential of gastric adenocarcinoma peritoneal metastasis via TNFR1 dependent manner. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A29.