IL-33-mediated Mast Cell Activation Promotes Gastric Cancer Through Macrophage Mobilization

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Jun 23

PMID 31227713

Citations 118

Authors

Moritz F Eissmann

Christine Dijkstra

Andrew Jarnicki

Toby Phesse

Jamina Brunnberg

Ashleigh R Poh

Nima Etemadi

Evelyn Tsantikos

Stefan Thiem

Nicholas D Huntington

Margaret L Hibbs

Alex Boussioutas

Michele A Grimbaldeston

Michael Buchert

Robert J J ODonoghue

Frederick Masson

Matthias Ernst

Affiliations

Soon will be listed here.

Abstract

The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.

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