Format

Send to

Choose Destination
Nat Commun. 2019 Jun 21;10(1):2735. doi: 10.1038/s41467-019-10676-1.

IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization.

Author information

1
Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia.
2
Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, 3010, Australia.
3
Cell Signaling and Cancer Laboratory, European Cancer Stem Cell Research Institute and Cardiff University, Cardiff, CF24 4HQ, UK.
4
Institute of Biochemistry, Goethe University Frankfurt, Frankfurt am Main, 60438, Frankfurt, Germany.
5
Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, and Department of Medical Biology, University of Melbourne, Melbourne, VIC, 3052, Australia.
6
Department of Immunology and Pathology, Monash University, Melbourne, VIC, 3004, Australia.
7
Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, and Department of Medical Biology, University of Melbourne, Melbourne, VIC, 3052, Australia.
8
Department of Medicine, University of Melbourne, Melbourne, VIC, 3050, Australia.
9
Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, 5000, Australia.
10
OMNI-Biomarker Development, Genentech Inc., South San Francisco, CA, 94080, USA.
11
Team 5, Centre of Physiopathology Toulouse-Purpan, INSERM UMR 1043/CNRS UMR 5282, University Toulouse III, CHU Purpan, 31024, Toulouse, France.
12
Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia. Matthias.ernst@onjcri.org.au.

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.

PMID:
31227713
PMCID:
PMC6588585
DOI:
10.1038/s41467-019-10676-1
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center