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

被引：181

作者：

Eissmann, Moritz F. ^{[1
,2
]}

Dijkstra, Christine ^{[1
,2
]}

Jarnicki, Andrew ^{[14
]}

Phesse, Toby ^{[1
,2
,9
,10
]}

Brunnberg, Jamina ^{[1
,2
,11
]}

Poh, Ashleigh R. ^{[1
,2
]}

Etemadi, Nima ^{[1
,2
,5
,12
]}

Tsantikos, Evelyn ^{[3
]}

Thiem, Stefan ^{[1
,2
]}

Huntington, Nicholas D. ^{[4
,5
]}

Hibbs, Margaret L. ^{[3
]}

Boussioutas, Alex ^{[6
]}

Grimbaldeston, Michele A. ^{[7
,8
,13
]}

Buchert, Michael ^{[1
,2
]}

O'Donoghue, Robert J. J. ^{[1
,2
,14
]}

Masson, Frederick ^{[1
,2
,15
]}

Ernst, Matthias ^{[1
,2
]}

机构：

[1] La Trobe Univ, Canc & Inflammat Lab, Olivia Newton John Canc Res Inst, Heidelberg, Vic 3084, Australia

[2] La Trobe Univ, Sch Canc Med, Heidelberg, Vic 3084, Australia

[3] Monash Univ, Dept Immunol & Pathol, Melbourne, Vic 3004, Australia

[4] Univ Melbourne, Mol Immunol Div, Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3052, Australia

[5] Univ Melbourne, Dept Med Biol, Melbourne, Vic 3052, Australia

[6] Univ Melbourne, Dept Med, Melbourne, Vic 3050, Australia

[7] Univ South Australia, Ctr Canc Biol, Adelaide, SA 5000, Australia

[8] SA Pathol, Adelaide, SA 5000, Australia

[9] European Canc Stem Cell Res Inst, Cell Signaling & Canc Lab, Cardiff CF24 4HQ, S Glam, Wales

[10] Cardiff Univ, Cardiff CF24 4HQ, S Glam, Wales

[11] Goethe Univ Frankfurt, Inst Biochem, D-60438 Frankfurt, Germany

[12] Univ Melbourne, Cell Signalling & Cell Death Div, Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3052, Australia

[13] Genentech Inc, OMNI & Bionnarker Dev, San Francisco, CA 94080 USA

[14] Univ Melbourne, Dept Pharmacol & Therapeut, Melbourne, Vic 3010, Australia

[15] Univ Toulouse III, CHU Purpan, Ctr Physiopathol Toulouse Purpan, Team 5,INSERM,UMR 1043,CNRS,UMR 5282, F-31024 Toulouse, France

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

英国医学研究理事会;

关键词：

GENE-EXPRESSION; POOR-PROGNOSIS; INTERLEUKIN; 33; BREAST-CANCER; TUMOR STAGE; RECEPTOR; IL-33; ANGIOGENESIS; TUMORIGENESIS; INFLAMMATION;

D O I：

10.1038/s41467-019-10676-1

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 tumorassociated 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 ll6. 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.

引用

页数：16

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