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Hyperactive gp130/STAT3-driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development

Hill, David, Yu, Liang, Gao, Hugh, Balic, Jesse J., West, Alison, Oshima, Hiroko, McLeod, Louise, Oshima, Masanobu, Gallimore, Awen M., D'Costa, Kimberley, Bhathal, Prithi S., Sievert, William, Ferrero, Richard L., Jenkins, Brendan J. and Jones, Gareth W. 2018. Hyperactive gp130/STAT3-driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development. International Journal of Cancer 143 (1) , pp. 167-178. 10.1002/ijc.31298

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Abstract

Tertiary lymphoid structures (TLSs) display phenotypic and functional characteristics of secondary lymphoid organs, and often develop in tissues affected by chronic inflammation, as well as in certain inflammation-associated cancers where they are prognostic of improved patient survival. However, the mechanisms that govern the development of tumour-associated TLSs remain ill-defined. Here, we observed tumour-associated TLSs in a preclinical mouse model (gp130F/F) of gastric cancer, where tumourigenesis is dependent on hyperactive STAT3 signalling through the common IL-6 family signalling receptor, gp130. Gastric tumourigenesis was associated with the development of B and T cell-rich submucosal lymphoid aggregates, containing CD21+ cellular networks and high endothelial venules. Temporally, TLS formation coincided with the development of gastric adenomas and induction of homeostatic chemokines including Cxcl13, Ccl19 and Ccl21. Reflecting the requirement of gp130-driven STAT3 signalling for gastric tumourigenesis, submucosal TLS development was also STAT3-dependent, but independent of the cytokine IL-17 which has been linked with lymphoid neogenesis in chronic inflammation and autoimmunity. Interestingly, upregulated lymphoid chemokine expression and TLS formation were also observed in a chronic gastritis model induced by Helicobacter felis infection. Tumour-associated TLSs were also observed in patients with intestinal-type gastric cancer, and a gene signature linked with TLS development in gp130F/F mice was associated with advanced clinical disease, but was not prognostic of patient survival. Collectively, our in vivo data reveal that hyperactive gp130-STAT3 signalling closely links gastric tumourigenesis with lymphoid neogenesis, and while a TLS gene signature was associated with advanced gastric cancer in patients, it did not indicate a favourable prognosis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Publisher: Wiley
ISSN: 0020-7136
Funders: CARBS Research Committee Internal Schemes, Fujitsu, NERC, Horizon 2020, Arthritis Research UK: Grant number 20305, Medical Research Council, Wellcome Trust, Cancer Research UK, Victorian Government's Operational Infrastructure Support Program, National Health and Medical Research Council of Australia (NHMRC), NHMRC Senior Research Fellowships, Australian Government Australian Postgraduate Award, Life Sciences Research Network Wales, International Postgraduate Scholarship (Monash University)
Date of First Compliant Deposit: 16 February 2018
Date of Acceptance: 30 January 2018
Last Modified: 15 Apr 2019 08:37
URI: http://orca.cf.ac.uk/id/eprint/109197

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