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

David G. Hill, Liang Yu, Hugh Gao, Jesse J. Balic, Alison West, Hiroko Oshima, Louise McLeod, Masanobu Oshima, Awen Gallimore, Kimberley D'Costa, Prithi S. Bhathal, William Sievert, Richard L. Ferrero, Brendan J. Jenkins, Gareth W. Jones

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)167-178
Number of pages12
JournalInternational Journal of Cancer
Volume143
Issue number1
DOIs
Publication statusPublished - 1 Jul 2018

Keywords

  • ectopic lymphoid structures
  • gastric cancer
  • interleukin-17
  • STAT3
  • tertiary lymphoid structures

Cite this

Hill, David G. ; Yu, Liang ; Gao, Hugh ; Balic, Jesse J. ; West, Alison ; Oshima, Hiroko ; McLeod, Louise ; Oshima, Masanobu ; Gallimore, Awen ; D'Costa, Kimberley ; Bhathal, Prithi S. ; Sievert, William ; Ferrero, Richard L. ; Jenkins, Brendan J. ; Jones, Gareth W. / Hyperactive gp130/STAT3-driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development. In: International Journal of Cancer. 2018 ; Vol. 143, No. 1. pp. 167-178.
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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.",
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author = "Hill, {David G.} and Liang Yu and Hugh Gao and Balic, {Jesse J.} and Alison West and Hiroko Oshima and Louise McLeod and Masanobu Oshima and Awen Gallimore and Kimberley D'Costa and Bhathal, {Prithi S.} and William Sievert and Ferrero, {Richard L.} and Jenkins, {Brendan J.} and Jones, {Gareth W.}",
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Hyperactive gp130/STAT3-driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development. / Hill, David G.; Yu, Liang; Gao, Hugh; Balic, Jesse J.; West, Alison; Oshima, Hiroko; McLeod, Louise; Oshima, Masanobu; Gallimore, Awen; D'Costa, Kimberley; Bhathal, Prithi S.; Sievert, William; Ferrero, Richard L.; Jenkins, Brendan J.; Jones, Gareth W.

In: International Journal of Cancer, Vol. 143, No. 1, 01.07.2018, p. 167-178.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Hyperactive gp130/STAT3-driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development

AU - Hill, David G.

AU - Yu, Liang

AU - Gao, Hugh

AU - Balic, Jesse J.

AU - West, Alison

AU - Oshima, Hiroko

AU - McLeod, Louise

AU - Oshima, Masanobu

AU - Gallimore, Awen

AU - D'Costa, Kimberley

AU - Bhathal, Prithi S.

AU - Sievert, William

AU - Ferrero, Richard L.

AU - Jenkins, Brendan J.

AU - Jones, Gareth W.

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N2 - 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.

AB - 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.

KW - ectopic lymphoid structures

KW - gastric cancer

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