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Hill DG
; Yu L
; Gao H
; Balic JJ
; West A
; Oshima H
; McLeod L
; Oshima M
; Gallimore A
; D'Costa K
; Bhathal PS
; Sievert W
; Ferrero RL
; Jenkins BJ
; Jones GW
Int J Cancer
2018[Jul]; 143
(1
): 167-178
PMID29417587
show ga
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 (gp130(F/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 gp130(F/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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