title: Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis.
abstract: Signalling by the toll-like receptor (TLR) family of pathogen recognition receptors has emerged as a key molecular component in the pathogenesis of an increasing number of inflammatory-related cancers, among which gastric cancer rates as the second most lethal cancer world-wide. The myeloid differentiation factor 88 (MyD88) adapter molecule has a critical role in mediating innate immune signalling by members of the TLR and interleukin (IL)-1 families, and has been associated with either pro- or antitumourigenic responses in various cancer models. However, little is known about the in vivo role of MyD88 adapter-like (Mal)/TIR-domain containing adapter protein (TIRAP), which is restricted to facilitating TLR4 and TLR2 signalling. To interrogate the role of these innate immune signalling components in gastric tumourigenesis, here we have employed the spontaneous gastric cancer gp130(F/F) mouse model, in which TLR2 promotes the growth of gastric tumours. Genetic ablation of Myd88 in gp130(F/F) mice suppressed tumourigenesis and was associated with increased apoptosis and reduced proliferation in the gastric tumour epithelium, comparable to that observed previously upon deletion of Tlr2 in gp130(F/F) mice. By contrast, the tumour burden in gp130(F/F):Mal(-/-) mice was equivalent to their gp130(F/F) littermates. At the molecular level, suppressed tumourigenesis in gp130(F/F):Myd88(-/-) mice correlated with reduced expression and activation of TLR2-regulated protumourigenic genes and signalling pathways, respectively. Consistent with the previously defined non-essential role for TLR2 in gastric tumour inflammation, the extent of inflammatory cell infiltrates in gastric tumours from gp130(F/F):Mal(-/-) and gp130(F/F):Myd88(-/-) mice remained unaltered compared with gp130(F/F) mice. Collectively, our data reveal a differential, but inflammation-independent, requirement for Mal and MyD88 during TLR2-promoted gastric tumourigenesis.
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: C L
authors.initials: CL
authors.lastname: Kennedy
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Najdovska
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Tye
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: L
authors.initials: L
authors.lastname: McLeod
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.affiliation: Ludwig Institute of Cancer Research, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Jarnicki
authors.affiliation: Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: P S
authors.initials: PS
authors.lastname: Bhathal
authors.affiliation: Ludwig Institute of Cancer Research, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Putoczki
authors.affiliation: Ludwig Institute of Cancer Research, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Ernst
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: B J
authors.initials: BJ
authors.lastname: Jenkins
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013274:Stomach Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2