title: Deficiency of the myeloid differentiation primary response molecule MyD88 leads to an early and rapid development of Helicobacter-induced gastric malignancy.
abstract: Approximately 50% of the world's population is infected with Helicobacter pylori, leading to chronic inflammation, which increases the risk for gastric adenocarcinoma. MyD88 is a key adaptor molecule in inflammatory pathways involved in interleukin 1 (IL-1)/IL-18/Toll-like receptor signaling and has been shown to have divergent effects in carcinogenesis. The role of MyD88 in Helicobacter-induced gastric malignancy is unknown. Using a mouse model of Helicobacter-induced gastric cancer, we assessed the role of MyD88 in cancer development by evaluating gastric histopathology, apoptosis, proliferation, and cytokine expression. Infection of MyD88-deficient (Myd88(-/-)) mice with Helicobacter resulted in early and rapid advancement to gastric dysplasia as early as 25 weeks postinfection. The progression of Helicobacter-induced disease to precancerous and cancerous lesions in the absence of MyD88 signaling was accompanied by increased gastric epithelial apoptosis and proliferation. In addition, inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), IL-6, and IL-1β were highly expressed in association with the development of gastric dysplasia. These data suggest that MyD88 signaling retards development and progression to cancer during Helicobacter infection. This is the first study to show evidence of MyD88 protection in an infection-driven inflammation-associated cancer model.
authors.affiliation: Department of Biology and Center for Microbial Sciences, San Diego State University, San Diego, California, USA.
authors.forename: Anirban
authors.initials: A
authors.lastname: Banerjee
authors.forename: Soracha
authors.initials: S
authors.lastname: Thamphiwatana
authors.forename: Ellese M
authors.initials: EM
authors.lastname: Carmona
authors.forename: Barry
authors.initials: B
authors.lastname: Rickman
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Doran
authors.forename: Marygorret
authors.initials: M
authors.lastname: Obonyo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000166:cytology; D005753:Gastric Mucosa / Q000166:cytology; D015964:Gene Expression Regulation, Bacterial; D016481:Helicobacter Infections / Q000150:complications*; D016480:Helicobacter pylori / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D011230:Precancerous Conditions / Q000382:microbiology / Q000473:pathology; D000081207:Primary Immunodeficiency Diseases; D013274:Stomach Neoplasms / Q000382:microbiology* / Q000473:pathology / Q000503:physiopathology
chemical_list: D016207:Cytokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88