title: Toll-like receptor 7 regulates pancreatic  carcinogenesis in mice and humans.
abstract: Pancreatic ductal adenocarcinoma is an aggressive cancer that interacts with stromal cells to produce a highly inflammatory tumor microenvironment that promotes tumor growth and invasiveness. The precise interplay between tumor and stroma remains poorly understood. TLRs mediate interactions between environmental stimuli and innate immunity and trigger proinflammatory signaling cascades. Our finding that TLR7 expression is upregulated in both epithelial and stromal compartments in human and murine pancreatic cancer led us to postulate that carcinogenesis is dependent on TLR7 signaling. In a mouse model of pancreatic cancer, TLR7 ligation vigorously accelerated tumor progression and induced loss of expression of PTEN, p16, and cyclin D1 and upregulation of p21, p27, p53, c-Myc, SHPTP1, TGF-β, PPARγ, and cyclin B1. Furthermore, TLR7 ligation induced STAT3 activation and interfaced with Notch as well as canonical NF-κB and MAP kinase pathways, but downregulated expression of Notch target genes. Moreover, blockade of TLR7 protected against carcinogenesis. Since pancreatic tumorigenesis requires stromal expansion, we proposed that TLR7 ligation modulates pancreatic cancer by driving stromal inflammation. Accordingly, we found that mice lacking TLR7 exclusively within their inflammatory cells were protected from neoplasia. These data suggest that targeting TLR7 holds promise for treatment of human pancreatic cancer.
authors.affiliation: Department of Surgery, S. Arthur Localio Laboratory, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Ochi
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Graffeo
authors.forename: Constantinos P
authors.initials: CP
authors.lastname: Zambirinis
authors.forename: Adeel
authors.initials: A
authors.lastname: Rehman
authors.forename: Michael
authors.initials: M
authors.lastname: Hackman
authors.forename: Nina
authors.initials: N
authors.lastname: Fallon
authors.forename: Rocky M
authors.initials: RM
authors.lastname: Barilla
authors.forename: Justin R
authors.initials: JR
authors.lastname: Henning
authors.forename: Mohsin
authors.initials: M
authors.lastname: Jamal
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Rao
authors.forename: Stephanie
authors.initials: S
authors.lastname: Greco
authors.forename: Michael
authors.initials: M
authors.lastname: Deutsch
authors.forename: Marco V
authors.initials: MV
authors.lastname: Medina-Zea
authors.forename: Usama
authors.initials: U
authors.lastname: Bin Saeed
authors.forename: Melvin O
authors.initials: MO
authors.lastname: Ego-Osuala
authors.forename: Cristina
authors.initials: C
authors.lastname: Hajdu
authors.forename: George
authors.initials: G
authors.lastname: Miller
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C495348:TLR7 protein, human; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7