Document Detail


Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans.
MedLine Citation:
PMID:  23023703     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Atsuo Ochi; Christopher S Graffeo; Constantinos P Zambirinis; Adeel Rehman; Michael Hackman; Nina Fallon; Rocky M Barilla; Justin R Henning; Mohsin Jamal; Raghavendra Rao; Stephanie Greco; Michael Deutsch; Marco V Medina-Zea; Usama Bin Saeed; Melvin O Ego-Osuala; Cristina Hajdu; George Miller
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-12-26     Completed Date:  2013-01-15     Revised Date:  2013-12-13    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4118-29     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Carcinoma, Pancreatic Ductal / genetics,  immunology,  metabolism*,  pathology
Cell Transformation, Neoplastic / genetics,  immunology,  metabolism*,  pathology
Gene Expression Regulation, Neoplastic / genetics,  immunology
Humans
Immunity, Innate / genetics
Inflammation / genetics,  immunology,  metabolism,  pathology
MAP Kinase Signaling System / genetics,  immunology
Membrane Glycoproteins / genetics,  immunology,  metabolism*
Mice
Mice, Mutant Strains
Neoplasm Proteins / genetics,  immunology,  metabolism*
Pancreatic Neoplasms / genetics,  immunology,  metabolism*,  pathology
Toll-Like Receptor 7 / genetics,  immunology,  metabolism*
Grant Support
ID/Acronym/Agency:
CA155649/CA/NCI NIH HHS; DK085278/DK/NIDDK NIH HHS; P30 CA016087/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Membrane Glycoproteins; 0/Neoplasm Proteins; 0/TLR7 protein, human; 0/Tlr7 protein, mouse; 0/Toll-Like Receptor 7
Comments/Corrections

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