The Journal of clinical investigation, 2012-11, Vol.122 (11), p.4118-4129
2012
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- Autor(en) / Beteiligte
- Titel
- Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans
- Ist Teil von
- The Journal of clinical investigation, 2012-11, Vol.122 (11), p.4118-4129
- Ort / Verlag
- United States: American Society for Clinical Investigation
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9738eISSN: 1558-8238DOI: 10.1172/jci63606Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3484447
- Format
- –
- Schlagworte
- Adenocarcinoma, Animal models, Animals, Biomedical research, c-Myc protein, Cancer cells, Carcinogenesis, Carcinoma, Pancreatic Ductal - genetics, Carcinoma, Pancreatic Ductal - immunology, Carcinoma, Pancreatic Ductal - metabolism, Carcinoma, Pancreatic Ductal - pathology, Care and treatment, Cell Transformation, Neoplastic - genetics, Cell Transformation, Neoplastic - immunology, Cell Transformation, Neoplastic - metabolism, Cell Transformation, Neoplastic - pathology, Cyclin B1, cyclin D1, Data processing, Development and progression, Environmental effects, Gene Expression Regulation, Neoplastic - genetics, Gene Expression Regulation, Neoplastic - immunology, Genetic aspects, Genetic regulation, Growth factors, Humans, Immunity, Immunity, Innate - genetics, Inflammation, Inflammation - genetics, Inflammation - immunology, Inflammation - metabolism, Inflammation - pathology, Invasiveness, Leukocytes, MAP kinase, MAP Kinase Signaling System - genetics, MAP Kinase Signaling System - immunology, Membrane Glycoproteins - genetics, Membrane Glycoproteins - immunology, Membrane Glycoproteins - metabolism, Mice, Mice, Mutant Strains, Microenvironments, Neoplasia, Neoplasm Proteins - genetics, Neoplasm Proteins - immunology, Neoplasm Proteins - metabolism, NF- Kappa B protein, Notch protein, p53 protein, Pancreatic cancer, Pancreatic Neoplasms - genetics, Pancreatic Neoplasms - immunology, Pancreatic Neoplasms - metabolism, Pancreatic Neoplasms - pathology, Peroxisome proliferator-activated receptors, PTEN protein, Signal transduction, Stat3 protein, stromal cells, TLR7 protein, Toll-Like Receptor 7 - genetics, Toll-Like Receptor 7 - immunology, Toll-Like Receptor 7 - metabolism, Toll-like receptors, Transforming growth factor- beta, Tumorigenesis