Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans

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

Research output: Contribution to journalArticle

104 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4118-4129
Number of pages12
JournalJournal of Clinical Investigation
Volume122
Issue number11
DOIs
StatePublished - Nov 1 2012

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Ochi, A., Graffeo, C. S., Zambirinis, C. P., Rehman, A., Hackman, M., Fallon, N., Barilla, R. M., Henning, J. R., Jamal, M., Rao, R., Greco, S., Deutsch, M., Medina-Zea, M. V., Saeed, U. B., Ego-Osuala, M. O., Hajdu, C., & Miller, G. (2012). Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans. Journal of Clinical Investigation, 122(11), 4118-4129. https://doi.org/10.1172/JCI63606