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Citations to this article

Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans
Atsuo Ochi, … , Cristina Hajdu, George Miller
Atsuo Ochi, … , Cristina Hajdu, George Miller
Published October 1, 2012
Citation Information: J Clin Invest. 2012;122(11):4118-4129. https://doi.org/10.1172/JCI63606.
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Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans

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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

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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British Journal of Cancer 2013
Role of bacterial infections in pancreatic cancer
DS Michaud
Carcinogenesis 2013
Induction of TRIF- or MYD88-dependent pathways perturbs cell cycle regulation in pancreatic cancer
CP Zambirinis, A Ochi, R Barilla, S Greco, M Deutsch, G Miller
Cell cycle (Georgetown, Tex.) 2013
Signaling via MYD88 in the pancreatic tumor microenvironment: A double-edged sword
CP Zambirinis, G Miller
OncoImmunology 2013
The activation of TLR7 regulates the expression of VEGF, TIMP1, MMP2, IL-6, and IL-15 in Hela cells
L Li, FW Cheng, F Wang, B Jia, X Luo, SQ Zhang
Molecular and Cellular Biochemistry 2013
Trial Watch
E Vacchelli, A Eggermont, C Sautès-Fridman, J Galon, L Zitvogel, G Kroemer, L Galluzzi
OncoImmunology 2013
Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes
KE Craven, J Gore, JL Wilson, M Korc
Oncotarget 2010
Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2009

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