TY - JOUR
T1 - TLR9 ligation in pancreatic stellate cells promotes tumorigenesis
AU - Zambirinis, Constantinos P.
AU - Levie, Elliot
AU - Nguy, Susanna
AU - Avanzi, Antonina
AU - Barilla, Rocky
AU - Xu, Yijie
AU - Seifert, Lena
AU - Daley, Donnele
AU - Greco, Stephanie H.
AU - Deutsch, Michael
AU - Jonnadula, Saikiran
AU - Torres-Hernandez, Alejandro
AU - Tippens, Daniel
AU - Pushalkar, Smruti
AU - Eisenthal, Andrew
AU - Saxena, Deepak
AU - Ahn, Jiyoung
AU - Hajdu, Cristina
AU - Engle, Dannielle D.
AU - Tuveson, David
AU - Miller, George
N1 - Funding Information:
We thank the New York University Langone Medical Center (NYU LMC) Histopathology Core Facility, supported in part by the Cancer Center Support grant P30CA01608; the NYU LMC Flow Cytometry Core Facility, supported in part by the Cancer Center Support grant P30CA016087; the NYU LMC Microscopy Core Facility; and the NYU LMC BioRepository Center, supported in part by the Cancer Center Support Grant P30CA016087, and by grant UL1 TR000038 from the National Center for the Advancement of Translational Science (NCA TS). This work was supported by NCI CA168611 (G. Miller), CA155649 (G. Miller), CA193111 (G. Miller and A. Torres-Hernandez), Department of Defense Peer Reviewed Medical Research Program (G. Miller), German Research Foundation (L. Seifert), the Lustgarten Foundation (G. Miller), AACR-PanCan (G. Miller), the Panpaphian Association of America (C.P. Zambirinis), the Irene and Bernard Schwartz Fellowship in GI Oncology (D. Daley), and the National Pancreas Foundation (C.P. Zambirinis). The authors declare no competing financial interests.
Publisher Copyright:
© 2015 Zambirinis et al.
PY - 2015/11/16
Y1 - 2015/11/16
N2 - Modulation of Toll-like receptor (TLR) signaling can have protective or protumorigenic effects on oncogenesis depending on the cancer subtype and on specific inflammatory elements within the tumor milieu. We found that TLR9 is widely expressed early during the course of pancreatic transformation and that TLR9 ligands are ubiquitous within the tumor microenvironment. TLR9 ligation markedly accelerates oncogenesis, whereas TLR9 deletion is protective. We show that TLR9 activation has distinct effects on the epithelial, inflammatory, and fibrogenic cellular subsets in pancreatic carcinoma and plays a central role in cross talk between these compartments. Specifically, TLR9 activation can induce proinflammatory signaling in transformed epithelial cells, but does not elicit oncogene expression or cancer cell proliferation. Conversely, TLR9 ligation induces pancreatic stellate cells (PSCs) to become fibrogenic and secrete chemokines that promote epithelial cell proliferation. TLR9-activated PSCs mediate their protumorigenic effects on the epithelial compartment via CCL11. Additionally, TLR9 has immune-suppressive effects in the tumor microenvironment (TME) via induction of regulatory T cell recruitment and myeloid- derived suppressor cell proliferation. Collectively, our work shows that TLR9 has protumorigenic effects in pancreatic carcinoma which are distinct from its influence in extrapancreatic malignancies and from the mechanistic effects of other TLRs on pancreatic oncogenesis.
AB - Modulation of Toll-like receptor (TLR) signaling can have protective or protumorigenic effects on oncogenesis depending on the cancer subtype and on specific inflammatory elements within the tumor milieu. We found that TLR9 is widely expressed early during the course of pancreatic transformation and that TLR9 ligands are ubiquitous within the tumor microenvironment. TLR9 ligation markedly accelerates oncogenesis, whereas TLR9 deletion is protective. We show that TLR9 activation has distinct effects on the epithelial, inflammatory, and fibrogenic cellular subsets in pancreatic carcinoma and plays a central role in cross talk between these compartments. Specifically, TLR9 activation can induce proinflammatory signaling in transformed epithelial cells, but does not elicit oncogene expression or cancer cell proliferation. Conversely, TLR9 ligation induces pancreatic stellate cells (PSCs) to become fibrogenic and secrete chemokines that promote epithelial cell proliferation. TLR9-activated PSCs mediate their protumorigenic effects on the epithelial compartment via CCL11. Additionally, TLR9 has immune-suppressive effects in the tumor microenvironment (TME) via induction of regulatory T cell recruitment and myeloid- derived suppressor cell proliferation. Collectively, our work shows that TLR9 has protumorigenic effects in pancreatic carcinoma which are distinct from its influence in extrapancreatic malignancies and from the mechanistic effects of other TLRs on pancreatic oncogenesis.
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U2 - 10.1084/jem.20142162
DO - 10.1084/jem.20142162
M3 - Article
C2 - 26481685
AN - SCOPUS:84964391958
VL - 212
SP - 2077
EP - 2094
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 12
ER -