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 - Publisher Copyright:
© 2015 Zambirinis et al.
PY - 2015/10/16
Y1 - 2015/10/16
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.
KW - Animals
KW - Cell Line, Tumor
KW - Cell Proliferation/genetics
KW - Cell Transformation, Neoplastic/drug effects
KW - Cells, Cultured
KW - Chemokine CCL11/metabolism
KW - Chemokines/metabolism
KW - Epithelial Cells/metabolism
KW - Immunoblotting
KW - Ligands
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Microscopy, Confocal
KW - Oligodeoxyribonucleotides/pharmacology
KW - Pancreatic Neoplasms/genetics
KW - Pancreatic Stellate Cells/metabolism
KW - Signal Transduction/genetics
KW - Toll-Like Receptor 9/genetics
KW - Tumor Microenvironment/drug effects
UR - http://www.scopus.com/inward/record.url?scp=84964391958&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000368248200011&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1084/jem.20142162
DO - 10.1084/jem.20142162
M3 - Article
C2 - 26481685
SN - 0022-1007
VL - 212
SP - 2077
EP - 2094
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 12
ER -