title: Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer.
abstract: Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers. TLR-stimulated pancreatic cancer cells were specifically investigated for activated signaling pathways of VEGF/PDGF and anti-apoptotic Bcl-xL expression as well as tumor cell growth. The primary pancreatic cancers and cell lines expressed TLR2, -4, and -9. TLR-specific stimulation resulted in activated MAP-kinase signaling, most likely via autoregulative stimulation of demonstrated TLR-induced VEGF and PDGF expression. Moreover, TLR activation prompted the expression of Bcl-xL and has been demonstrated for the first time to induce tumor cell proliferation in pancreatic cancer. These findings strongly suggest that pancreatic cancer cells use specific Toll like receptor signaling to promote tumor cell proliferation and emphasize the particular role of TLR2, -4, and -9 in this autoregulative process of tumor cell activation and proliferation in pancreatic cancer.
authors.affiliation: Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, 97080 Wuerzburg, Germany. Grimmig_T@ukw.de.
authors.forename: Tanja
authors.initials: T
authors.lastname: Grimmig
authors.affiliation: Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, 97080 Wuerzburg, Germany. Moench_R@ukw.de.
authors.forename: Romana
authors.initials: R
authors.lastname: Moench
authors.affiliation: Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, 97080 Wuerzburg, Germany. Jennifer.Kreckel@uni-wuerzburg.de.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kreckel
authors.affiliation: Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, 97080 Wuerzburg, Germany. stephanie-haack@web.de.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Haack
authors.affiliation: Surgical Clinic Mannheim, University of Heidelberg, 68167 Mannheim, Germany. felix.rueckert@umm.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Rueckert
authors.affiliation: Medical School, Evangelic Faculty of Paraná, 80730-000 Curitiba, Brazil. robertarehder1@gmail.com.
authors.forename: Roberta
authors.initials: R
authors.lastname: Rehder
authors.affiliation: Brigham and Women's Hospital, Transplant Research Center, Harvard Medical School, Boston, MA 02115, USA. STRIPATHI@PARTNERS.ORG.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: Medical School, Evangelic Faculty of Paraná, 80730-000 Curitiba, Brazil. marcondes.ribas@gmail.com.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ribas
authors.affiliation: Brigham and Women's Hospital, Transplant Research Center, Harvard Medical School, Boston, MA 02115, USA. ACHANDRAKER@PARTNERS.ORG.
authors.forename: Anil
authors.initials: A
authors.lastname: Chandraker
authors.affiliation: Department of Surgery I, University of Wuerzburg, 97080 Wuerzburg, Germany. Germer_c@ukw.de.
authors.forename: Christoph T
authors.initials: CT
authors.lastname: Germer
authors.affiliation: Department of Surgery I, University of Wuerzburg, 97080 Wuerzburg, Germany. gasser_m@ukw.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Gasser
authors.affiliation: Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, 97080 Wuerzburg, Germany. waaga_a@ukw.de.|Brigham and Women's Hospital, Transplant Research Center, Harvard Medical School, Boston, MA 02115, USA. waaga_a@ukw.de.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Waaga-Gasser
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005455:Fluorescent Antibody Technique; D006801:Humans; D020935:MAP Kinase Signaling System; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D050500:Pancreatitis, Chronic / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D010982:Platelet-Derived Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D042461:Vascular Endothelial Growth Factor A; D051020:bcl-X Protein
keywords: TLR2; TLR4; TLR9; inflammation; pancreatic cancer; tumor growth