Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer.

Tanja Grimmig,Carmen Ribas,Felix Rueckert,Romana Moench,Jennifer Kreckel,Stephanie Haack,Martin Gasser,Roberta Rehder,Ana Waaga-Gasser,Sudipta Tripathi,Anil Chandraker,Christoph Germer

doi:10.3390/ijms17122060

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.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal type of digestive cancer with a five-year survival rate of about 7%
In esophageal cancer TLR3, -4, -7, and -9 overexpression has been demonstrated in 70%, 72%, 67%, and 78% of patient tumors, respectively, and, as in breast cancer, poor prognosis was associated with elevated TLR3 expression on tumor cells, patients expressing increased TLR9 associated with fibroblasts exhibited improved survival [12,13,14]
We analyzed whether other Toll like receptors such as TLR2, -4, and -9 are expressed in pancreatic cancer and may influence tumor cell signaling and proliferation to elucidate their potential for therapeutic strategies in this devastating tumor

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal type of digestive cancer with a five-year survival rate of about 7%. In addition to a panel of pathogen-associated molecular patterns (PAMPs) including cell-wall components like lipopolysaccharide (LPS) as well as microbial DNA and RNA, DAMPs which arise from inflammation and cellular injury can stimulate TLRs and induce TLR signaling that supports an inflammatory microenvironment [5,6]. In esophageal cancer TLR3, -4, -7, and -9 overexpression has been demonstrated in 70%, 72%, 67%, and 78% of patient tumors, respectively, and, as in breast cancer, poor prognosis was associated with elevated TLR3 expression on tumor cells, patients expressing increased TLR9 associated with fibroblasts exhibited improved survival [12,13,14]. In one report, enhanced TLR4 expression was identified in 69% of patients with pancreatic cancer and correlated with increased NF-κB signaling, enhanced hypoxia-inducible factor-1α (HIF-1α) expression, and dramatically reduced patient survival [13,15]

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