Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant neoplasms and registers rising death rates in western countries. Due to its late detection in advanced stages, its extremely aggressive nature and the minimal effectiveness of currently available therapies, PDAC is a challenging problem in the clinical field. One characteristic of PDAC is a distinct desmoplasia consisting of fibroblasts, endothelial and immune cells as well as non-cellular components, contributing to therapy resistance. It is well established that the NF-κB signaling pathway controls inflammation, cancer progression and apoptosis resistance in PDAC. This study attempts to identify NF-κB target genes mediating therapy resistance of humane PDAC cell lines towards death ligand induced apoptosis. By using a genome wide unbiased approach the chemokine CX3CL1 was established as a central NF-κB target gene mediating therapy resistance. While no direct impact of CX3CL1 expression on cancer cell apoptosis was identified in co-culture assays it became apparent that CX3CL1 is acting in a paracrine fashion, leading to an increased recruitment of inflammatory cells. These inflammatory cells in turn mediate apoptosis resistance of PDAC cells. Therefore, our data dissect a bifunctional cross-signaling pathway in PDAC between tumor and immune cells giving rise to therapy resistance.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in Western countries
Given the fact that the inducible but not constitutive NF-κB activity prevents death receptor mediated signaling in PDAC cells [14], the present study aimed to identify RelA target genes jointly responsible for TNF alpha related apoptosis inducing ligand (TRAIL) mediated apoptosis resistance in pancreatic cancer cells
In a second transcriptome analysis resistant Panc1 cells were first treated with specific siRNA towards the most abundant NF-κB subunit RelA or control siRNA and treated with TRAIL to identify RelA dependent TRAIL target genes
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in Western countries. The interaction of attracted immune cells with cancer cells gained particular attention because cytokines secreted by immune cells seem to promote the initiation, propagation and metastasis of tumors [4]. A continuously increasing body of evidence shows that in addition to the desmoplastic cells the cancer cells express a variety of cytokines to create a tumor-promoting microenvironment. Pancreatic cancer cells secrete for instance IL-13 to stimulate tumor promoting macrophages [5] or the chemokine CCL20 which facilitates the attraction of immune cells providing resistance against death receptor ligand mediated apoptosis [6]. A third modality of cytokine mediated tumor promotion, cancer cells express cytokine receptors and foster via the binding of the corresponding ligand an autocrine signaling loop which promotes cancer cell growth [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
