Differential Roles of Tumor Necrosis Factor Ligand Superfamily Members as Biomarkers in Pancreatic Cancer.

Ines Pombeiro,Sanchari Roy,Tom Luedde,Ulf Neumann,Marcel Binnebösel,Christian Trautwein,Mark Luedde,Florian Schueller,Frank Tacke,Wenzel Schoening,Christoph Roderburg,Mihael Vucur,Lukas Niewenhuisen,Sven Loosen

doi:10.3390/jcm7070175

Ines Pombeiro, Sanchari Roy + Show 12 more

Open Access

https://doi.org/10.3390/jcm7070175

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Abstract

The tumor necrosis factor–related weak inducer of apoptosis (TWEAK) belongs to the tumor necrosis factor ligand superfamily, which was shown to play an important role in inflammatory and malignant gastrointestinal diseases, including colitis or colorectal cancer. However, in contrast to other members of the TNF ligand superfamily, its role as a biomarker in pancreatic cancer is currently unknown. We analyzed serum levels of A proliferation-inducing ligand (APRIL) and TWEAK in 134 patients with pancreatic cancer. Results were compared with 50 healthy controls and correlated with clinical data. Intratumoral expression of APRIL and TWEAK in pancreatic cancer was analysed using the datasets made available by the TCGA-LIHC project. APRIL serum levels were significantly elevated in patients with pancreatic cancer compared to healthy controls, which is in line with previous findings. Notably, the diagnostic accuracy of circulating APRIL levels was similar to CA19-9, an established tumor marker for pancreatic cancer. In contrast, serum concentrations of TWEAK were decreased in pancreatic cancer patients. Interestingly, no differences in TWEAK concentrations became apparent between different clinical subgroups of pancreatic cancer. Moreover, within our cohort of patients, TWEAK levels did not correlate with the patients’ prognosis and the diagnostic as well as prognostic potential of TWEAK was lower than CA 19-9, when analyzed in this setting. Finally, using data from the TCGA-LIHC project, we demonstrate that expression levels of TWEAK and APRIL represent prognostic markers for patients’ survival according to Kaplan-Meier curve analyses. TWEAK and APRIL serum concentrations are regulated differently in patients with pancreatic cancer, highlighting diverse roles of variant TNF ligands in this type of cancer.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the 12th most common cancer worldwide [1]
A proliferation-inducing ligand (APRIL) serum levels were significantly elevated in patients with pancreatic cancer compared to healthy controls, which is in line with previous findings
APRIL Serum Concentrations Are Elevated in Patients with Pancreatic Cancer

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the 12th most common cancer worldwide [1]. Prognostic biomarkers could represent a useful tool to divide pancreatic cancer patients into different subgroups, providing each patient an optimal personalized therapeutic approach according to the individual likelihood to benefit from a specific surgical, chemotherapeutic, or conservative treatment [3]. The TNF superfamily ligands represent a class of type II transmembrane proteins, exerting their biological activity as non-covalently bound trimers [9]. Activation of TNF receptor (TNFR) members has been shown to play a pivotal role during infectious and inflammatory diseases. Besides TNF, different members of the TNF ligand superfamily including A proliferation inducing ligand (APRIL) and tumor necrosis factor–related weak inducer of apoptosis (TWEAK) have been implicated in the pathogenesis of cancer [10,11,12,13]

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