Cytoplasmic TRAIL-R1 is a positive prognostic marker in PDAC

Jan-Paul Gundlach,Christoph Röcken,Christian Röder,Christine Böger,Thomas Becker,Franka Maria Schlegel,Holger Kalthoff,Charlotte Hauser,Anna Trauzold,Jan-Hendrik Egberts

doi:10.1186/s12885-018-4688-8

Jan-Paul Gundlach, Christoph Röcken + Show 8 more

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https://doi.org/10.1186/s12885-018-4688-8

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Abstract

BackgroundThe death receptors TRAIL-R1 and TRAIL-R2 are frequently overexpressed in cancer and there is an emerging evidence for their important role in malignant progression, also in the case of pancreatic ductal adenocarcinoma (PDAC). In their canonical localization at the plasma membrane, TRAIL-R1/−R2 may induce cell death and/or pro-inflammatory signaling leading to cell migration, invasion and metastasis. Although, they have repeatedly been found intracellular, in the cytoplasm and in the nucleus, their functions in intracellular locations are still not well understood. Likewise, studies dealing with the prognostic relevance of TRAIL-Rs located in particular cellular compartments are very rare. For PDAC, the correlation of nuclear TRAIL-R2 with worse patients’ prognosis has been shown recently. Corresponding data on TRAIL-R1 are not available so far.MethodsIn the present study we analyzed the expression of TRAIL-R1 in 106 PDACs and 28 adjacent, peritumoral non-malignant pancreatic ducts with special emphasis on its cytoplasmic and nuclear localization and correlated the immunohistochemical findings with clinico-pathological patient characteristics.ResultsTRAIL-R1 was found in 93.4% of all PDAC samples. Cytoplasmic staining was present with very similar intensity in tumor and normal tissue. In contrast, nuclear TRAIL-R1 staining was significantly stronger in tumor compared to normal tissue (p = 0.006). Interestingly, we found that the number of cells with cytoplasmic TRAIL-R1 staining negatively correlates with tumor grading (p = 0.043). No such correlation could be detected for nuclear TRAIL-R1. Neither, cytoplasmic nor nuclear TRAIL-R1 staining showed a correlation with other clinico-pathological parameter such as pTNM categories. However, Kaplan-Meier analyses revealed significantly prolonged median survival of patients with positive cytoplasmic TRAIL-R1 expression in more than 80% of tumor cells compared to patients with tumors containing a smaller quantity of cells positively stained for cytoplasmic TRAIL-R1 (20 vs. 8 months; p = 0.004).ConclusionCytoplasmic TRAIL-R1 is a positive prognostic marker for patients with PDAC. Our findings indicate that loss of cytoplasmic TRAIL-R1 results in recurrent disease with more malignant phenotype thus suggesting anti-tumor activities of cytoplasmic TRAIL-R1 in PDAC.

Highlights

The death receptors TNFrelated apoptosis inducing ligand (TRAIL)-R1 and TRAIL-R2 are frequently overexpressed in cancer and there is an emerging evidence for their important role in malignant progression, in the case of pancreatic ductal adenocarcinoma (PDAC)
It became evident that TRAIL-R1 and TRAIL-R2 may respond to TRAIL - apart from apoptosis induction - with activation of different non-apoptotic signal transduction pathways like NF-kB, ERK1/ERK2, JNK, Src and AKT [4], which can lead to the inhibition of apoptosis as well as to cell proliferation, migration and invasion
In PDAC cells, others and we have shown that regardless of the simultaneous presence of TRAIL-R1 and TRAIL-R2 at the cell surface, these cells use predominantly TRAIL-R1 when treated with recombinant TRAIL [9, 10]

Summary

Introduction

The death receptors TRAIL-R1 and TRAIL-R2 are frequently overexpressed in cancer and there is an emerging evidence for their important role in malignant progression, in the case of pancreatic ductal adenocarcinoma (PDAC) In their canonical localization at the plasma membrane, TRAIL-R1/−R2 may induce cell death and/or pro-inflammatory signaling leading to cell migration, invasion and metastasis. TNF-related apoptosis inducing ligand (TRAIL) and its death inducing receptors TRAIL-R1 and TRAIL-R2 are promising candidates for the development of such novel targeted strategies The rationale behind this assumption is the original observations that i) TRAIL induces apoptosis preferentially in tumor cells leaving normal healthy cells alive; ii) tumor cells usually express high levels of either TRAIL-R1 or TRAIL-R2 or both. In PDAC cells, others and we have shown that regardless of the simultaneous presence of TRAIL-R1 and TRAIL-R2 at the cell surface, these cells use predominantly TRAIL-R1 when treated with recombinant TRAIL [9, 10]

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