Different somatostatin and CXCR4 chemokine receptor expression in gastroenteropancreatic neuroendocrine neoplasms depending on their origin

Rebekka Mai,Elisa Neubauer,Amelie Lupp,Tina Träger,Daniel Kaemmerer,Richard P Baum,Stefan Schulz,Jörg Sänger

doi:10.1038/s41598-019-39607-2

Rebekka Mai, Elisa Neubauer + Show 6 more

Open Access

https://doi.org/10.1038/s41598-019-39607-2

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Abstract

Somatostatin receptors (SST), especially SST2A, are known for their overexpression in well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). The chemokine receptor CXCR4, in contrast, is considered to be present mainly in highly proliferative and advanced tumors. However, comprehensive data are still lacking on potential differences in SST or CXCR4 expression pattern in GEP-NEN in dependence on the place of origin. Overall, 412 samples from 165 GEP-NEN patients, comprising both primary tumors (PT) and metastases (MTS), originating from different parts of the gastrointestinal tract or the pancreas were evaluated for SST and CXCR4 expression by means of immunohistochemistry using monoclonal antibodies. SST2A was present in 85% of PT with a high intensity of expression, followed by SST5 (23%), CXCR4 (21%), SST3 (10%), SST1 (9%), and SST4 (4%). PT displayed higher SST2A and chromogranin A (CgA) expression levels than MTS. In both PT and MTS lower SST2A and CgA expression levels were found in tumors originating from the appendix or colon, compared to tumors from other origins. Tumors derived from appendix or colon were associated with significantly worse patient outcomes. Positive correlations were noted between SST2A and CgA as well as between CXCR4 and Ki-67 expression levels. SST2A and CgA negativity of the tumors was significantly associated with poor patient outcomes. All in all, SST2A was the most prominent receptor expressed in the GEP-NEN samples investigated. However, expression levels varied considerably depending on the location of the primary tumor.

Highlights

Somatostatin receptors (SST), especially SST2A, are well known for their overexpression in well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), where they serve as the molecular basis for SST-based diagnostics and treatment modalities
Insets in E–H: for adsorption controls the anti-SST antibodies and the anti-CXCR4 antibody were incubated with 10 μg/ml of the peptide used for immunizations (+Peptide)
The present study revealed a distinct correlation between SST2A and chromogranin A (CgA) expression, confirming previous results[37]

Summary

Introduction

Somatostatin receptors (SST), especially SST2A, are well known for their overexpression in well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), where they serve as the molecular basis for SST-based diagnostics and treatment modalities. The chemokine receptor CXCR4, in contrast, is considered to be present mainly in highly proliferative and advanced tumors In many studies, it has been demonstrated, that elevated CXCR4 expression is associated with rapid tumor progression, high invasiveness, early metastasis, and poor patient outcome[1,2]. Apart from that, it has been suggested that malignancy as well as overall survival rates may differ depending on the localization of the GEP-NEN along the gastrointestinal tract, with higher malignancy (Ki-67 levels) and lower survival rates in hindgut as compared to foregut tumors[18]. The aim of the present study was to re-evaluate SST and CXCR4 expression in a large set of formalin-fixed, paraffin-embedded GEP-NEN samples originating from stomach, duodenum/jejunum, ileum, appendix, colon, rectum or pancreas by using well characterized rabbit monoclonal antibodies[19,20,21,22,23] and to correlate the expression with clinical data

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