Wnt/β-Catenin Signaling Regulates CXCR4 Expression and [68Ga] Pentixafor Internalization in Neuroendocrine Tumor Cells.

Alexander Weich,Alexander Meining,Theodor Kudlich,Judit Pongracz,Wolfgang Weich,Michael Scheurlen,Sophia Gawlas,Dorothee Rogoll,Lars Mayer

doi:10.3390/diagnostics11020367

Alexander Weich, Alexander Meining + Show 7 more

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https://doi.org/10.3390/diagnostics11020367

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Journal: Diagnostics	Publication Date: Feb 22, 2021
Citations: 7	License type: CC BY 4.0

Affiliation: University Hospital Würzburg, University of Pecs

Abstract

Loss of Somatostatin Receptor 2 (SSTR2) expression and rising CXC Chemokine Receptor Type 4 (CXCR4) expression are associated with dedifferentiation in neuroendocrine tumors (NET). In NET, CXCR4 expression is associated with enhanced metastatic and invasive potential and worse prognosis but might be a theragnostic target. Likewise, activation of Wnt/β-catenin signaling may promote a more aggressive phenotype in NET. We hypothesized an interaction of the Wnt/β-catenin pathway with CXCR4 expression and function in NET. The NET cell lines BON-1, QGP-1, and MS-18 were exposed to Wnt inhibitors (5-aza-CdR, quercetin, and niclosamide) or the Wnt activator LiCl. The expressions of Wnt pathway genes and of CXCR4 were studied by qRT-PCR, Western blot, and immunohistochemistry. The effects of Wnt modulators on uptake of the CXCR4 ligand [68Ga] Pentixafor were measured. The Wnt activator LiCl induced upregulation of CXCR4 and Wnt target gene expression. Treatment with the Wnt inhibitors had opposite effects. LiCl significantly increased [68Ga] Pentixafor uptake, while treatment with Wnt inhibitors decreased radiopeptide uptake. Wnt pathway modulation influences CXCR4 expression and function in NET cell lines. Wnt modulation might be a tool to enhance the efficacy of CXCR4-directed therapies in NET or to inhibit CXCR4-dependent proliferative signaling. The underlying mechanisms for the interaction of the Wnt pathway with CXCR4 expression and function have yet to be clarified.

Highlights

Neuroendocrine neoplasia (NEN) is a heterogeneous group of tumors with increasing incidence originating from cells of the neuroendocrine system
In the three cell lines, the effects of different Wnt-modulators on canonical Wnt signal transduction were characterized by Quantitative RT-PCR (qRT-PCR) of the Wnt effector β-catenin and the Wnt target genes MYC, TCF7, and CCND1 (Figure 1)
Its pathological overexpression in various hemalogic and solid neoplasms as well as in NEN was found to be associated with the acquisition tologic and solid neoplasms as well as in NEN was found to be associated with the acquiof a mesenchymal phenotype favoring proliferation, invasion, and metastasis as well as a sition of a mesenchymal phenotype favoring proliferation, invasion, and metastasis as poorer prognosis when compared to tumors with low CXC Chemokine Receptor Type 4 (CXCR4) expression [4,5]

Summary

Introduction

Neuroendocrine neoplasia (NEN) is a heterogeneous group of tumors with increasing incidence originating from cells of the neuroendocrine system. Two thirds of all neuroendocrine tumors develop in the gastrointestinal tract or the pancreas [1,2]. Neuroendocrine carcinomas (NEC) are undifferentiated tumors with high proliferation rates (Ki-67 > 80%), whereas the histologically differentiated neuroendocrine tumors (NET) typically show proliferation rates between 1% and 50%. NET retain histological characteristics and functional properties of the original neuroendocrine tissue. This may result in tissue-specific expression of somatostatin receptors [1]. The clinically most relevant receptor in NET is somatostatin receptor type 2 (SSTR2), which is expressed by most well-differentiated NET and represents the pivotal diagnostic and therapeutic target in

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Conclusion