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Differential somatostatin, CXCR4 chemokine and endothelin A receptor expression in WHO grade I–IV astrocytic brain tumors

  • Original Article – Cancer Research
  • Published:
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Abstract

Purpose

Glioblastomas represent the most common primary malignant tumor of the nervous system and the most frequent type of astrocytic tumors. Despite improved therapeutic options, prognosis has remained exceptionally poor over the last two decades. Therefore, new treatment approaches are urgently needed. An overexpression of somatostatin (SST) as well as chemokine CXCR4 and endothelin A (ETA) receptors has been shown for many types of cancer. Respective expression data for astrocytic brain tumors, however, are scarce and contradictory.

Methods

SST subtype, CXCR4 and ETA expression was comparatively evaluated in a total of 57 grade I–IV astrocytic tumor samples by immunohistochemistry using well-characterized monoclonal antibodies.

Results

Overall, receptor expression on the tumor cells was only very low. SST5 was the most prominently expressed receptor, followed by SST3, ETA, SST2 and CXCR4. In contrast, tumor capillaries displayed strong SST2, SST3, SST5, CXCR4 and ETA expression. Presence of SST5, CXCR4 and ETA on tumor cells and of SST3, CXCR4 and ETA on microvessels gradually increased from grade II to grade IV tumors. Ki-67 values correlated significantly with CXCR4 expression on tumor cells and with vascular SST3, CXCR4 or ETA positivity. SST5 or CXCR4 positivity of tumor cells and vascular SST3 or CXCR4 expression negatively correlated with patient outcome.

Conclusions

Though having some prognostic value, SST, CXCR4 or ETA expression on astrocytic tumor cells is clearly of no therapeutic relevance. Indirect targeting of these highly vascularized tumors via SST3, SST5, CXCR4 or ETA on the microvessels, in contrast, may represent a promising additional therapeutic strategy.

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Abbreviations

CXCR4:

C–X–C motif chemokine receptor 4

ETA:

Endothelin receptor A

SST:

Somatostatin receptor

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Funding

The Theranostic Research Center, Zentralklinik Bad Berka, 99437 Bad Berka, Germany, provided funding for this research.

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Author notes

  1. Franziska Lange and Daniel Kaemmerer contributed equally to the first authorship.

Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Str. 1, 07747, Jena, Germany

    Franziska Lange, Stefan Schulz & Amelie Lupp

  2. Department of General and Visceral Surgery, Zentralklinik Bad Berka, Bad Berka, Germany

    Daniel Kaemmerer

  3. Department of Neurosurgery, Zentralklinik Bad Berka, Bad Berka, Germany

    Julianne Behnke-Mursch

  4. Institute of Pathology, University Medical Centre Göttingen, University of Göttingen, Göttingen, Germany

    Wolfgang Brück

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  1. Franziska Lange
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Contributions

Conceived and designed the experiments: Daniel Kaemmerer, Amelie Lupp. Provided the tumor samples: Julianne Behnke-Mursch, Wolfgang Brück. Provided the antibodies: Stefan Schulz. Acquired the clinical data: Daniel Kaemmerer. Performed the experiments: Franziska Lange, Amelie Lupp. Analyzed the data: Franziska Lange, Amelie Lupp. Interpreted the data: Amelie Lupp. Wrote the paper: Amelie Lupp. Revised critically the manuscript: Franziska Lange, Daniel Kaemmerer, Julianne Behnke-Mursch, Wolfgang Brück, Stefan Schulz. Each of the authors has approved the manuscript and acknowledges that he or she participated sufficiently in the work to take public responsibility for its content.

Corresponding author

Correspondence to Amelie Lupp.

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Conflict of interest

Daniel Kaemmerer received funding and support for travelling to meetings by the companies Ipsen and Pfizer. All other authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Permission was gained from the local ethics committee (Ethikkommission der Landesärztekammer Thüringen) for this retrospective analysis. For this type of study formal consent is not required. All data were recorded and analyzed anonymously.

Electronic supplementary material

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432_2018_2645_MOESM1_ESM.tif

Supplemental Figure S1: Typical examples of positive control immunostainings for somatostatin receptors (SST) and CXCR4. SST2, SST3 and SST5: pancreatic islets; CXCR4: germinal center of a lymph node; ETA: placenta. Immunohistochemistry (red-brown color), counterstaining with hematoxylin; scale bar: 20 µm (TIF 18252 KB)

432_2018_2645_MOESM2_ESM.tif

Supplemental Figure S2: Overall survival of patients with WHO grade I-IV astrocytic brain tumors (log-rank-test: p = 0.003) (TIF 929 KB)

Supplementary material 3 (DOCX 23 KB)

Supplementary material 4 (DOCX 22 KB)

Supplementary material 5 (DOCX 22 KB)

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Lange, F., Kaemmerer, D., Behnke-Mursch, J. et al. Differential somatostatin, CXCR4 chemokine and endothelin A receptor expression in WHO grade I–IV astrocytic brain tumors. J Cancer Res Clin Oncol 144, 1227–1237 (2018). https://doi.org/10.1007/s00432-018-2645-1

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