J Cancer 2018; 9(6):929-940. doi:10.7150/jca.23042

Research Paper

CXCR4/CXCR7/CXCL12-Axis in Follicular Thyroid Carcinoma

Thomas Artur Werner1, Christina Maria Forster1, Levent Dizdar1, Pablo Emilio Verde2, Katharina Raba3, Matthias Schott4, Wolfram Trudo Knoefel1, Andreas Krieg1✉

1. Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
2. Coordination Centre for Clinical Trials, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany
3. Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany
4. Division of Endocrinology, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany

Abstract

Background: Follicular thyroid carcinoma's (FTC) often benign course is partially due to adjuvant radioactive iodine (RAI) treatment. However, once the tumour has spread and fails to retain RAI, the therapeutic options are limited and the outcome is poor. In this subset of patients, the identification of novel druggable biomarkers appears invaluable. Here, we investigated the stage dependent expression and functional role of the C-X-C chemokine receptors type 4 and 7 (CXCR4/7) in FTC.

Methods: CXCR4/7 expression was examined in 44 FTC and corresponding non-neoplastic thyroid specimens as well as 10 FTC distant metastases and 18 follicular adenomas using tissue microarray technology. Expression levels were correlated with clinicopathological variables as well as overall and recurrence free survival. Changes regarding cell cycle activation, tumour cell invasiveness and mRNA expression of genes related to epithelial-mesenchymal transition (EMT) were investigated after treatment with recombinant human SDF1α/CXCL12 (rh-SDF1α) and CXCR4 antagonists AMD3100 and WZ811.

Results: CXCR4/7 expression was associated with large tumour size, advanced UICC stage as well as shorter overall and recurrence free survival. CXCR4 was significantly higher expressed in distant metastases than in primary tumour cores. In addition, rh-SDF1α induced invasive growth, cell cycle activation and EMT, while CXCR4 antagonists significantly reduced FTC invasiveness in vitro.

Conclusion: Here we provide first evidence of the biological importance of the CXCR4/CXCR7/CXCL12 axis in FTC. Our findings underscore the therapeutic potential of this chemokine receptor family in advanced FTC and offer new valuable insight into the oncogenesis of metastatic FTC.

Keywords: CXCR4, CXCR7, CXCL12, FTC, metastasis

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How to cite this article:
Werner TA, Forster CM, Dizdar L, Verde PE, Raba K, Schott M, Knoefel WT, Krieg A. CXCR4/CXCR7/CXCL12-Axis in Follicular Thyroid Carcinoma. J Cancer 2018; 9(6):929-940. doi:10.7150/jca.23042. Available from http://www.jcancer.org/v09p0929.htm