CXCR4/CXCR7/CXCL12 axis promotes an invasive phenotype in medullary thyroid carcinoma

Background: Medullary thyroid carcinoma (MTC) is a rare and challenging endocrine malignancy. Once spread, the therapeutic options are limited and the outcome poor. For these patients, the identification of new druggable biological markers is of great importance. Here, we investigated the prognostic and biological role of the C-X-C chemokine receptors type 4 and 7 (CXCR4/7) in MTC. Methods: Eighty-six MTC and corresponding non-neoplastic thyroid specimens were immunohistochemically stained for CXCR4/7 using tissue microarray technology and expression levels correlated with clinicopathological variables. Medullary thyroid carcinoma cell line TT was treated with recombinant human SDF1 alpha/CXCL12 (rh-SDF1 alpha) and CXCR4 antagonists AMD3100 and WZ811. Changes in cell cycle activation, tumour cell invasiveness as well as changes in mRNA expression levels of genes associated with epithelial-mesenchymal transition (EMT) were investigated. Results: High CXCR4 expression was associated with large tumour size and metastatic disease. CXCR4 antagonists significantly reduced tumour cell invasiveness, while the treatment with rh-SDF1 alpha stimulated invasive growth, caused cell cycle activation and induced EMT. Conclusions: The CXCR4/CXCR7/CXCL12 axis plays an important role in MTC. We provide first evidence that the chemokine receptors might serve as potential therapeutic targets in patients with advanced MTC and offer new valuable insight into the underlying molecular machinery of metastatic MTC.