Platelet-derived growth factor receptor-α promotes lymphatic metastases in papillary thyroid cancer

Lymph node metastases are common in papillary thyroid cancer (PTC) and can be resistant to surgical extirpation or radioiodine ablation. We examined the role of platelet-derived growth factor receptor (PDGFR) in mediating lymph node metastases in PTC. Clinical specimens of PTC (n = 137) were surveyed in a tissue array and by western blots to examine the relationship between expression of the alpha and beta subunits of PDGFR and lymph node metastases. PDGFR-a was found at high levels in primary tumours with known lymphatic metastases but not in those tumours lacking nodal involvement (p < 0.0001). However, PDGFR-beta expression was not linked to metastatic disease (p = 0.78) as it was found in virtually all PTC specimens. A matching analysis in fresh PTC specimens (n = 13) confirmed that PDGFR-alpha expression was strongly linked to metastatic spread (p = 0.0047). PDGFR-alpha and -beta were not found in normal thyroid tissue (p < 0.0001). PTC cell lines selectively expressing PDGFR-alpha or -beta were assessed for invasive potential and activation of downstream signal transduction pathways. PTC cell lines expressing PDGFR-alpha responded to PDGF-BB stimulation with increased invasive potential and this process can be blocked by the tyrosine kinase receptor inhibitor sunitinib (p < 0.009). Cell lines with only PDGFR-beta, or no PDGFR, did not show significant changes in invasive potential. Activation of PDGFR-alpha led to downstream up-regulation of both the MAPK/ERK and PI3K/Akt pathways and disruption of either pathway is sufficient to block PDGFR-mediated increases in invasive potential. Thus, PDGFR-alpha is associated with lymph node metastases in papillary thyroid carcinoma and PDGFR-a promotes increased invasive potential in PTC cell lines. PDGFR-a is a strong candidate for a diagnostic biomarker to identify patients at risk of nodal metastases. Our results also strengthen the rationale for selection of tyrosine kinase receptor inhibitors that target PDGFR in the treatment of progressive, metastatic PTC. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.