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

Abstract

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 α and β subunits of PDGFR and lymph node metastases. PDGFR-α 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-β 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-α expression was strongly linked to metastatic spread (p = 0.0047). PDGFR-α and -β were not found in normal thyroid tissue (p < 0.0001). PTC cell lines selectively expressing PDGFR-α or -β were assessed for invasive potential and activation of downstream signal transduction pathways. PTC cell lines expressing PDGFR-α 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-β, or no PDGFR, did not show significant changes in invasive potential. Activation of PDGFR-α 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-α is associated with lymph node metastases in papillary thyroid carcinoma and PDGFR-α promotes increased invasive potential in PTC cell lines. PDGFR-α 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.

Autotaxin is an inflammatory mediator and therapeutic target in thyroid cancer

“…PDGF-AA levels are higher in malignancy (Fig. 2C) indicating probable activation of the PDGFRa cascade and its signalling pathways that are strongly associated with cell migration and angiogenesis as shown for papillary thyroid cancer (Xue et al 2012, Zhang et al 2012. Conversely, the level of TRAIL ligand (CD253), a central driver of apoptosis (Oikonomou & Pintzas 2013), was decreased by 75% in primary tumours compared to normal tissue (Fig.…”

“…Immunohistochemistry was performed on formalin-fixed, 5 mm paraffin-embedded tissue sections (Zhang et al 2012, Benesch et al 2014b Table 1, see section on supplementary data given at the end of this article for a list of analytes). Tissue specimens (5-10 mg) were homogenized in 200 ml of 20 mM Tris HCl (pH 7.5) buffer with 0.5% Tween 20, 150 mM NaCl and protease inhibitor, centrifuged for 10 min at 4 8C and then the supernatant was transferred to a fresh tube.…”

Lenvatinib and other tyrosine kinase inhibitors for the treatment of radioiodine refractory, advanced, and progressive thyroid cancer

“…Moreover, DTCs, as well as many other human tumors, has mutations or overexpression of some receptors such as vascular endothelial growth factor receptor 1–3 (VEGF-R 1–3), fibroblast growth factor receptor 1–4 (FGF-R 1–4), and platelets-derived growth factor receptor alpha (PDGF-R α). The TKI can exert a block of these receptors, thus limiting angiogenesis and lymphangiogenesis 18,19…”

PDGFRα Regulates Follicular Cell Differentiation Driving Treatment Resistance and Disease Recurrence in Papillary Thyroid Cancer

“…Sample cores on the tissue array that were fragmented or incomplete were not scored. As described in multiple reports, the cytoplasmic staining of PDGFRα and PDGFRβ was assessed for each case, in triplicate, as 3 +, (strong, diffuse), 2 + (strong, focal), 1 + (weak staining), or 0 (minimal staining) (Zhang et al, 2012, Gonzalez-Campora et al, 2011, Barreca et al, 2011). …”