Platelet derived growth factor receptor-alpha promotes lymphatic metastases in papillary thyroid cancer
The Journal of Pathology, 07/05/2012
Zhang J et al. – Thus PDGFR-alpha is associated with lymph node metastases in papillary thyroid carcinoma and that PDGFR-alpha promotes increased invasive potential in PTC cell lines. PDGFR-alpha 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.Methods
- 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 the PDGFR receptor and lymph node metastases.
- PDGFR-alpha 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-alpha 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-alpha 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.