Department of Surgery, University of Alberta, Edmonton, Canada.
J Pathol. 2012 Oct;228(2):241-50. doi: 10.1002/path.4069. Epub 2012 Sep 4.
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.
淋巴结转移在甲状腺乳头状癌（PTC）中很常见，并且可能对手术切除或放射性碘消融有抗性。我们研究了血小板衍生生长因子受体（PDGFR）在介导 PTC 淋巴结转移中的作用。通过组织阵列和 Western blot 检查了 137 例 PTC 临床标本，以研究 PDGFR-α和-β亚基的表达与淋巴结转移之间的关系。在已知有淋巴转移的原发肿瘤中发现 PDGFR-α高水平表达，但在无淋巴结受累的肿瘤中则没有（p<0.0001）。然而，PDGFR-β的表达与转移性疾病无关（p=0.78），因为它几乎存在于所有 PTC 标本中。对 13 例新鲜 PTC 标本的匹配分析证实，PDGFR-α的表达与转移扩散密切相关（p=0.0047）。PDGFR-α和-β在正常甲状腺组织中均未发现（p<0.0001）。评估了选择性表达 PDGFR-α或-β的 PTC 细胞系的侵袭潜力和下游信号转导途径的激活。表达 PDGFR-α的 PTC 细胞系在受到 PDGF-BB 刺激后，侵袭潜力增加，而这种过程可以被酪氨酸激酶受体抑制剂舒尼替尼阻断（p<0.009）。只有 PDGFR-β或没有 PDGFR 的细胞系在侵袭潜力方面没有明显变化。PDGFR-α的激活导致 MAPK/ERK 和 PI3K/Akt 途径的下游上调，并且破坏任何一条途径都足以阻断 PDGFR 介导的侵袭潜力增加。因此，PDGFR-α与甲状腺乳头状癌的淋巴结转移有关，PDGFR-α促进 PTC 细胞系侵袭潜力的增加。PDGFR-α是识别有淋巴结转移风险的患者的诊断生物标志物的有力候选者。我们的研究结果还为选择靶向 PDGFR 的酪氨酸激酶受体抑制剂治疗进展性、转移性 PTC 提供了更强的理论依据。
