Sancho Margarida, Vieira Joaquim Miguel, Casalou Cristina, Mesquita Marta, Pereira Teresa, Cavaco Branca Maria, Dias Sérgio, Leite Valeriano
Molecular Endocrinology, Centro de Investigação de Patobiologica Molecular (CIPM), Instituto Português de Oncologia Francisco Gentil, Rua Professor Lima Basto, 1099-023 Lisboa, Portugal.
J Endocrinol. 2006 Oct;191(1):229-38. doi: 10.1677/joe.1.06688.
The chemokine receptor CCR7 plays a critical role in lymphocyte and dendritic cell trafficking into and within lymph nodes, the preferential metastatic site for papillary (PTC) and medullary (MTC) thyroid carcinomas. In order to determine a possible role for CCR7 in mediating the metastatic behaviour of thyroid carcinomas, we analysed its expression in normal and tumoral thyroid tissues of different histotypes and studied the in vitro effects of its activation by the CCR7 ligand, CCL21. Using real-time quantitative-PCR, we observed that CCR7 expression was higher in PTCs and MTCs than in follicular and poorly differentiated thyroid carcinomas. CCR7 expression was ninefold higher in classic compared with follicular variants of PTCs, and its expression in MTCs was significantly correlated with lymph node metastases. Immunohistochemical staining for CCR7 showed protein expression in neoplastic thyroid cells, with higher intensity in PTCs, MTCs and their lymph node metastases (LNMs). We further showed that CCL21 stimulation of a CCR7-expressing thyroid tumour cell line (TPC-1) promotes cell proliferation and migration, and the chemotactic effect of CCL21 in these cells involves actin polymerization, increased beta1-integrin expression and increased matrix metalloproteinase secretion. Taken together, our results demonstrate that CCR7 activation on thyroid carcinoma cells by CCL21 - a chemokine abundantly expressed in lymph nodes - favours tissue invasion and cell proliferation, and therefore may promote thyroid carcinoma growth and LNM.
趋化因子受体CCR7在淋巴细胞和树突状细胞迁移至淋巴结以及在淋巴结内迁移的过程中发挥着关键作用，而淋巴结是乳头状甲状腺癌（PTC）和髓样甲状腺癌（MTC）的优先转移部位。为了确定CCR7在介导甲状腺癌转移行为中可能发挥的作用，我们分析了其在不同组织学类型的正常和肿瘤性甲状腺组织中的表达，并研究了其CCR7配体CCL21激活后的体外效应。通过实时定量PCR，我们观察到CCR7在PTC和MTC中的表达高于滤泡状和低分化甲状腺癌。与PTC的滤泡状变体相比，经典型PTC中CCR7的表达高9倍，并且其在MTC中的表达与淋巴结转移显著相关。CCR7的免疫组化染色显示在甲状腺肿瘤细胞中有蛋白表达，在PTC、MTC及其淋巴结转移灶（LNMs）中表达强度更高。我们进一步表明，CCL21对表达CCR7的甲状腺肿瘤细胞系（TPC-1）的刺激促进细胞增殖和迁移，并且CCL21在这些细胞中的趋化作用涉及肌动蛋白聚合、β1整合素表达增加和基质金属蛋白酶分泌增加。综上所述，我们的结果表明，淋巴结中大量表达的趋化因子CCL21对甲状腺癌细胞上CCR7的激活有利于组织侵袭和细胞增殖，因此可能促进甲状腺癌生长和LNMs。
