Biological role and potential therapeutic targeting of the chemokine receptor CXCR4 in undifferentiated thyroid cancer
Biological role and potential therapeutic targeting of the chemokine receptor CXCR4 in undifferentiated thyroid cancer
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DOI：
10.1158/0008-5472.can-07-0899
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发表时间：
2007-12-15
期刊：
影响因子：
11.2
通讯作者：
Melillo, Rosa Marina
中科院分区：
文献类型：
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作者：
De Falco, Valentina;Guarino, Valentina;Melillo, Rosa Marina
间变性甲状腺癌(ATC)是一种罕见的甲状腺癌类型，预后极差。尽管进行了适当的治疗，包括手术、放疗和化疗，但这种癌症总是致命的。CXCR4是基质细胞衍生因子-1(SDF-1)/CXCL12趋化因子的受体，在包括甲状腺乳头状癌在内的多种实体瘤中均有表达。在这里，我们发现ATC细胞系在mRNA和蛋白质水平上都过表达CXCR4。此外，我们还通过实时荧光定量聚合酶链式反应和免疫组织化学方法发现CXCR4在ATC临床标本中的表达高于正常甲状腺组织。SDF-1诱导ATC细胞增殖，细胞外信号调节蛋白和蛋白激酶B/AKT的磷酸化增加。这些作用可被特异性的CXCR4拮抗剂AMD3100和CXCR4 RNA干扰所阻断。此外，AMD3100有效地抑制了裸鼠接种不同ATC细胞的肿瘤生长，因此，我们认为CXCR4靶向治疗人类ATC是一种新的潜在策略。
Anaplastic thyroid carcinoma (ATC) is a rare thyroid cancer type with an extremely poor prognosis. Despite appropriate treatment, which includes surgery, radiotherapy, and chemotherapy, this cancer is invariably fatal. CXCR4 is the receptor for the stromal cell-derived factor-1 (SDF-1)/CXCL12 chemokine and it is expressed in a variety of solid tumors, including papillary thyroid carcinoma. Here, we show that ATC cell lines overexpress CXCR4, both at the level of mRNA and protein. Furthermore, we found that CXCR4 was overexpressed in ATC clinical samples, with respect to normal thyroid tissues by real-time PCR and immunohistochemistry. Treatment of ATC cells with SDF-1 induced proliferation and increase in phosphorylation of extracellular signal-regulated kinases and protein kinase B/AKT. These effects were blocked by the specific CXCR4 antagonist AMD3100 and by CXCR4 RNA interference. Moreover, AMD3100 effectively reduced tumor growth in nude mice inoculated with different ATC cells.,thus, we suggest that CXCR4 targeting is a novel potential strategy in the treatment of human ATC.