Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs
Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs
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DOI：
10.1002/ijc.20410
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发表时间：
2004-11-01
影响因子：
6.4
通讯作者：
Entschladen, F
中科院分区：
文献类型：
--
作者：
Lang, K;Drell, TL;Entschladen, F
肿瘤细胞的主动迁移是肿瘤转移发展和癌症进展的关键要求，受包括神经递质在内的信号物质的调节。我们使用时间推移视频显微镜和计算机辅助分析迁移路径，研究了肿瘤细胞在三维胶原基质中的迁移。肿瘤细胞的迁移是由去甲肾上腺素、多巴胺和P物质诱导的。我们证明，使用MDA-MB-468乳腺癌细胞和PC-3前列腺癌细胞，这种诱导迁移可以被临床上建立的分别针对β2肾上腺素受体、D2受体或神经激肽I受体的特异性受体拮抗剂所抑制。所有被研究的神经递质都显著激活了环磷酸腺苷反应元件结合蛋白(CREB)。此外，微阵列分析显示，向高运动性肿瘤细胞类型的基因表达发生了变化，包括α2整合素上调，这是胶原蛋白迁移过程中必不可少的黏附受体。肿瘤抑制因子明胶蛋白的基因表达下调。流式细胞仪和免疫印迹分别在蛋白水平上证实了这两个关键的改变。因此，神经递质通过直接调节基因表达和增加迁移活性来诱导转移性肿瘤细胞类型，这可以通过现有的神经递质拮抗剂来防止。(C)2004年Wiley-Liss公司
The active migration of tumor cells, a crucial requirement for metastasis development and cancer progression, is regulated by signal substances including neurotransmitters. We investigated the migration of tumor cells within a three-dimensional collagen matrix using time-lapse videomicroscopy and computer-assisted analysis of the migration path. Tumor cell migration is induced by norepinephrine, dopamine and substance P. We show that this induced migration, using MDA-MB-468 breast and PC-3 prostate carcinoma cells, can be inhibited by using specific, clinically established receptor antagonists to the beta2-adrenoceptor, the D2 receptor, or the neurokinin-I receptor, respectively. All of the investigated neurotransmitters significantly activated the cyclic adenosine-monophosphate response element binding protein (CREB). Furthermore, microarray analysis revealed changes of gene expression toward a highly motile tumor cell type, including an upregulation of the alpha2 integrin, which is an essential adhesion receptor for collagen in migration. The gene for the tumor suppressor gelsolin was downregulated. These 2 critical alterations were confirmed on the protein level by flow-cytometry and immunoblotting, respectively. Neurotransmitters thus induce a metastatogenic tumor cell type by directly regulating gene expression and increased migratory activity, which can be prevented by established neurotransmitter antagonists. (C) 2004 Wiley-Liss, Inc.