Migration deficit in monocyte-macrophages in human ovarian cancer
Migration deficit in monocyte-macrophages in human ovarian cancer
复制标题
DOI：
10.1007/s00262-007-0401-5
复制
发表时间：
2008-05-01
影响因子：
5.8
通讯作者：
Marincola, Francesco M.
中科院分区：
文献类型：
--
作者：
Freedman, Ralph S.;Ma, Qing;Marincola, Francesco M.
目的探讨表达互补受体的单核细胞/巨噬细胞（MO/MA）对上皮性卵巢癌（EOC）肿瘤环境中产生的趋化因子的迁移反应。方法检测趋化因子受体CCR1、CCR5和CXCR4在EOC相关腹水和血MO/MA中的表达；在MO/MA迁移实验中，它们对互补趋化因子的反应；在肌动蛋白聚合实验中，它们对f -肌动蛋白含量的反应。然后利用经过验证的cDNA微阵列分析来检查可与细胞迁移识别的途径基因的改变。结果腹水和EOC血MO/MA表达CCR1、CCR5和CXCR4，但差异不显著。CCR1和CCR5在腹水中的细胞表面表达水平高于正常血液，而CXCR4在腹水MO/MA中的表达水平较低。EOC相关的腹水或血液中MO/MA不能响应CC配体RANTES和CXCR4反应性趋化因子SDF1 （CXCL12）而迁移。腹水和大多数EOC血MO/MA在聚合/解聚试验中的表现也与正常血MO不同。对纯化的腹水MO/MA的cDNA基因分析表明，与正常血液MO相比，腹水MO/MA中与趋化因子产生、局灶黏着、肌动蛋白细胞骨架功能和白细胞跨内皮迁移有关的基因在腹水MO/MA中下调。此外，EOC患者血液中的PBMC cDNA也显示出与腹水MO/MA相似的基因谱。结论EOC患者体内MO/MA的迁移和聚合/解聚活性的缺陷以及关键途径基因的显著下调表明，系统来源的MO在EOC患者肿瘤部位的积累可能涉及其他机制。
Purpose To examine the migration responses of monocyte/macrophages (MO/MA) expressing complementary receptors to chemokines produced in the tumor environment of epithelial ovarian cancer (EOC).Methods We examined the expression of the chemokine receptors, CCR1, CCR5, and CXCR4, on EOC associated ascitic and blood MO/MA; their response to complementary chemokines in a MO/MA migration assay and the F-actin content in an actin polymerization assay. A validated cDNA microarray assay was then utilized to examine alterations in pathway genes that can be identified with cell migration.Results Ascitic and EOC blood MO/MA express CCR1, CCR5 and CXCR4, but differently. Cell surface expression levels for CCR1 and CCR5 were higher in ascites than that of normal blood in contrast to CXCR4 levels in ascitic MO/MA which were lower. EOC associated ascitic or blood MO/MA failed to migrate in response to the CC ligand RANTES and to the CXCR4 reactive chemokine, SDF1 (CXCL12). Ascitic and most EOC blood MO/MA also behaved differently from normal blood MO in the polymerization/depolymerization assay. A cDNA gene analysis of purified ascitic MO/MA demonstrated that a number of genes involved with chemokine production, focal adhesion, actin cytoskeletal function and leukocyte transendothelial migration were down-regulated in the ascitic MO/MA when compared to normal blood MO. Moreover, PBMC cDNA from EOC patients' blood also showed gene profiles similar to that of ascitic MO/MA.Conclusions Defective migration and polymerization/depolymerization activity of MO/MA from EOC patients and a significant down-regulation of critical pathway genes suggest that other mechanisms might be involved in the accumulation of systemically derived MO at the tumor site of EOC patients.