Bronger Holger, König Jörg, Kopplow Kathrin, Steiner Hans-Herbert, Ahmadi Rezvan, Herold-Mende Christel, Keppler Dietrich, Nies Anne T
Division of Tumor Biochemistry, German Cancer Research Center.
Cancer Res. 2005 Dec 15;65(24):11419-28. doi: 10.1158/0008-5472.CAN-05-1271.
Delivery of therapeutic agents to the brain and its neoplasms depends on the presence of membrane transport proteins in the blood-brain barrier and in the target cells. The cellular and subcellular localization of these membrane transporters determines the drug accessibility to the brain and its tumors. We therefore analyzed the expression and localization of six members of the multidrug resistance protein family of ATP-dependent efflux pumps (ABCC1-ABCC6, formerly MRP1-MRP6) and of six organic anion uptake transporters (OATP1A2, OATP1B1, OATP1B3, OATP1C1, OATP2B1, and OATP4A1) in 61 human glioma specimens of different histologic subtypes. Real-time PCRs indicated expressions of ABCC1, ABCC3, ABCC4, and ABCC5. In addition, we detected expressions of the OATP uptake transporter genes SLCO1A2, SLCO1C1, SLCO2B1, and SLCO4A1. At the protein level, however, only OATP1A2 and OATP2B1 were detectable by immunofluorescence microscopy in the luminal membrane of endothelial cells forming the blood-brain barrier and the blood-tumor barrier, but not in the glioma cells. ABCC4 and ABCC5 proteins were the major ABCC subfamily members in gliomas, localized both at the luminal side of the endothelial cells and in the glioma cells of astrocytic tumors and in the astrocytic portions of oligoastrocytomas. These results indicate that expression of ABCC4 and ABCC5 is associated with an astrocytic phenotype, in accordance with their expression in astrocytes and with the higher chemoresistance of astrocytic tumors as compared with oligodendrogliomas. Our data provide a basis for the assessment of the role of uptake transporters and efflux pumps in the accessibility of human gliomas for chemotherapeutic agents.
治疗药物向脑及其肿瘤的递送取决于血脑屏障和靶细胞中膜转运蛋白的存在。这些膜转运蛋白的细胞和亚细胞定位决定了药物进入脑及其肿瘤的难易程度。因此，我们分析了61例不同组织学亚型的人类胶质瘤标本中ATP依赖性外排泵多药耐药蛋白家族的6个成员（ABCC1 - ABCC6，原MRP1 - MRP6）和6个有机阴离子摄取转运体（OATP1A2、OATP1B1、OATP1B3、OATP1C1、OATP2B1和OATP4A1）的表达和定位。实时PCR显示ABCC1、ABCC3、ABCC4和ABCC5有表达。此外，我们检测到OATP摄取转运体基因SLCO1A2、SLCO1C1、SLCO2B1和SLCO4A1的表达。然而，在蛋白质水平上，通过免疫荧光显微镜仅在内皮细胞形成血脑屏障和血肿瘤屏障的腔膜中检测到OATP1A2和OATP2B1，而在胶质瘤细胞中未检测到。ABCC4和ABCC5蛋白是胶质瘤中ABCC亚家族的主要成员，定位于内皮细胞的腔侧以及星形细胞瘤的胶质瘤细胞和少突星形细胞瘤的星形细胞部分。这些结果表明，ABCC4和ABCC5的表达与星形细胞表型相关，这与它们在星形胶质细胞中的表达以及与少突胶质细胞瘤相比星形细胞瘤具有更高的化疗耐药性一致。我们的数据为评估摄取转运体和外排泵在人类胶质瘤对化疗药物的可及性中的作用提供了基础。
