Department of Pathology, Kyorin University Faculty of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.
Oncol Rep. 2011 Feb;25(2):333-9. doi: 10.3892/or.2010.1102. Epub 2010 Dec 13.
Most tumors in the central nervous system are drug resistant partly because of the presence of the blood-brain barrier (BBB) between circulating blood and tumor tissues. Primary central nervous system lymphoma (PCNSL) is one of the exceptions, as it is highly sensitive to high-dose methotrexate (MTX)-based chemotherapy. The aim of this study was to evaluate the BBB function of tumor capillary endothelial cells in PCNSL. Expression of three major drug efflux transporters that belong to the ATP-binding cassette (ABC) superfamily, P-glycoprotein encoded by the human multidrug resistance gene (MDR1 Pgp; ABCB1), breast cancer resistance protein (BCRP; ABCG2), and multidrug resistance-associated protein 1 (MRP1; ABCC1), was evaluated. Immunohistochemistry was performed in capillary endothelial cells of 30 tumor areas from 22 PCNSL cases and compared with that of 30 gliomas. The microenvironment around tumor capillaries was assessed by examining the distribution of astrocytes and by counting the number of macrophages and T-cells, the principal cytokine producers. In PCNSL, expression of MDR1 Pgp and BCRP in tumor capillary endothelial cells was decreased in 63 and 93% of tumor areas examined, respectively, and these reduction levels differed significantly from those of gliomas (P<0.05). When the PCNSLs were further segregated by way of infiltration of tumor cells into three patterns (dense, perivascular and sparse), decreased MDR1 Pgp and BCRP in tumor capillary endothelial cells were much more prominent in dense and perivascular patterns. In all tumors and non-tumor areas of the brain, MRP1 was undetected on capillary endothelial cells. Assessment of the microenvironment around the tumor capillaries suggested that dissociation from astrocytes and infiltration of macrophages and T-cells was involved in the down-regulation of MDR1 Pgp and BCRP in capillary endothelial cells. In conclusion, we report that expression of the major ABC transporters of the BBB, MDR1 Pgp and BCRP, decreases in tumor capillary endothelial cells of PCNSL. Thus, decreased expression may permit delivery of chemotherapeutic agents to the tumor tissues.
大多数中枢神经系统肿瘤具有抗药性，部分原因是在循环血液和肿瘤组织之间存在血脑屏障（BBB）。原发性中枢神经系统淋巴瘤（PCNSL）是一个例外，因为它对高剂量甲氨蝶呤（MTX）为基础的化疗高度敏感。本研究旨在评估 PCNSL 肿瘤毛细血管内皮细胞的 BBB 功能。评估了属于三磷酸腺苷（ATP）结合盒（ABC）超家族的三种主要药物外排转运蛋白的表达，即人类多药耐药基因（MDR1 Pgp）编码的 P-糖蛋白（ABCBl）、乳腺癌耐药蛋白（BCRP；ABCG2）和多药耐药相关蛋白 1（MRP1；ABCC1）。对 22 例 PCNSL 病例的 30 个肿瘤区域的毛细血管内皮细胞进行了免疫组织化学染色，并与 30 个胶质瘤进行了比较。通过检查星形胶质细胞的分布和计数巨噬细胞和 T 细胞（主要细胞因子产生细胞）的数量来评估肿瘤毛细血管周围的微环境。在 PCNSL 中，在检查的 63%和 93%的肿瘤区域中，肿瘤毛细血管内皮细胞中 MDR1 Pgp 和 BCRP 的表达分别降低，这些降低水平与胶质瘤明显不同（P<0.05）。当 PCNSL 进一步通过肿瘤细胞浸润分为三种模式（密集、血管周围和稀疏）时，密集和血管周围模式中肿瘤毛细血管内皮细胞中 MDR1 Pgp 和 BCRP 的降低更为明显。在所有肿瘤和大脑非肿瘤区域，毛细血管内皮细胞上均未检测到 MRP1。对肿瘤毛细血管周围微环境的评估表明，与星形胶质细胞分离以及巨噬细胞和 T 细胞浸润与毛细血管内皮细胞中 MDR1 Pgp 和 BCRP 的下调有关。总之，我们报告 PCNSL 肿瘤毛细血管内皮细胞中 BBB 的主要 ABC 转运蛋白 MDR1 Pgp 和 BCRP 的表达降低。因此，表达降低可能允许化疗药物递送至肿瘤组织。
