EXPRESSION OF THE MULTIDRUG RESISTANCE GENE-PRODUCT (P-GLYCOPROTEIN) IN HUMAN NORMAL AND TUMOR-TISSUES
EXPRESSION OF THE MULTIDRUG RESISTANCE GENE-PRODUCT (P-GLYCOPROTEIN) IN HUMAN NORMAL AND TUMOR-TISSUES
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DOI：
10.1177/38.9.1974900
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发表时间：
1990-09-01
影响因子：
3.2
通讯作者：
MELAMED, MR
中科院分区：
文献类型：
--
作者：
CORDONCARDO, C;OBRIEN, JP;MELAMED, MR
我们的特点是正常的人类组织分布和肿瘤表达的人多药耐药基因（MDR 1）的产物P-糖蛋白（Pgp）的人正常和肿瘤组织的冷冻组织切片的免疫组化染色，使用三种小鼠单克隆抗体（MAB）识别至少两个不同的表位的Pgp。在正常人体组织中检测到Pgp表达于具有分泌/排泄功能的特化上皮细胞、胎盘中的滋养层细胞和血组织屏障部位的毛细血管内皮细胞。这些单克隆抗体的染色模式有显着差异。小鼠单克隆抗体HB-241和HYB-612各自识别Pgp的细胞外表位，而小鼠单克隆抗体C219检测羧基末端细胞内表位，并且最近报道与MDR 3基因产物交叉反应。HYB-241和HYB-612强烈染色内皮细胞和滋养层细胞，而C219在这些细胞上呈弱阳性或不反应。同样，C219强烈染色肝细胞、骨骼肌和心肌纤维的胆极，而HYB-241和HYB-612对这些细胞不起反应。对多种人类肿瘤进行了免疫病理学研究。人类肿瘤上的Pgp表达最常在结肠癌、肾癌和肾上腺癌中检测到;很少在肺癌和胃癌以及某些生殖细胞肿瘤中检测到;并且在测试的乳腺癌和子宫内膜癌中检测不到。少数肉瘤和黑色素瘤、神经母细胞瘤、神经胶质瘤和嗜铬细胞瘤均未检测到Pgp表达。不同肿瘤类型的不同病例中染色强度和模式不同;虽然观察到均匀的免疫反应性，但在单个组织切片中表达的异质性更常见。Pgp在具有不同生理功能的多种正常组织中的表达的发现表明，Pgp的作用可能不仅限于排泄外源性物质。Pgp在脑和睾丸毛细血管中的表达可能解释了长春新碱和放线菌素D等药物无法渗透到这些组织中，从而使它们仍然是恶性细胞的药理学避难所。虽然Pgp表达现在可以在多种人类肿瘤中检测到，但需要进一步的研究来确定这一发现的可能意义。
We have characterized the normal human tissue distribution and tumor expression of the human multidrug resistance gene (MDR1) product p-glycoprotein (Pgp) by immunohistochemical staining of frozen tissue sections of human normal and tumor tissues, using three mouse monoclonal antibodies (MAb) which recognize at least two different epitopes of Pgp. Pgp expression on normal human tissues was detected in specialized epithelial cells with secretory/excretory functions, trophoblasts in the placenta, and on endothelial cells of capillary blood vessels at blood-tissue barrier sites. There were significant differences in the staining patterns of these MAb. Mouse MAb HB-241 and HYB-612 each recognize an extracellular epitope of Pgp, whereas mouse MAb C219 detects a carboxy terminal intracellular epitope and has recently been reported to crossreact with the MDR3 gene product. HYB-241 and HYB-612 strongly stain endothelial cells and trophoblasts, whereas C219 is weakly positive or unreactive on these cells. Likewise, C219 strongly stains the biliary pole of hepatocytes, skeletal and heart muscle fibers, whereas HYB-241 and HYB-612 are unreactive on these cells. Immunopathological studies were performed on a wide variety of human tumors. Pgp expression on human tumors was most commonly detected in colon, renal and adrenal carcinomas; rarely in lung and gastric carcinomas and certain germ cell tumors; and was undetectable in breast and endometrial carcinomas tested. Few sarcomas and none of the melanomas, neuroblastomas, gliomas, and pheochromocytomas had detectable Pgp expression. Intensity and pattern of staining varied among different cases of a given tumor type; although homogeneous immunoreactivity was observed, heterogeneity of expression in a single histological section was more common. The finding of Pgp expression in a variety of normal tissues with diverse physiological functions suggests that the role of Pgp may not be limited to excretion of xenobiotics. Pgp expession in capillaries of the brain and testis may explain the failure of drugs such as vincristine and actinomycin-D to penetrate into these tissues, allowing them to remain as pharmacological sanctuaries for malignant cells. Although Pgp expression can now be detected in a variety of human tumors, further studies are needed to establish the possible significance of this finding.