Scheffer G L, de Jong M C, Monks A, Flens M J, Hose C D, Izquierdo M A, Shoemaker R H, Scheper R J
Department of Pathology, Free University Medical Center, Amsterdam, The Netherlands.
Br J Cancer. 2002 Jun 17;86(12):1943-50. doi: 10.1038/sj.bjc.6600354.
The rat monoclonal antibody LMR-12 was shown earlier to react with a plasma membrane protein, upregulated in multidrug-resistant cell lines. In this study, we observed distinct LMR-12 staining in 36 out of 55 non-drug-selected tumour cell lines, including melanomas, renal cell-, colon- and lung carcinomas, whereas in other tumour types, such as leukaemia and ovarian cancer, LMR-12 staining was generally low or absent. The cDNA encoding the LMR-12 antigen was isolated from a library of the multidrug-resistant human fibrosarcoma cell line HT1080/DR4 by expression cloning in MOP8 cells. Sequence analysis showed that the LMR-12 antigen is identical to the major histocompatibility complex class I molecule beta 2-microglobulin (beta2-m). The LMR-12/ beta2-m staining results were confirmed by mRNA microarray data from an independent National Cancer Institute study, as well as by newly obtained reverse transcriptase polymerase chain reaction data. Further analysis of the microarray data showed that beta2-m levels closely reflected levels of major histocompatibility complex class I heavy chains and the transporter associated with antigen processing. Since the ABC transporter associated with antigen processing was previously shown to contribute to multidrug-resistance, it may very well be that the observed LMR-12/ beta2-m levels are secondary to (elevated) levels of the transporter associated with antigen processing. A perspective arising from the present study is that drug resistant tumour cells may, by having elevated levels of major histocompatibility complex related molecules, be particular good candidates for alternative therapeutic therapies, such as cytotoxic T cell mediated immune-therapies.
大鼠单克隆抗体LMR-12早前被证明可与一种在多药耐药细胞系中上调的质膜蛋白发生反应。在本研究中，我们观察到在55个未经过药物筛选的肿瘤细胞系中，有36个出现了明显的LMR-12染色，包括黑色素瘤、肾细胞癌、结肠癌和肺癌细胞系，而在其他肿瘤类型中，如白血病和卵巢癌，LMR-12染色通常较低或无染色。通过在MOP8细胞中进行表达克隆，从多药耐药的人纤维肉瘤细胞系HT1080/DR4的文库中分离出编码LMR-12抗原的cDNA。序列分析表明，LMR-12抗原与主要组织相容性复合体I类分子β2-微球蛋白（β2-m）相同。LMR-12/β2-m的染色结果通过美国国立癌症研究所一项独立研究的mRNA微阵列数据以及新获得的逆转录酶聚合酶链反应数据得到了证实。对微阵列数据的进一步分析表明，β2-m水平密切反映了主要组织相容性复合体I类重链和与抗原加工相关的转运体的水平。由于先前已表明与抗原加工相关的ABC转运体与多药耐药有关，很可能观察到的LMR-12/β2-m水平是与抗原加工相关的转运体（水平升高）的继发结果。本研究产生的一个观点是，耐药肿瘤细胞可能由于主要组织相容性复合体相关分子水平升高，特别适合作为替代治疗方法的候选对象，如细胞毒性T细胞介导的免疫疗法。
