Kokhaei Parviz, Abdalla Amir Osman, Hansson Lotta, Mikaelsson Eva, Kubbies Manfred, Haselbeck Anton, Jernberg-Wiklund Helena, Mellstedt Håkan, Osterborg Anders
Department of Oncology, Karolinska Institutet, Stockholm, Sweden.
Clin Cancer Res. 2007 Jun 15;13(12):3536-44. doi: 10.1158/1078-0432.CCR-06-2828.
Erythropoietin (EPO) and EPO receptor (EPO-R) expression have been reported in solid tumors and are claimed to regulate tumor growth; however, no data have been published on this issue in B-cell malignancies or normal lymphoid cells. This report describes genomic/protein EPO-R expression and in vitro effects of recombinant human EPO (epoetin) in B-cell chronic lymphocytic leukemia (B-CLL), mantle-cell lymphoma (MCL), and multiple myeloma (MM).
Blood samples were obtained from patients with B-CLL, MCL, and healthy volunteers, and bone marrow was obtained from MM patients. EPO-R mRNA was detected by reverse transcription-PCR. EPO-R surface expression was investigated by flow cytometry using digoxigenin-labeled epoetin and polyclonal rabbit anti-EPO-R antibody for intracellular receptor. Tumor cell stimulation was determined in vitro using [(3)H]thymidine incorporation and CD69 expression after exposure to epoetin alpha or beta or darbepoetin alpha.
EPO-R mRNA was detected in mononuclear cells from 32 of 41 (78%) B-CLL and 5 of 7 (71%) MCL patients, and 21 of 21 (100%) MM samples. Expression was also detected in highly purified T cells from six of eight B-CLL patients, four of four MM patients, and normal donor B and T cells. Surface EPO-R protein was not detected. Intracellular EPO-R staining with anti-EPO-R antibodies was unspecific. No tumor-stimulatory effect was observed with high epoetin concentrations.
EPO-R gene is frequently expressed in lymphoid malignancies and normal B and T cells. However, there was no surface protein expression and no epoetin-induced in vitro stimulation of tumor B cells, indicating that epoetin therapy in vivo is likely to be safe in patients with lymphoid malignancies.
已有报道称实体瘤中存在促红细胞生成素（EPO）和促红细胞生成素受体（EPO-R）表达，并声称其可调节肿瘤生长；然而，关于B细胞恶性肿瘤或正常淋巴细胞中此问题尚无数据发表。本报告描述了B细胞慢性淋巴细胞白血病（B-CLL）、套细胞淋巴瘤（MCL）和多发性骨髓瘤（MM）中EPO-R的基因组/蛋白表达以及重组人促红细胞生成素（依泊汀）的体外效应。
采集B-CLL、MCL患者的血样以及健康志愿者的血样，并采集MM患者的骨髓。通过逆转录聚合酶链反应检测EPO-R mRNA。使用地高辛标记的依泊汀和抗细胞内受体的多克隆兔抗EPO-R抗体，通过流式细胞术研究EPO-R的表面表达。在暴露于α或β依泊汀或α-达贝泊汀后，使用[³H]胸腺嘧啶核苷掺入和CD69表达在体外测定肿瘤细胞刺激情况。
在41例B-CLL患者中的32例（78%）、7例MCL患者中的5例（71%）以及21例MM样本中的21例（100%）的单核细胞中检测到EPO-R mRNA。在8例B-CLL患者中的6例、4例MM患者中的4例以及正常供体的B和T细胞中的高度纯化T细胞中也检测到表达。未检测到表面EPO-R蛋白。用抗EPO-R抗体进行细胞内EPO-R染色不具有特异性。高浓度依泊汀未观察到肿瘤刺激作用。
EPO-R基因在淋巴恶性肿瘤以及正常B和T细胞中频繁表达。然而，未检测到表面蛋白表达，且依泊汀未在体外诱导肿瘤B细胞刺激，这表明依泊汀治疗对淋巴恶性肿瘤患者在体内可能是安全的。
