Pantel K, Izbicki J R, Angstwurm M, Braun S, Passlick B, Karg O, Thetter O, Riethmüller G
Institut für Immunologie, Ludwig-Maximilians-Universität, München, Germany.
Cancer Res. 1993 Mar 1;53(5):1027-31.
Present diagnostic techniques do not allow the detection of early metastatic spread of tumor cells, although this spread largely determines the clinical course of patients with small primary cancers. By use of monoclonal antibody CK2 to the epithelial cytokeratin component number 18 (CK18), individual disseminated carcinoma cells present in bone marrow of cancer patients can now be identified (G. Schlimok, I. Funke, B. Holzmann, G. Göttlinger, G. Schmidt, H. Häuser, S. Swierkot, H. H. Warnecke, B. Schneider, H. Koprowski, and G. Riethmüller, Proc. Natl. Acad. Sci. USA, 84: 8672-8676, 1987; F. Lindemann, G. Schlimok, P. Dirschedl, J. Witte, and G. Riethmüller, Lancet, 340: 685-689, 1992). In the present study, we applied this approach to patients with operable non-small cell lung cancer. CK18 was expressed on 84 of 88 (95.5%) primary adenocarcinomas and squamous cell carcinomas. Irrespective of primary tumor histology, single aspirates of iliac bone marrow from 18 of 82 (21.9%) lung cancer patients exhibited between 1 and 531 CK18+ cells/4 x 10(5) nucleated marrow cells. The specificity of our assay is underlined by the small rate of "false-positive" cells being observed in only 2 of 117 (1.7%) marrow samples from control patients with no evidence for an epithelial malignancy at the time of aspiration. Comparison with established risk factors demonstrated positive correlations (P < 0.05) between the size and histological grade of the primary carcinoma and cytokeratin positivity in iliac bone marrow. In contrast, the association with the metastatic involvement of regional lymph nodes was only weak (P = 0.09). Following a median observation period of 13 months, patients who displayed cytokeratin-positive cells in iliac bone marrow at the time of primary surgery relapsed more frequently as compared to patients with a negative marrow finding (66.7 versus 36.6%; P < 0.05). This difference was even more pronounced by comparing the rates of manifest skeleton metastasis observed in both groups (26.7 versus 2.4%; P < 0.005). Finally, colabeling of CK18+ cells in marrow with monoclonal antibodies to proliferation-associated markers, such as the nucleolar antigen p120 or the tyrosine kinase receptor erbB2, exemplified the oncogenic capacity of CK18+ micrometastatic cells. In conclusion, CK18+ cells present in the bone marrow of patients with apparently operable non-small cell lung cancer exhibit the potential to form solid metastases. Therefore, the approach presented here may be used to determine the risk of early relapse in operable non-small cell lung cancer with potential consequences for adjuvant therapy.
目前的诊断技术无法检测到肿瘤细胞的早期转移扩散，尽管这种扩散在很大程度上决定了原发性小癌症患者的临床病程。通过使用针对上皮细胞角蛋白成分18（CK18）的单克隆抗体CK2，现在可以识别癌症患者骨髓中存在的单个播散癌细胞（G.施利莫克、I.芬克、B.霍尔兹曼、G.戈特林格、G.施密特、H.豪泽、S.斯维尔科特、H.H.瓦内克、B.施耐德、H.科普罗夫斯基和G.里特米勒，《美国国家科学院院刊》，84:8672 - 8676，1987；F.林德曼、G.施利莫克、P.迪尔施德、J.维特和G.里特米勒，《柳叶刀》，340:685 - 689，1992）。在本研究中，我们将这种方法应用于可手术的非小细胞肺癌患者。88例原发性腺癌和鳞状细胞癌中有84例（95.5%）表达CK18。无论原发性肿瘤的组织学类型如何，82例肺癌患者中有18例（21.9%）的髂骨骨髓单个吸出物显示每4×10⁵有核骨髓细胞中有1至531个CK18⁺细胞。在抽吸时无上皮恶性肿瘤证据的对照患者的117份骨髓样本中，仅2份（1.7%）观察到“假阳性”细胞，这突出了我们检测方法的特异性。与既定风险因素的比较表明，原发性癌灶的大小和组织学分级与髂骨骨髓中的细胞角蛋白阳性之间存在正相关（P < 0.05）。相比之下，与区域淋巴结转移受累的关联较弱（P = 0.09）。在中位观察期13个月后，与骨髓检查结果为阴性的患者相比，初次手术时髂骨骨髓中显示细胞角蛋白阳性细胞的患者复发更频繁（66.7%对36.6%；P < 0.05）。通过比较两组中明显的骨骼转移率，这种差异更加明显（26.7%对2.4%；P < 0.005）。最后，用针对增殖相关标志物的单克隆抗体，如核仁抗原p120或酪氨酸激酶受体erbB2对骨髓中的CK18⁺细胞进行共标记，例证了CK18⁺微转移细胞的致癌能力。总之，明显可手术的非小细胞肺癌患者骨髓中存在的CK18⁺细胞具有形成实体转移瘤的潜力。因此，本文介绍的方法可用于确定可手术的非小细胞肺癌早期复发的风险，这对辅助治疗可能具有重要意义。
