Soikkeli J, Lukk M, Nummela P, Virolainen S, Jahkola T, Katainen R, Harju L, Ukkonen E, Saksela O, Hölttä E
Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland.
J Pathol. 2007 Oct;213(2):180-9. doi: 10.1002/path.2229.
Melanoma is notorious for its high tendency to metastasize and its refractoriness to treatment thereafter. Metastasis is believed to occur mostly through the lymphatic system, and the status of sentinel lymph nodes is currently recognized as the best prognostic indicator. Unfortunately, the lymphatic metastatic process is still poorly understood and the occurrence of sentinel node metastases (micrometastases) may be underestimated. We performed genome-wide gene expression analyses of melanoma lymph node micrometastases and macrometastases, and of primary melanomas and benign naevi, to characterize the early metastatic cells molecularly and to disclose the best diagnostic markers and rational targets for therapy. Significance analysis of microarrays identified 22 over- and five under-expressed genes with > or = four-fold changes in the micrometastases. Of these genes, MLANA, TYR, MIA, ERBB3, PRAME, and SPP1 were tested as potential markers by RT-PCR and immunohistochemistry. In a prospective study of 160 patients, our graded MLANA and TYR RT-PCR analyses disclosed clinically significant metastases, as assessed by disease recurrence, better than histological and immunohistochemical examinations. These results strongly suggest the clinical implementation of quantifiable RT-PCR assays to confirm and complement the pathological examination of sentinel node metastases. Furthermore, SPP1 and PRAME proved valuable as melanoma-specific markers capable of differentiating melanoma cells from benign naevi in the sentinel lymph nodes. Importantly, these two genes may also prove to be ideal targets for drug development and therapy. Most molecular traits of the micrometastases were already present in the primary tumours, suggesting that micrometastasis to sentinel lymph nodes is a fairly non-selective process.
黑色素瘤因其高转移倾向及后续治疗难治性而声名狼藉。转移被认为主要通过淋巴系统发生，前哨淋巴结状态目前被公认为最佳预后指标。不幸的是，淋巴转移过程仍知之甚少，前哨淋巴结转移（微转移）的发生率可能被低估。我们对黑色素瘤淋巴结微转移和宏转移以及原发性黑色素瘤和良性痣进行了全基因组基因表达分析，以便从分子水平上表征早期转移细胞，并揭示最佳诊断标志物和合理的治疗靶点。微阵列显著性分析确定了22个在微转移中有≥4倍变化的过表达基因和5个低表达基因。在这些基因中，通过逆转录聚合酶链反应（RT-PCR）和免疫组织化学对黑色素瘤抗原（MLANA）、酪氨酸酶（TYR）、黑色素瘤抑制因子（MIA）、表皮生长因子受体3（ERBB3）、黑色素瘤优先表达抗原（PRAME）和分泌型磷蛋白1（SPP1）进行了潜在标志物检测。在一项对160例患者的前瞻性研究中，我们分级的MLANA和TYR RT-PCR分析显示，通过疾病复发评估，其检测临床显著转移的能力优于组织学和免疫组织化学检查。这些结果强烈表明应临床应用可量化的RT-PCR检测来确认和补充前哨淋巴结转移的病理检查。此外，SPP1和PRAME被证明是有价值的黑色素瘤特异性标志物，能够在前哨淋巴结中将黑色素瘤细胞与良性痣区分开来。重要的是，这两个基因也可能被证明是药物开发和治疗的理想靶点。微转移的大多数分子特征在原发性肿瘤中就已存在，这表明前哨淋巴结微转移是一个相当非选择性的过程。
