Mimori Koshi, Fukagawa Takeo, Kosaka Yoshimasa, Kita Yoshiaki, Ishikawa Kenji, Etoh Tsuyoshi, Iinuma Hisae, Sasako Mitsuru, Mori Masaki
Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan.
Clin Cancer Res. 2008 May 1;14(9):2609-16. doi: 10.1158/1078-0432.CCR-07-4354.
Recent studies of cancer metastasis have focused on the role of premetastatic gene expression and circulating tumor cells. We did a blind prospective study in gastric cancer to assess the significance of isolated tumor cells (ITC) and to test the hypothesis that vascular endothelial growth factor receptor-1 (VEGFR-1) is expressed within the bone marrow at tumor-specific, premetastatic sites.
Both bone marrow and peripheral blood samples from 810 gastric cancer patients were collected at the Central Hospital, National Cancer Center (Tokyo, Japan). The samples were transferred to Kyushu University Hospital (Beppu, Japan) where they were analyzed by quantitative real-time reverse transcription-PCR for three epithelial cell markers, carcinoembryonic antigen, cytokeratin-19, and cytokeratin-7, as well as VEGFR-1.
ITCs were observed in peripheral blood and bone marrow even in early stages of gastric cancer. The frequency of ITC in bone marrow was significantly associated with the stage of disease by ANOVA (P < 0.01). Gastric cancer metastasized when ITCs were observed in the presence of VEGFR-1. In the 380 patients who were ITC negative and showed low VEGFR-1 expression, synchronous (at the time of surgery) and heterochronous (recurrent) metastases were not observed.
ITCs circulate even in early stages of disease. Furthermore, elevated expression of VEGFR-1 facilitates the establishment of hematogenous metastases in gastric cancer. This study indicates that the simultaneous presence of ITC and VEGFR-1 expression at premetastatic sites is clinically significant for disease progression.
近期关于癌症转移的研究聚焦于转移前基因表达和循环肿瘤细胞的作用。我们对胃癌进行了一项盲法前瞻性研究，以评估分离肿瘤细胞（ITC）的意义，并检验血管内皮生长因子受体-1（VEGFR-1）在肿瘤特异性转移前骨髓部位表达的假说。
从日本东京国立癌症中心中央医院收集了810例胃癌患者的骨髓和外周血样本。样本被转移至日本别府九州大学医院，在那里通过定量实时逆转录聚合酶链反应分析三种上皮细胞标志物（癌胚抗原、细胞角蛋白-19和细胞角蛋白-7）以及VEGFR-1。
即使在胃癌早期，外周血和骨髓中也观察到了ITC。通过方差分析，骨髓中ITC的频率与疾病分期显著相关（P < 0.01）。当在存在VEGFR-1的情况下观察到ITC时，胃癌发生转移。在380例ITC阴性且VEGFR-1表达低的患者中，未观察到同步（手术时）和异时（复发）转移。
即使在疾病早期，ITC也会循环。此外，VEGFR-1表达升高促进胃癌血行转移的发生。本研究表明，转移前部位ITC和VEGFR-1表达同时存在对疾病进展具有临床意义。
