Uchida Daisuke, Onoue Tomitaro, Tomizuka Yoshifumi, Begum Nasima Mila, Miwa Yoshihiro, Yoshida Hideo, Sato Mitsunobu
Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, 3-18-15 Kuramoto, Tokushima 770-8504, Japan.
Mol Cancer Res. 2007 Jul;5(7):685-94. doi: 10.1158/1541-7786.MCR-06-0368.
We have previously shown that a stromal cell-derived factor-1 (SDF-1; CXCL12)/CXCR4 system is involved in the establishment of lymph node metastasis, but not in that of distant metastasis, in oral squamous cell carcinoma (SCC). In this study, we investigated the role of the autocrine SDF-1/CXCR4 system, with a focus on distant metastasis in oral SCC cells. The immunohistochemical staining of SDF-1 and CXCR4 using primary oral SCCs and metastatic lymph nodes showed a significantly higher number of SDF-1-positive cases among the metastatic lymph nodes than among the primary oral SCCs, which was associated with a poor survival rate among those of the former group. The forced expression of SDF-1 in B88 cells, which exhibit functional CXCR4 and lymph node metastatic potential (i.e., the autocrine SDF-1/CXCR4 system), conferred enhanced cell motility and anchorage-independent growth potential onto the cells. Orthotopic inoculation of the transfectant into nude mice was associated with an increase in the number of metastatic lymph nodes and more aggressive metastatic foci in the lymph nodes. Furthermore, the SDF-1 transfectant (i.e., the autocrine SDF-1/CXCR4 system) exhibited dramatic metastasis to the lung after i.v. inoculation, whereas the mock transfectant (i.e., the paracrine SDF-1/CXCR4 system) did not. Under the present conditions, AMD3100, a CXCR4 antagonist, significantly inhibited the lung metastasis of the SDF-1 transfectant, ameliorated body weight loss, and improved the survival rate of tumor-bearing nude mice. These results suggested that, in cases of oral SCC, the paracrine SDF-1/CXCR4 system potentiates lymph node metastasis, but distant metastasis might require the autocrine SDF-1/CXCR4 system.
我们之前已经表明，基质细胞衍生因子-1（SDF-1；CXCL12）/CXCR4系统参与口腔鳞状细胞癌（SCC）淋巴结转移的形成，但不参与远处转移的形成。在本研究中，我们研究了自分泌SDF-1/CXCR4系统的作用，重点关注口腔SCC细胞的远处转移。使用原发性口腔SCC和转移性淋巴结对SDF-1和CXCR4进行免疫组化染色显示，转移性淋巴结中SDF-1阳性病例的数量明显高于原发性口腔SCC，这与前一组患者的低生存率相关。在具有功能性CXCR4和淋巴结转移潜能的B88细胞（即自分泌SDF-1/CXCR4系统）中强制表达SDF-1，赋予细胞增强的运动能力和不依赖贴壁的生长潜能。将转染子原位接种到裸鼠体内与转移性淋巴结数量增加以及淋巴结中更具侵袭性的转移灶有关。此外，SDF-1转染子（即自分泌SDF-1/CXCR4系统）静脉注射接种后出现显著的肺转移，而mock转染子（即旁分泌SDF-1/CXCR4系统）则没有。在当前条件下，CXCR4拮抗剂AMD3100显著抑制SDF-1转染子的肺转移，改善体重减轻，并提高荷瘤裸鼠的生存率。这些结果表明，在口腔SCC病例中，旁分泌SDF-1/CXCR4系统增强淋巴结转移，但远处转移可能需要自分泌SDF-1/CXCR4系统。
