Stromal cell-derived factor-1/CXCR4システムによる口腔癌のリンパ節転移・遠隔転移機構の解析

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We have previously demonstrated that the association between the expression of CXCR4 in oral squamous cell carcinoma (SCC) cells and stromal cell-derived factor (SDF)-1 produced by the lymphatic stromal cells was critical for the lymph node metastasis of oral SCC. Although the process of metastases in cancer cells is generally associated with morphological change, so-called epithelial-mesenchymal transition (EMT), the role of EMT in the metastatic process induced by the SDF-1/CXCR4 system remains unknown. On the other hand, it has been considered that the SDF-1/CXCR4 system mainly regulates distant metastases in cancer excluding oral SCC, by which cancer cells utilize SDF-1 produced by specific organs. In cases of oral SCC, the expression of CXCR4 is frequently detected ; however, distant metastasis is clinically very rare, and the relation between the expression of CXCR4 and distant metastasis remains unclear. Thus, in the present study, I investigated the role of SDF-1/CXCR4 systems in the association of EMT in the metastatic process and in the relation of distant metastasis. Oral SCC cells, B88 and HNt, which have functional CXCR4 and lymph node metastatic potentials, were found to lose their epithelial cell morphology due to SDF-1 in the serumstarved condition. In this context, the downregulation of epithelial markers, cytokeratin, E-cadherin and β-catenin, and the upregulation of mesenchymal markers, vimentin and snail, were detected. Furthermore, upregulation of vimentin and the morphological change in 3-dimensional cultures by treatment with SDF-1 were impaired with phosphatidylinositol 3 kinase inhibitor, wortmannin. These results suggested that EMT induced by the SDF-1/CXCR4 system might be involved in the lymph node metastasis of oral SCCs via activation of the PI3K-Akt/PKB pathway. 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 cancer cells in lymph nodes than among those in primary oral SCCs. Among all 6 patients with lung metastases, co-expression of SDF-1 and CXCR4 was detected. Thus, under the hypothesis that acquisition of the SDF-1/CXCR4 autocrine loop might be involved in the distant metastatic potential, I established B88-SDF-1 cells, by which SDF-1 was forcibly expressed. B88-SDF-1 cells acquired enhanced cell motility and anchorage-independent growth potential. Inoculation of B88-SDF-1 cells into nude mice resulted in the enhancement of metastatic potential to the lymph nodes and in the acquisition of metastatic potential to distant organs. When genes regulated by the SDF-1/CXCR4 autocrine loop were investigated with cDNA microarray analysis, many functionally unknown genes were identified. Three genes upregulated in B88-SDF-1 cells with cDNA microarray analysis were found to be upregulated by RT-PCR, whose expressions were inhibited by a CXCR4 antagonist, AMD3100. AMD3100 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 SCCs, the SDF-1/CXCR4 paracrine loop potentiates lymph node metastasis associated with EMT, but distant metastasis might require the SDF-1/CXCR4 autocrine loop.

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