ケモカインシステムによる口腔癌のリンパ節転移機構

Recently, it has been suggested that chemokine and its receptor interactions determine the destination of the penetrating tumor cells in several types of cancer. However, little information is available on the lymph node metastasis in oral squamous cell carcinoma (SCC). In this review, I would like to summarize the regulation of lymph node metastasis by the chemokine system in oral SCC using lymph node metastatic (HNt and B88) and non-metastatic (IH and BHY) oral SCC cells. Of 13 kinds of chemokine receptors examined by multiplex reverse transcriptase-polymerase chain reaction (RT-PCR), only CXCR4 expression was up-regulated in HNt and B88 cells. CXCR4 ligand, stromal cell-derived factor-1 (SDF-1 ; also called CXCL12), induced characteristic calcium fluxes and cell migration only in the CXCR4-expressing cells. Stable transfectant of CXCR4, IH-CXCR4, acquired the lymph node metastatic potentials in the orthotopic inoculation of nude mice. SDF-1 rapidly activated extracellular signal-regulated kinase (ERK)1/2 and Akt/protein kinase B (PKB) in B88 and IH-CXCR4 cells, and their synthetic inhibitors attenuated the migration by SDF-1. SDF-1 was detected in all the lymph node extracts and conditioned media from lymphatic fibroblast by the enzyme-linked immunosorbent assay. Moreover, the localization of SDF-1 in the submandibular lymph nodes was mainly in the stromal cells. The conditioned media from lymphatic fibroblasts promoted the migration of B88 cells, which was blocked by the CXCR4 neutralization. By using immunohistochemistry, the expression of CXCR4 was observed in 57.3% of the subjects and was significantly associated with lymph node metastasis (P=0.0417), the mode of invasion (P=0.0002) and recurrence of the tumors (P=0.0185). Moreover, the CXCR4-positive group showed a significantly poorer survival than the CXCR4-negative group (P=0.0401). Next, experimental chemotherapy was performed in the IH-CXCR4 tumor by the treatment of a mitogen-activated protein kinase/ERK kinase inhibitor, U0126, or a phosphatidylinositol 3 kinase inhibitor, Wortmannin. These kinase inhibitors markedly inhibited the lymph node metastasis of IH-CXCR4 cells. Moreover, vesnarinone, a novel anti-cancer drug, significantly down-regulated CXCR4 protein and mRNA. These results suggested that SDF-1/CXCR4 system regulates the establishment of lymph node metastasis in patients with oral SCC. It can be considered that blocking of SDF-1/CXCR4 system by the kinase inhibitors or vesnarinone might be a way to protect the patients with oral SCC from lymph node metastasis.

公開日:2010年1月24日で登録したコンテンツは、国立情報学研究所において電子化したものです。