(Cancer Sci 2010; 101: 1073�C1079) ""Lymph node metastasis is a poor prognostic factor for patients with head and neck squamous cell carcinoma (HNSCC). However, its molecular mechanism has not yet been fully understood. In our study, we investigated the expression of CCR4 and its ligand CCL22 in the HNSCC tumor microenvironment and found that the CCR4/CCL22 axis was involved in lymph node metastasis of HNSCC. CCR4 was expressed in 20 of Bortezomib ic50
31 (64.5%) human tongue cancer tissues, and its expression was significantly correlated with lymph node metastasis (p < 0.01) and lymphatic invasion (p < 0.05). CCR4 was expressed in three of five human HNSCC cell lines tested. CCR4+ HNSCC cells, but not CCR4? cells, showed enhanced migration toward CCL22, indicating that functional CCR4 was expressed in HNSCC cell lines. CCL22 was also expressed in cancer cells (48.4% of tongue cancer tissues) or CD206+ M2-like macrophages infiltrated in tumors and draining lymph nodes. CCL22 produced by cancer cells or CD206high M2-like macrophages increased the cell motility of CCR4+ HNSCC cells in vitro in an autocrine or paracrine manner. In the mouse SCCVII in vivo model, CCR4+ cancer cells, but not CCR4? cells, metastasized to lymph nodes which contained CCL22 producing M2-like macrophages. These results demonstrate that lymph node metastasis of CCR4+ HNSCC is promoted by CCL22 in an autocrine or M2-like macrophage-dependent paracrine manner. Therefore, the CCR4/CCL22 Panobinostat
axis may be an attractive target for the development of diagnostic and therapeutic strategies for patients with HNSCC. Head and neck squamous cell carcinoma (HNSCC) has a global incidence of 630,000 cases and causes 350,000 deaths annually.1 Recent advances in multimodal combined therapy have improved loco-regional control of HNSCC.2 However, over the last decade, the overall 5-year survival rate of HNSCC has been only moderately improved, in part due to metastasis.2�C4 Lymph nodes are the primary sites of metastasis of HNSCC before distant metastasis occurs.3�C5 The presence of lymph node metastasis is strongly associated with poor clinical outcome in patients with HNSCC.4, 6�C8 Therefore, it is essential to elucidate the mechanisms underlying selleck screening library
lymph node metastasis of HNSCC for improvement of diagnostic and therapeutic strategies for patients with HNSCC. Chemokines have recently been implicated in organ-specific metastasis of cancer cells. The role of ectopic expression of chemokine receptors on cancer cells has been reported to be involved in metastasis. For example, the involvement of CXCR4 in metastasis was indicated in more than 20 different cancers.9�C11 In HNSCC, CXCR4 and CCR7 expression in primary cancers has been found to correlate with lymph node metastasis.