Autocrine and paracrine loops between cancer cells and macrophages promote lymph node metastasis via CCR4/CCL22 in head and neck squamous cell carcinoma
Autocrine and paracrine loops between cancer cells and macrophages promote lymph node metastasis via CCR4/CCL22 in head and neck squamous cell carcinoma
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DOI：
10.1002/ijc.27966
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发表时间：
2013-06-15
影响因子：
6.4
通讯作者：
Kawakami, Yutaka
中科院分区：
文献类型：
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作者：
Tsujikawa, Takahiro;Yaguchi, Tomonori;Kawakami, Yutaka
对于头颈部鳞状细胞癌(HNSCC)来说，淋巴结转移是一个预后不良的因素。然而，其分子机制尚不完全清楚。在本研究中，我们研究了CCR4及其配体CCL22在HNSCC肿瘤微环境中的表达，发现CCR4/CCL22轴参与了HNSCC的淋巴转移。CCR4在31例舌癌组织中表达20例(64.5%)，其表达与舌癌的淋巴结转移(P<；0.01)和淋巴侵袭(P<；0.05)显著相关。CCR4在所检测的5个人HNSCC细胞系中有3个表达。CCR4+HNSCC细胞向CCL22迁移能力增强，提示功能性CCR4在HNSCC细胞系中表达。CCL22也表达于癌细胞(占舌癌组织的48.4%)或CD206+M2样巨噬细胞在肿瘤和引流淋巴结中的表达。癌细胞或CD206高表达的M2样巨噬细胞产生的CCL22在体外以自分泌或旁分泌的方式增加CCR4+HNSCC细胞的运动能力。在小鼠SCCVII体内模型中，CCR4+癌细胞而不是CCR4细胞转移到含有CCL22产生M2样巨噬细胞的淋巴结。这些结果表明CCR4+HNSCC的淋巴转移是由CCL22以自分泌或M2样巨噬细胞旁分泌的方式促进的。因此，CCR4/CCL22轴可能是开发HNSCC诊断和治疗策略的一个有吸引力的靶点。
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 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 axis may be an attractive target for the development of diagnostic and therapeutic strategies for patients with HNSCC.