Watari Kosuke, Shibata Tomohiro, Kawahara Akihiko, Sata Ken-ichi, Nabeshima Hiroshi, Shinoda Ai, Abe Hideyuki, Azuma Koichi, Murakami Yuichi, Izumi Hiroto, Takahashi Takashi, Kage Masayoshi, Kuwano Michihiko, Ono Mayumi
Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan.
PLoS One. 2014 Jun 12;9(6):e99568. doi: 10.1371/journal.pone.0099568. eCollection 2014.
Tumors formed by a highly metastatic human lung cancer cell line are characterized by activated signaling via vascular endothelial growth factor (VEGF)-C through its receptor (VEGFR-3) and aggressive lymph node metastasis. In this study, we examined how these highly metastatic cancers acquired aggressive lymph node metastasis. Compared with their lower metastatic counterparts, the highly metastatic tumors formed by this cell line expressed higher amounts of interleukin (IL)-1α, with similarly augmented expression of IL-1α and IL-1β by tumor stromal cells and of VEGF-A and VEGF-C by tumor-associated macrophages. These tumor-associated macrophages were mainly of the M2 type. Administration of a macrophage-targeting drug suppressed the production of these potent angiogenic and lymphangiogenic factors, resulting in decreased tumor growth, angiogenesis, lymphangiogenesis, and lymph node metastasis. In Matrigel plug assays, the highly metastatic cells formed tumors that were extensively infiltrated by M2-type macrophages and exhibited enhanced angiogenesis and lymphangiogenesis. All of these responses were suppressed by the IL-1 receptor (IL-1R) antagonist anakinra. Thus, the IL-1α-driven inflammatory activation of angiogenesis and lymphangiogenesis seems to provide a highly metastatic tumor microenvironment favorable for lymph node metastasis through cross-talk with macrophages. Accordingly, the IL-1R/M2-type macrophage axis may be a good therapeutic target for patients with this form of lung cancer.
由一种高转移性人肺癌细胞系形成的肿瘤的特征在于，通过血管内皮生长因子（VEGF）-C经由其受体（VEGFR-3）激活信号传导，并具有侵袭性淋巴结转移。在本研究中，我们研究了这些高转移性癌症是如何获得侵袭性淋巴结转移的。与低转移性对应物相比，由该细胞系形成的高转移性肿瘤表达更高水平的白细胞介素（IL）-1α，肿瘤基质细胞中IL-1α和IL-1β的表达以及肿瘤相关巨噬细胞中VEGF-A和VEGF-C的表达也同样增加。这些肿瘤相关巨噬细胞主要为M2型。给予一种巨噬细胞靶向药物可抑制这些强效血管生成和淋巴管生成因子的产生，从而导致肿瘤生长、血管生成、淋巴管生成和淋巴结转移减少。在基质胶栓试验中，高转移性细胞形成的肿瘤被M2型巨噬细胞广泛浸润，并表现出增强的血管生成和淋巴管生成。所有这些反应均被IL-1受体（IL-1R）拮抗剂阿那白滞素抑制。因此，IL-1α驱动的血管生成和淋巴管生成的炎症激活似乎通过与巨噬细胞的相互作用提供了一个有利于淋巴结转移的高转移性肿瘤微环境。因此，IL-1R/M2型巨噬细胞轴可能是这种肺癌患者的一个良好治疗靶点。
