251. Tumor-Derived Interleukin-1 Promotes Lymphangiogenesis and Lymph Node Metastasis through M2-Type Macrophages
- Author
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Hideyuki Abe, Kosuke Watari, Ken Ichi Sata, Michihiko Kuwano, Ai Shinoda, Hiroshi Nabeshima, Masayoshi Kage, Yuichi Murakami, Mayumi Ono, Takashi Takahashi, Hiroto Izumi, Tomohiro Shibata, Akihiko Kawahara, and Koichi Azuma
- Subjects
Male ,Vascular Endothelial Growth Factor A ,Pathology ,Angiogenesis ,Vascular Endothelial Growth Factor C ,lcsh:Medicine ,Lung and Intrathoracic Tumors ,Metastasis ,chemistry.chemical_compound ,Animal Cells ,Neoplasms ,Molecular Cell Biology ,Basic Cancer Research ,Medicine and Health Sciences ,Lymphoid Organs ,Lymphangiogenesis ,lcsh:Science ,Multidisciplinary ,Neovascularization, Pathologic ,Interleukin ,Vascular endothelial growth factor ,Drug Combinations ,Vascular endothelial growth factor A ,Neutrophil Infiltration ,Oncology ,Vascular endothelial growth factor C ,Lymphatic Metastasis ,Cytokines ,Proteoglycans ,Collagen ,Chemokines ,Anatomy ,Cellular Types ,Signal Transduction ,Research Article ,medicine.medical_specialty ,Stromal cell ,Immune Cells ,Immunology ,Biology ,Models, Biological ,Lymphatic System ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Cell Proliferation ,Macrophages ,lcsh:R ,Receptors, Interleukin-1 ,Biology and Life Sciences ,Cancers and Neoplasms ,Cell Biology ,Molecular Development ,medicine.disease ,Coculture Techniques ,Mice, Inbred C57BL ,Interleukin 1 Receptor Antagonist Protein ,chemistry ,Immune System ,lcsh:Q ,Clinical Immunology ,Laminin ,Interleukin-1 ,Developmental Biology - Abstract
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.
- Published
- 2014