title: Tumor-derived interleukin-1 promotes lymphangiogenesis and lymph node metastasis through M2-type macrophages.
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.
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Watari
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kawahara
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Sata
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nabeshima
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Shinoda
authors.affiliation: Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Abe
authors.affiliation: Department of Internal Medicine, Division of Respirology, Neurology, and Rheumatology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Azuma
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; St. Mary's Hospital, Kurume, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Department of Occupational Pneumology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Izumi
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kage
authors.affiliation: Laboratory of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Michihiko
authors.initials: M
authors.lastname: Kuwano
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D042583:Lymphangiogenesis / Q000187:drug effects; D008207:Lymphatic Metastasis / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D011509:Proteoglycans / Q000378:metabolism; D017472:Receptors, Interleukin-1; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism
chemical_list: D018925:Chemokines; D004338:Drug Combinations; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D007797:Laminin; D011509:Proteoglycans; D017472:Receptors, Interleukin-1; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; C059485:matrigel; D003094:Collagen