Tumor-derived interleukin-1 promotes lymphangiogenesis and lymph node metastasis through M2-type macrophages

PLoS One. 2014 Jun 12;9(6):e99568. doi: 10.1371/journal.pone.0099568. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Chemokines / metabolism
  • Coculture Techniques
  • Collagen / metabolism
  • Drug Combinations
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / pharmacology
  • Interleukin-1 / metabolism*
  • Laminin / metabolism
  • Lymphangiogenesis* / drug effects
  • Lymphatic Metastasis / pathology*
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Male
  • Mice, Inbred C57BL
  • Models, Biological
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neovascularization, Pathologic / pathology
  • Neutrophil Infiltration / drug effects
  • Proteoglycans / metabolism
  • Receptors, Interleukin-1
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor C / metabolism

Substances

  • Chemokines
  • Drug Combinations
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Laminin
  • Proteoglycans
  • Receptors, Interleukin-1
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C
  • matrigel
  • Collagen

Grant support

This research was supported by JSPS KAKENHI Grant Numbers 23112515, 23300350 (to MO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.