Inflammatory stimuli from macrophages and cancer cells synergistically promote tumor growth and angiogenesis

Cancer Sci. 2007 Dec;98(12):2009-18. doi: 10.1111/j.1349-7006.2007.00633.x. Epub 2007 Oct 9.


The focus of the present study was whether and how infiltrating macrophages play a role in angiogenesis and the growth of cancer cells in response to the inflammatory cytokine interleukin (IL)-1beta. Lewis lung carcinoma cells overexpressing IL-1beta grew faster and induced greater neovascularization than a low IL-1beta-expressing counterpart in vivo. When macrophages were depleted using clodronate liposomes, both neovascularization and tumor growth were reduced in the IL-1beta-expressing tumors. Co-cultivation of IL-1beta-expressing cancer cells with macrophages synergistically augmented neovascularization and the migration of vascular endothelial cells. In these co-cultures, production of the angiogenic factors vascular endothelial growth factor-A and IL-8, monocyte chemoattractant protein-1, and matrix metalloproteinase-9 were increased markedly. The production of these factors, induced by IL-1beta-stimulated lung cancer cells, was blocked by a nuclear factor (NF)-kappaB inhibitor, and also by the knockdown of p65 (NF-kappaB) and c-Jun using small interference RNA, suggesting involvement of the transcription factors NF-kappaB and AP-1. These results demonstrated that macrophages recruited into tumors by monocyte chemoattractant protein-1 and other chemokines could play a critical role in promoting tumor growth and angiogenesis, through interactions with cancer cells mediated by inflammatory stimuli.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Clodronic Acid / pharmacology
  • Drug Synergism
  • Humans
  • Inflammation / physiopathology*
  • Interleukin-1beta / pharmacology
  • Lung Neoplasms / pathology*
  • Macrophages / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms / blood supply*
  • Neoplasms / pathology*
  • Neovascularization, Pathologic / pathology*
  • Transplantation, Heterologous
  • U937 Cells


  • Interleukin-1beta
  • Clodronic Acid