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

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Abstract
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)‐1β. Lewis lung carcinoma cells overexpressing IL‐1β grew faster and induced greater neovascularization than a low IL‐1β‐expressing counterpart in vivo. When macrophages were depleted using clodronate liposomes, both neovascularization and tumor growth were reduced in the IL‐1β‐expressing tumors. Co‐cultivation of IL‐1β‐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‐1β‐stimulated lung cancer cells, was blocked by a nuclear factor (NF)‐κB inhibitor, and also by the knockdown of p65 (NF‐κB) and c‐Jun using small interference RNA, suggesting involvement of the transcription factors NF‐κB 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. (Cancer Sci 2007; 98: 2009–2018)