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

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)-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.