Inflammatory stimuli from macrophages and cancer cells synergistically promote tumor growth and angiogenesis.
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.
Kimura
Yusuke N
YN
Research Center for Innovative Cancer Therapy and Department of Surgery, Kurume University, Kurume 830-0011, Japan.
Watari
Kosuke
K
Fotovati
Abbas
A
Hosoi
Fumihito
F
Yasumoto
Kosei
K
Izumi
Hiroto
H
Kohno
Kimitoshi
K
Umezawa
Kazuo
K
Iguchi
Haruo
H
Shirouzu
Kazuo
K
Takamori
Sinzo
S
Kuwano
Michihiko
M
Ono
Mayumi
M
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004002:Clodronic Acid / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000494:pharmacology; D008175:Lung Neoplasms / Q000473:pathology*; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000473:pathology*; D014183:Transplantation, Heterologous; D020298:U937 Cells
D053583:Interleukin-1beta; D004002:Clodronic Acid