Carcinogenesis Advance Access originally published online on April 1, 2004
Carcinogenesis 2004 25(9):1559-1565; doi:10.1093/carcin/bgh158
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Carcinogenesis vol.25 no.9 © Oxford University Press 2004; all rights reserved.
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Tumour-derived and host-derived nitric oxide differentially regulate breast carcinoma metastasis to the lungs
1 EPHE/INSERM/Laboratoire d'immunologie et immunothérapie des cancers, Unité 517 et IFR 100, Université de Bourgogne, Dijon, France, 2 Institut Universitaire de Pathologie, CHUV, Lausanne, Switzerland and 3 Service de médecine nucléaire, Centre Georges-François Leclerc, et IFR 100 de l'INSERM, Dijon, France
4 To whom correspondence should be addressed Email: jean-francois.jeannin{at}u-bourgogne.fr
To study the role of nitric oxide (NO) in lung metastasis of breast carcinoma, we isolated two cell clones (H and J) from the parental EMT-6 murine breast carcinoma cell line, based on their differential NO production. In vitro, EMT-6 J cells, but not EMT-6H cells, constitutively expressed inducible NO synthase (NOS II) and secreted high levels of NO. IL-1ß increased NO production in both clones, and TNF-
had a synergistic effect on IL-1ß-induced NO production, but NO production by EMT-6 J cells was always higher than by EMT-6H cells. Proliferation, survival and adhesion to lung-derived endothelial cells of both clones were similar and were not affected by NO. In vivo, both clones similarly located in the lungs of syngeneic mice 48 h after injection. However, EMT-6H cells were significantly more tumorigenic than EMT-6 J cells as assessed at later time points. Injection of EMT-6 J cells and simultaneous treatment of mice with aminoguanidine (AG), a NOS II inhibitor, significantly increased tumour formation. Injection of EMT-6H and EMT-6 J cells into NOS II-deficient mice resulted in a significant survival increase as compared with wild-type animals. Simultaneous administration of AG increased the death rate of NOS II-deficient mice injected with EMT-6 J cells. These results demonstrate that: (i) NO does not influence the early stages of tumour metastasis to the lungs and (ii) NOS II expression in tumour cells reduces, while NOS II expression in host cells enhances, tumour nodule development. In conclusion, the cellular origin and the local NO production are critical in the metastatic process.
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