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(American Journal of Pathology. 2006;169:294-302.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060073

The Role of Nicotinamide Adenine Dinucleotide Phosphate Oxidase-Derived Reactive Oxygen Species in the Acquisition of Metastatic Ability of Tumor Cells

Futoshi Okada^*, Masanobu Kobayashi, Hiroki Tanaka, Tokushige Kobayashi, Hiroshi Tazawa^¶, Yoshihito Iuchi^*, Kunishige Onuma^*, Masuo Hosokawa^||, Mary C. Dinauer^** and Nicholas H. Hunt

From the Department of Biomolecular Function,^* Graduate School of Medical Science, Yamagata University, Yamagata, Japan ; the Institute for Genetic Medicine and Oncorex, Hokkaido University, Sapporo, Japan; the Department of Pathology, Asahikawa Medical College, Asahikawa, Japan; the Biochemistry Division,^¶ National Cancer Center Research Institute, Tokyo, Japan; Health Sciences University of Hokkaido,|| School of Nursing and Social Services, Ishikari-Tobetsu, Japan; the Departments of Pediatrics and of Medical and Molecular Genetics,^** Herman B. Wells Center for Pediatric Research, James Whitcomb Riley Hospital for Children, Indiana University Medical Center, Indianapolis, Indiana; and the Institute for Biomedical Research, University of Sydney, Sydney, Australia

We examined the role of phagocyte-derived oxygen radicals in tumor cell acquisition of metastatic phenotype by comparing gp91^phox–/– mice and C57BL/6J wild-type (WT) mice. The gp91^phox–/– mouse is deficient in the gp91^phox gene, an essential subunit of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase that generates superoxide anion. QR-32 fibrosarcoma cells are nonmetastatic but are converted into metastatic tumors once in contact with foreign body (gelatin sponge)-induced phagocytes in vivo. Compared to QR-32 cells co-implanted with the foreign body in WT mice, those in gp91^phox–/– mice exhibited reduced metastasis. There was no difference in the incidence of primary tumors after injection of B16BL6 melanoma cells in WT and gp91^phox–/– mice. However, after resection of the primary tumors, metastases were reduced in gp91^phox–/– mice. Thymosin ß4 gene expression and cell motility/invasion were seen in the tumors from WT mice but not in those from gp91^phox–/– mice. Adoptive transfer of phagocytes from WT mice, but not those from gp91^phox–/– mice, restored the metastatic ability of tumors grown in gp91^phox–/– mice. These findings show that tumor metastatic behavior can primarily be endowed by phagocyte-derived superoxide anion and its oxidative metabolites, which are generated through activation of nicotinamide adenine dinucleotide phosphate oxidase.