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, Nicholas H. Hunt

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

We examined the role of phagocyte-derived oxygen radicals in tumor cell acquisition of metastatic phenotype by comparing gp91phox-/- mice and C57BL/6J wild-type (WT) mice. The gp91phox-/- mouse is deficient in the gp91phox 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 gp91phox-/- mice exhibited reduced metastasis. There was no difference in the incidence of primary tumors after injection of B16BL6 melanoma cells in WT and gp91phox-/- mice. However, after resection of the primary tumors, metastases were reduced in gp91phox-/- mice. Thymosin β4 gene expression and cell motility/invasion were seen in the tumors from WT mice but not in those from gp91phox-/- mice. Adoptive transfer of phagocytes from WT mice, but not those from gp91phox-/- mice, restored the metastatic ability of tumors grown in gp91phox-/- 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.

Original languageEnglish
Pages (from-to)294-302
Number of pages9
JournalAmerican Journal of Pathology
Volume169
Issue number1
DOIs
Publication statusPublished - Jul 2006
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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