The role of nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species in the acquisition of metastatic ability of tumor cells - PubMed (original) (raw)

The role of nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species in the acquisition of metastatic ability of tumor cells

Futoshi Okada et al. Am J Pathol. 2006 Jul.

Abstract

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 beta4 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.

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Figures

Figure 1

Figure 1

Decreased acquisition of metastatic ability of tumor cells grown in gp91_phox_−/− mice. QR-32 tumor cells (A–C, 1 × 105) were subcutaneously (s.c.) co-implanted with gelatin sponge, and B16BL6 cells (D–F, 4 × 105 in 0.05 ml) were injected into the hind footpad (i.f.), respectively, of WT mice and gp91_phox_−/− mice (A and D). The metastasis incidence (B and E) and number of colonies per lung (C and F) were counted. *P < 0.001 versus WT. The actual number of incidences is indicated above each bar (number of mice with tumor or metastasis/number of mice tested).

Figure 2

Figure 2

Growth of primary tumors in gp91_phox_−/− mice and WT mice after subcutaneous or intrafootpad injections of tumor cells. Growth curves of QR-32 cells (1 × 105 cells) co-implanted with gelatin sponge (A), QRsP-11 tumor cells (1 × 106 cells) injected subcutaneously (B), B16BL6 cells (4 × 105 cells) injected into hind footpad (C), and B16BL6 cells (1 × 106 cells) injected subcutaneously (D) into WT and gp91_phox_−/− mice, respectively. ○, WT mice; •, gp91_phox_−/− mice; ▵, gp91_phox_−/− mice with adoptively transferred WT phagocytes; ▴, gp91_phox_−/− mice with adoptively transferred gp91_phox_−/− phagocytes. *P < 0.01; gp91_phox_−/− versus WT mice, and gp91_phox_−/− mice with adoptively transferred WT phagocytes versus gp91_phox_−/− mice with adoptively transferred gp91_phox_−/− phagocytes. Data are mean diameters of the arising tumors at each injection and are representative results of at least two separate experiments producing similar results.

Figure 3

Figure 3

Restored metastatic ability of tumor cells by adoptive transfer of inflammatory phagocytes obtained from WT mice. Adoptively transferred inflammatory phagocytes obtained from WT mice recovered acquisition of metastatic potential of tumor cells of both tumor cell lines. *P < 0.05 and **P < 0.001 versus adjacent group.

Figure 4

Figure 4

Decreased acquisition of spontaneous metastatic ability of B16BL6 melanoma cells after subcutaneous injection into gp91_phox_−/− mice. B16BL6 melanoma cells (1 × 106) were injected subcutaneously into WT mice and gp91_phox_−/− mice. The mice were sacrificed for necropsy when they were in a moribund state. *P < 0.05 and **P < 0.01 versus WT mice.

Figure 5

Figure 5

Thymosin β4 gene expression and corresponding cell motility/invasion were augmented in tumor cells grown in WT mice but not those grown in gp91_phox_−/− mice. Tumor cells were established from QR-32 cells co-implanted with gelatin sponge in gp91phox−/− mice (QRsP/gp91phox−/−) and those in WT mice (QRsP/WT). B16BL6 cells were implanted into footpad in gp91phox−/− mice and in WT mice and established cell lines BL6/gp91phox−/− and BL6/WT, respectively. RT-PCR analysis for thymosin β4 and GAPDH (A), phagokinetic track patterns (B and C) and invasion through transwell (D and E) are shown. Each bar represents the mean ± SD of at least two independent experiments.*P < 0.001 and **P < 0.05, compared with tumors in WT with lowest motility or invasion.

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