The role of nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species in the acquisition of metastatic ability of tumor cells
The role of nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species in the acquisition of metastatic ability of tumor cells
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DOI：
10.2353/ajpath.2006.060073
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发表时间：
2006-07-01
影响因子：
6
通讯作者：
Hunt, NH
中科院分区：
文献类型：
--
作者：
Okada, F;Kobayashi, M;Hunt, NH
我们通过比较gp91(Phox-/-)小鼠和C57BL/6J野生型(WT)小鼠，研究了吞噬细胞衍生的氧自由基在肿瘤细胞获得转移表型中的作用。Gp91(Phox-/-)小鼠缺乏gp91(Phox)基因，这是吞噬细胞烟酰胺腺嘌呤二核苷酸磷酸氧化酶的一个重要亚单位，能产生超氧阴离子。QR-32纤维肉瘤细胞是非转移性的，但在体内一旦与异物(明胶海绵)诱导的吞噬细胞接触就会转化为转移性肿瘤。与WT小鼠与异物共移植的QR-32细胞相比，gp91(Phox-/-)小鼠的转移减少。注射B16BL6黑色素瘤细胞后，WT和gp91(Phox-/-)小鼠的原发肿瘤发生率无差异。然而，在切除原发肿瘤后，gp91(Phox-/-)小鼠的转移减少。胸腺素β4基因表达和细胞运动/侵袭在WT小鼠肿瘤中可见，而在gp91(Phox-/-)小鼠肿瘤中未见。过继转移来自WT小鼠的吞噬细胞，而不是来自gp91(Phox-/-)小鼠的吞噬细胞，恢复了生长在gp91(Phox-/-)小鼠的肿瘤的转移能力。这些发现表明，肿瘤的转移行为主要是由吞噬细胞衍生的超氧阴离子及其氧化代谢产物赋予的，而超氧阴离子及其氧化代谢产物是通过激活烟酰胺腺嘌呤二核苷酸磷酸氧化酶而产生的。
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 beta 4 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.