Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress
Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress
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DOI：
10.1158/1078-0432.ccr-07-1614
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发表时间：
2008-01-01
影响因子：
11.5
通讯作者：
Fujii, Shingo
中科院分区：
文献类型：
--
作者：
Yamaguchi, Ken;Mandai, Masaki;Fujii, Shingo
目的：子宫内膜异位囊肿可转化为卵巢癌，如透明细胞癌和包膜样癌。我们推测，生殖期间子宫内膜异位囊肿反复出血所产生的富铁环境可能通过铁诱导的持续氧化应激在囊肿癌变中起关键作用。实验设计：分析21例包膜异位性卵巢囊肿、4例透明细胞癌和11例非子宫内膜异位性卵巢囊肿中游离“催化”铁、乳糖清氢酶、潜在抗氧化剂、脂质过氧化物和8-羟基-2′-脱氧鸟苷（8-OHdG）的浓度。同时对铁沉积和8-OHdG水平进行组织学分析。体外测定了包膜异位囊内内容物的活性氧含量和致突变性。结果：子宫内膜异位囊肿游离铁浓度（100.9 mmol/L）显著高于非子宫内膜异位囊肿游离铁浓度（0.075 mmol/L, P < 0.01）。乳糖脱氢酶、潜在抗氧化剂、脂质过氧化物和8-OHdG的平均浓度在包膜异位囊肿中也显著升高（P < 0.01）。游离铁浓度与8-OHdG浓度呈正相关（P < 0.01）。组织学上，与非子宫内膜异位症囊肿相比，子宫内膜异位症囊肿中铁的含量更高（P < 0.01）。伴有子宫内膜异位症的癌组8-OHdG水平高于无子宫内膜异位症的癌组（P < 0.05）。体外分析表明，包膜异位囊肿的内容物比其他包膜异位囊肿的内容物能产生更多的活性氧，并能更频繁地诱导基因突变。结论：包囊异位囊肿内容物中丰富的游离铁与较大的氧化应激和频繁的DNA突变密切相关。卵巢子宫内膜异位性囊肿在生育期间长期积累的红细胞产生氧化应激，这可能是导致子宫内膜异位性囊肿恶性变化的原因。
Purpose: Endometriotic cysts are known to transform into ovarian cancers, such as clear cell and enclometrioid carcinomas. We hypothesized that an iron-rich environment produced by the repetition of hemorrhage in the endometriotic cysts during the reproductive period may play a crucial role in carcinogenesis in the cysts through the iron-induced persistent oxidative stress.Experimental Design: Contents of human ovarian cysts, including 21 enclometriotic cysts, 4 clear cell carcinomas, and 11 nonendometriotic cysts, were analyzed for the concentrations of free "catalytic" iron, lactose clehydrogenase, potential antioxiclant, lipid peroxide, and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Iron deposition and 8-OHdG levels were also analyzed histologically. Reactive oxygen species and the mutagenicity of the contents in enclometriotic cyst were determined in vitro.Results: The concentration of free iron in endometriotic cysts (100.9 mmol/L) was significantly higher than that in nonendometriotic cysts (0.075 mmol/L; P < 0.01). The average concentrations of lactose dehydrogenase, potential antioxiclant, lipid peroxide, and 8-OHdG were also significantly higher in enclometriotic cysts (P < 0.01).There was a correlation between the concentration of free iron and that of 8-OHdG (P < 0.01). Histologically, we could observe iron deposits more abundantly in endometriotic cysts than in nonendometriotic cysts (P < 0.01).The level of 8-OHdG in carcinoma associated with endometriosis was higher than that of carcinoma without endometriosis (P < 0.05). In vitro analyses showed that the contents of enclometriotic cyst could produce more reactive oxygen species and could induce gene mutations more frequently than the contents in the other cysts.Conclusions: Abundant free iron in the contents of enclometriotic cysts was strongly associated with greater oxidative stress and frequent DNA mutations. A long-standing history of the RBCs accumulated in the ovarian endometriotic cysts during the reproductive period produces oxidative stress that is a possible cause for the malignant change of the endometriotic cyst.