Chen X, Ding Y W, Yang G y, Bondoc F, Lee M J, Yang C S
Laboratory for Cancer Research, College of Pharmacy, Rutgers University, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Carcinogenesis. 2000 Feb;21(2):257-63. doi: 10.1093/carcin/21.2.257.
Oxidative damage has long been related to carcinogenesis in human cancers and animal cancer models. Recently a rat esophageal adenocarcinoma (EAC) model was established in our laboratory by using esophagoduodenal anastomosis (EDA) plus iron supplementation. Our previous study suggested that iron supplementation enhanced inflammation and the production of reactive nitrogen species in the esophageal epithelium, which could contribute to esophageal adenocarcinogenesis. Here we further characterized oxidative damage in this model. We were particularly interested in how excess iron was deposited in the esophagus, and which cells were targeted by oxidative damage. Male Sprague-Dawley rats received iron supplementation (50 mg Fe/kg/month, i.p.) starting 4 weeks after EDA. The animals were killed at 11, 30 or 35 weeks after surgery. EAC appeared as early as week 11 after surgery, and increased over time, up to 60% at 35 weeks after surgery. All EACs were well-differentiated mucinous adenocarcinoma at the squamocolumnar junction. Iron deposition was found at the squamocolumnar junction and in the area with esophagitis. Esophageal iron overload could result from transient increase of blood iron after i.p. injection, and the overexpression of transferrin receptor in the premalignant columnar-lined esophagus (CLE) cells. Oxidative damage to DNA (8-hydroxy-2'-deoxyguanosine), protein (carbonyl content) and lipid (thiobarbituric acid reactive substance) in the esophagus was significantly higher than that of the non-operated control. CLE cells were believed to be the target cells of oxidative damage because they overexpressed heme oxygenase 1 and metallothionein, both known to be responsive to oxidative damage. We propose that oxidative damage plays an important role in the formation of EAC in the EDA model, and a similar situation may occur in humans with gastroesophageal reflux and iron over-nutrition.
氧化损伤长期以来一直与人类癌症及动物癌症模型中的致癌作用相关。最近，我们实验室通过食管十二指肠吻合术（EDA）加铁补充建立了大鼠食管腺癌（EAC）模型。我们之前的研究表明，铁补充增强了食管上皮中的炎症及活性氮物质的产生，这可能有助于食管腺癌的发生。在此，我们进一步对该模型中的氧化损伤进行了特征描述。我们特别感兴趣的是过量的铁如何在食管中沉积，以及哪些细胞是氧化损伤的靶细胞。雄性Sprague-Dawley大鼠在EDA术后4周开始接受铁补充（50 mg Fe/kg/月，腹腔注射）。在术后11、30或35周处死动物。EAC最早在术后11周出现，并随时间增加，在术后35周时高达60%。所有EAC均为鳞柱状交界处的高分化黏液腺癌。在鳞柱状交界处及食管炎区域发现了铁沉积。食管铁过载可能源于腹腔注射后血中铁的短暂增加，以及癌前柱状上皮食管（CLE）细胞中转铁蛋白受体的过表达。食管中DNA（8-羟基-2'-脱氧鸟苷）、蛋白质（羰基含量）和脂质（硫代巴比妥酸反应性物质）的氧化损伤明显高于未手术对照。CLE细胞被认为是氧化损伤的靶细胞，因为它们过表达血红素加氧酶1和金属硫蛋白，这两者均已知对氧化损伤有反应。我们提出氧化损伤在EDA模型中EAC的形成中起重要作用，在患有胃食管反流和铁营养过剩的人类中可能也会出现类似情况。
