Estradiol Alters Cell Growth in Nonmalignant Colonocytes and Reduces the Formation of Preneoplastic Lesions in the Colon
Estradiol Alters Cell Growth in Nonmalignant Colonocytes and Reduces the Formation of Preneoplastic Lesions in the Colon
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DOI：
10.1158/0008-5472.can-09-2348
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发表时间：
2009-12-01
期刊：
影响因子：
11.2
通讯作者：
Allred, Clinton D.
中科院分区：
文献类型：
--
作者：
Weige, Charles C.;Allred, Kimberly F.;Allred, Clinton D.
许多临床和动物研究表明，激素替代疗法可降低结肠肿瘤形成的风险。然而，大多数实验表明，雌二醇（E-2）不抑制恶性转化的结肠上皮细胞的生长。因此，本研究的重点是评估E-2在非癌性结肠细胞中的作用。E-2处理（0-10 nmol/L）以剂量反应方式减少了年轻成年小鼠结肠细胞（YAMC）（一种非恶性细胞系）的细胞生长并增加了凋亡活性。这些作用在YAMC-Ras细胞中丢失，YAMC-Ras细胞是具有单一恶性转化的同基因细胞系。与雌激素受体（ER）拮抗剂共处理抑制E-2在YAMC细胞中的生理效应，表明该反应是ER介导的。为了进一步研究E-2对结肠上皮细胞的作用，我们评价了用载体或E-2处理的卵巢切除野生型（WT）和ER β敲除（ER β KO）小鼠中肿瘤前病变的发展。与WT对照小鼠或接受任一治疗的ER β KO动物相比，WT E-2治疗的动物在结肠上皮中表现出显著更少的异常隐窝病灶和增加的凋亡活性。我们首次发现，E-2在体外改变了非转化的结肠细胞的生长，并且通过ER β介导的机制，E-2影响了非癌性结肠细胞的生理学，导致较少的癌前病变。总的来说，这些数据表明，E-2的保护作用主要发生在疾病发展的起始/促进阶段，并确定激素作为一种重要的化学保护剂。[Cancer Res 2009;69（23）：9118-24]
Numerous clinical and animal studies show that hormone replacement therapy reduces the risk of colon tumor formation. However, the majority of experiments have shown that estradiol (E-2) does not inhibit the growth of malignantly transformed colon epithelia. As such, the presented studies focused on evaluating the effects of E-2 in noncancerous colonocytes. E-2 treatments (0-10 nmol/L) reduced cell growth and increased apoptotic activity in young adult mouse colonocytes (YAMC), a nonmalignant cell line, in a dose-responsive manner. These effects were lost in the YAMC-Ras cells, an isogenic cell line with a single malignant transformation. Cotreatment with an estrogen receptor (ER) antagonist inhibited the physiologic effects of E-2 in YAMC cells, suggesting that the response is ER mediated. To further study the effect of E-2 on colonic epithelia, we evaluated the development of preneoplastic lesions in ovariectornized wild-type (WT) and ER beta knockout (ER beta KO) mice treated with either vehicle or E-2. WT E-2-treated animals exhibited significantly fewer aberrant crypt foci and increased apoptotic activity in colonic epithelia when compared with WT control mice or ER beta KO animals receiving either treatment. For the first time, we showed that E-2 alters the growth of nontransfornied colonocytes in vitro and that, through an ER beta-mediated mechanism, E-2 influences the physiology of noncancerous colonocytes, resulting in fewer preneoplastic lesions. Collectively, these data show that the protective actions of E-2 occur primarily during the initiation/promotion stages of disease development and identify the hormone as an important chemoprotective agent. [Cancer Res 2009;69(23):9118-24]