Dual inhibition of both the epidermal growth factor receptor and erbB2 effectively inhibits the promotion of skin tumors during two-stage carcinogenesis.
Dual inhibition of both the epidermal growth factor receptor and erbB2 effectively inhibits the promotion of skin tumors during two-stage carcinogenesis.
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DOI：
10.1158/1940-6207.capr-10-0010
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发表时间：
2010-08
期刊：
影响因子：
--
通讯作者：
DiGiovanni J
中科院分区：
文献类型：
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作者：
Kiguchi K;Kitamura T;Moore T;Rumi M;Chang HC;Treece D;Ruffino L;Connolly K;DiGiovanni J
已知受体酪氨酸激酶的 erbB 家族在正常上皮发育和上皮瘤形成中发挥重要作用。大量证据还表明，通过 EGFR 的信号传导在小鼠多阶段皮肤癌发生中发挥着重要作用。然而，人们对 erbB2 的作用知之甚少。在这项研究中，为了进一步检查 erbB2 和 EGFR 在上皮癌发生中的作用，我们检查了饮食中给予的 erbB2/EGFR 酪氨酸激酶双重抑制剂 (TKI) GW2974 对野生型和 BK5.erbB2 小鼠两阶段癌发生过程中皮肤肿瘤促进的影响。在 BK5.erbB2 小鼠中，erbB2 在表皮基底层过度表达，导致对皮肤肿瘤发展的敏感性升高。 GW2974 可有效抑制 12-O-十四烷酰佛波醇-13-乙酸酯 (TPA) 在野生型和 BK5.erbB2 小鼠中促进皮肤肿瘤的发生，但在 BK5.erbB2 小鼠中观察到更显着的效果。此外，当停止 GW2974 治疗时，这种抑制作用是可逆的。 GW2974 抑制 TPA 诱导的表皮过度增殖，这与 EGFR 和 erbB2 的激活减少相关。这些结果支持了这样的假设：EGFR和erbB2在两阶段皮肤癌发生过程中，特别是在肿瘤促进阶段，在皮肤肿瘤的发展中发挥重要作用。此外，BK5.erbB2 小鼠在肿瘤促进过程中对 GW2974 的抑制作用显着敏感，表明当 erbB2 作为致癌过程的早期事件过度表达或扩增时，该化合物具有更大的功效。
The erbB family of receptor tyrosine kinases are known to play important roles in both normal epithelial development and epithelial neoplasia. Considerable evidence also suggests that signaling through the EGFR plays an important role in multistage skin carcinogenesis in mice; however, less is known about the role of erbB2. In this study, to further examine the role of both erbB2 and EGFR in epithelial carcinogenesis, we examined the effect of a dual erbB2/EGFR tyrosine kinase inhibitor (TKI), GW2974, given in the diet on skin tumor promotion during two-stage carcinogenesis in both wild-type and BK5.erbB2 mice. In BK5.erbB2 mice, erbB2 is overexpressed in the basal layer of epidermis and leads to heightened sensitivity to skin tumor development. GW2974 effectively inhibited skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) in both wild-type and BK5.erbB2 mice, although a more marked effect was seen in BK5.erbB2 mice. In addition, this inhibitory effect was reversible when GW2974 treatment was withdrawn. GW2974 inhibited TPA-induced epidermal hyperproliferation, which correlated with reduced activation of both the EGFR and erbB2. These results support the hypothesis that both the EGFR and erbB2 play an important role in the development of skin tumors during two-stage skin carcinogenesis, especially during the tumor promotion stage. Furthermore, the marked sensitivity of BK5.erbB2 mice to the inhibitory effects of GW2974 during tumor promotion suggest greater efficacy for this compound when erbB2 is overexpressed or amplified as an early event in the carcinogenic process.