A mouse prostate cancer model induced by Hedgehog overexpression
A mouse prostate cancer model induced by Hedgehog overexpression
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DOI：
10.1007/s11373-005-9050-x
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发表时间：
2006-05-01
影响因子：
11
通讯作者：
Chang, Han-Hsin
中科院分区：
文献类型：
--
作者：
Chen, Bo-Yie;Lin, David Pei-Cheng;Chang, Han-Hsin
Hedgehog 是胚胎发育过程中的一种调节蛋白，其在成人组织中的异常激活与上皮-间质相互作用发生部位的肿瘤发生有关。在前列腺中，在晚期癌症进展和转移过程中观察到 Hedgehog 信号激活，但 Hedgehog 过度表达是否可以启动前列腺肿瘤发生仍不清楚。我们通过前列腺内注射和电穿孔引入了 Hedgehog 表达载体，以解决 Hedgehog 过度表达的影响。该操作在 30 天内引起了具有特征性前列腺上皮内瘤变甚至前列腺癌 (CaP) 表型的病变，免疫组织化学和蛋白质印迹检测表明 Hedgehog 过度表达。通过基底细胞标记物 p63 的不连续性、造口中 CK-8/CK-18 阳性上皮细胞的混合以及 α-SMA 阳性纤维肌鞘的缺失，证实了致瘤表型。在人类 CaP 样本中也发现了类似的 Hedgehog 过度表达。因此，Hedgehog过度表达诱导前列腺肿瘤从正常状态开始发生。此外，建立了Hedgehog过表达诱导的小鼠前列腺癌模型，可用于测试针对Hedgehog信号通路的新治疗方法。
Hedgehog is a regulatory protein during embryonic development and its abnormal activation in adult tissues has been implicated in tumorigenesis within sites where epithelial-mesenchymal interactions take place. In the prostate, Hedgehog signaling activation was observed during advanced cancer progression and metastasis, but whether Hedgehog overexpression can initiate prostate tumorigenesis remains unknown. We introduced a Hedgehog-expressing vector by intra-prostate injection and electroporation to address the effects of Hedgehog overexpression. The manipulation caused lesions with characteristic prostatic intraepithelial neoplasia or even prostatic cancer (CaP) phenotypes within 30 days, with Hedgehog overexpression demonstrated by immunohistochemistry and Western blot detections. The tumorigenic phenotypes were confirmed by discontinuity of basal cell marker p63, mix-up of CK-8/CK-18 positive epithelial cells in the stoma as well as absence of alpha-SMA positive fibro-muscular sheath. Comparable Hedgehog overexpression was found in human CaP specimen. Thus, Hedgehog overexpression induced prostate tumorigenesis starting from the normal status. Furthermore, a mouse prostate cancer model induced by Hedgehog overexpression was established and may be used for testing novel therapeutical approaches targeting at Hedgehog signaling pathway.