Hedgehog/Ras interactions regulate early stages of pancreatic cancer
Hedgehog/Ras interactions regulate early stages of pancreatic cancer
复制标题
DOI：
10.1101/gad.1470806
复制
发表时间：
2006-11-15
影响因子：
10.5
通讯作者：
Hebrok, Matthias
中科院分区：
文献类型：
--
作者：
di Magliano, Marina Pasca;Sekine, Shigeki;Hebrok, Matthias
胰腺导管腺癌（PDA）是一种致命的疾病，在美国每年有30万人受到影响。在PDA的发病机制中涉及到Hedgehog信号通路的失调。为了深入了解该通路在胰腺癌发生的不同阶段中的作用，我们建立了一个小鼠模型，其中Hedgehog信号在胰腺上皮中被特异性激活。转基因小鼠存活至成年并发展为未分化的癌，这表明上皮特异性Hedgehog信号足以驱动胰腺瘤变，但不会重现人类胰腺癌的发生。相反，Ras和Hedgehog信号的同时激活导致胰腺上皮内瘤变的广泛形成，这是人类PDA肿瘤发生的最早阶段，并加速了致死性。这些结果表明，在PDA形成的早期阶段，Hedgehog和Ras信号的合作。他们还将Hedgehog通路成分标记为早期和晚期胰腺导管肿瘤的相关治疗靶点。
Pancreatic ductal adenocarcinoma (PDA) constitutes a lethal disease that affects > 30,000 people annually in the United States. Deregulation of Hedgehog signaling has been implicated in the pathogenesis of PDA. To gain insights into the role of the pathway during the distinct stages of pancreatic carcinogenesis, we established a mouse model in which Hedgehog signaling is activated specifically in the pancreatic epithelium. Transgenic mice survived to adulthood and developed undifferentiated carcinoma, indicating that epithelium-specific Hedgehog signaling is sufficient to drive pancreatic neoplasia but does not recapitulate human pancreatic carcinogenesis. In contrast, simultaneous activation of Ras and Hedgehog signaling caused extensive formation of pancreatic intraepithelial neoplasias, the earliest stages of human PDA tumorigenesis, and accelerated lethality. These results indicate the cooperation of Hedgehog and Ras signaling during the earliest stages of PDA formation. They also mark Hedgehog pathway components as relevant therapeutic targets for both early and advanced stages of pancreatic ductal neoplasia.