Hedgehog signaling in upper digestive tract malignancy

描述(由申请人提供)：分泌型Hedgehog(HH)配体在各种组织的发育过程中发挥着重要的作用，最近的研究发现，在几个成年组织的损伤和修复过程中，HH信号的瞬时重新激活。有令人信服的证据表明，持续的HH信号可能在对损伤的异常反应中启动，与多种人类恶性肿瘤有关。此外，不受控制的HH途径活性可能是维持肿瘤所必需的，因为阻断HH信号会抑制几种类型的HH激活的肿瘤细胞的生长。有人提出，只有那些在胚胎发生或修复过程中利用HH途径的细胞类型才容易发生与HH途径相关的肿瘤发生，但这一概念尚未得到严格的检验。胃癌是全球第二大癌症死亡原因，绝大多数胃肿瘤与HH信号活性升高有关，HH配体Sonic hedgehog(Shh)和/或India Hedgehog(IHH)的异常高表达可归因于HH信号活性的升高。我们通过结构性地激活小鼠胃中的HH信号，建立了一个强大的胃腺癌模型，指出HH信号的失控在人类这些侵袭性肿瘤的发病机制中起到了因果作用。然而，目前尚不清楚HH信号的异常如何促进胃癌的发生，哪些前体细胞引起HH激活的胃癌，以及HH信号是否对已建立的肿瘤的维持是必需的。此外，HH信号在正常胃中的确切功能尚未建立，关于胃损伤和修复过程中HH信号活性变化的信息也很少，这可能是癌症发生的易感因素。在目标1中，我们建议鉴定在正常和病理改变的胃中表达HH途径成分的细胞类型，并确定HH信号的功能。在目标2中，我们将探讨HH信号在胃肿瘤生物学和维持中的作用。这些研究将为HH信号在正常胃和损伤胃中的作用以及去调控的HH信号在胃癌发病机制中的作用提供新的见解。

DESCRIPTION (provided by applicant): Secreted Hedgehog (Hh) ligands play important roles in growth and patterning of various tissues during development, and recent studies have uncovered transient reactivation of Hh signaling during injury and repair of several adult tissues. There is compelling evidence that sustained Hh signaling, which may be initiated during an aberrant response to injury, is associated with a wide variety of human malignancies. Moreover, uncontrolled Hh pathway activity may be required for tumor maintenance, since blockade of Hh signaling inhibits the growth of several types of 'Hh-activated' tumor cells. It has been proposed that only those cell types which utilize the Hh pathway during embryogenesis or repair are prone to Hh pathway-associated tumorigenesis, but this concept has not been rigorously tested. Gastric cancer is the 2nd most common cause of cancer mortality worldwide, and the great majority of gastric tumors are associated with elevated Hh signaling activity, attributed to abnormally high expression of the Hh ligands Sonic hedgehog (Shh) and/or Indian hedgehog (Ihh). We have generated a robust model of gastric adenocarcinoma by constitutively activating Hh signaling in mouse stomach, pointing to a causal role for deregulated Hh signaling in the pathogenesis of these aggressive tumors in humans. However, there is presently little insight into how aberrations in Hh signaling contribute to gastric tumorigenesis, which progenitor cells give rise to 'Hh-activated' gastric cancers, and whether Hh signaling is required for maintenance of established tumors. Moreover, the precise functions of Hh signaling in normal stomach have not yet been established, and there is a little information regarding changes in Hh signaling activity during gastric injury and repair, which can predispose to cancer development. In Aim 1, we propose to identify the cell types expressing Hh pathway components, and determine the function of Hh signaling, in normal and pathologically altered stomach. In Aim 2, we will explore the function of Hh signaling in gastric tumor biology and maintenance. The proposed studies will provide new insights into the functions of Hh signaling in normal and injured stomach, and the role of deregulated Hh signaling in the pathogenesis of gastric cancer.