Hedgehog signaling in upper digestive tract malignancy

描述（由申请人提供）：分泌型Hedgehog（Hh）配体在发育期间各种组织的生长和模式化中发挥重要作用，最近的研究已经发现在几种成年组织的损伤和修复期间Hh信号传导的短暂再激活。有令人信服的证据表明，持续的Hh信号，这可能是在一个异常的反应损伤启动，是与各种各样的人类恶性肿瘤。此外，不受控制的Hh通路活性可能是肿瘤维持所必需的，因为Hh信号传导的阻断抑制了几种类型的“Hh活化”肿瘤细胞的生长。已经提出，只有那些在胚胎发生或修复过程中利用Hh途径的细胞类型才易于发生Hh途径相关的肿瘤发生，但这一概念尚未得到严格的检验。胃癌是世界范围内癌症死亡率的第二大常见原因，并且绝大多数胃肿瘤与升高的Hh信号传导活性相关，这归因于Hh配体Sonic hedgehog（Shh）和/或Indian hedgehog（Ihh）的异常高表达。我们已经通过组成性激活小鼠胃中的Hh信号转导产生了一个强大的胃腺癌模型，指出了Hh信号转导失调在人类这些侵袭性肿瘤发病机制中的因果作用。然而，目前很少有洞察Hh信号的畸变如何有助于胃肿瘤的发生，祖细胞引起“Hh激活”胃癌，以及Hh信号是否需要维持已建立的肿瘤。此外，Hh信号在正常胃中的精确功能尚未建立，并且关于胃损伤和修复期间Hh信号活性的变化的信息很少，这可能易患癌症。在目的1中，我们提出了确定细胞类型表达Hh通路组件，并确定Hh信号转导的功能，在正常和病理改变的胃。目的2：探讨Hh信号在胃癌生物学和维持中的作用。这些研究将为了解Hh信号在正常胃和损伤胃中的功能以及Hh信号失调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.