Hedgehog signaling in upper digestive tract malignancy

描述（由申请人提供）：分泌的刺猬（Hh）配体在发育过程中各种组织的生长和模式中发挥重要作用，最近的研究发现Hh信号在几种成人组织的损伤和修复过程中瞬间再激活。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，肿瘤维持可能需要不受控制的Hh通路活性，因为Hh信号的阻断会抑制几种类型的“Hh激活”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通路的细胞类型才容易发生Hh通路相关的肿瘤发生，但这一概念尚未得到严格的验证。胃癌是全球第二大常见的癌症死亡原因，绝大多数胃肿瘤与Hh信号活性升高有关，这是由于Hh配体Sonic hedgehog （Shh）和/或Indian hedgehog （Ihh）的异常高表达。我们通过在小鼠胃中组成性地激活Hh信号，建立了一个强大的胃腺癌模型，指出Hh信号失调在人类这些侵袭性肿瘤的发病机制中起着因果作用。然而，目前对Hh信号异常如何促进胃肿瘤发生，即祖细胞引起“Hh激活”胃癌，以及Hh信号是否需要维持已建立的肿瘤的了解甚少。此外，Hh信号在正常胃中的确切功能尚未确定，关于胃损伤和修复过程中Hh信号活性的变化的信息很少，这可能易导致癌症的发生。在Aim 1中，我们提出在正常和病理改变的胃中鉴定表达Hh通路组分的细胞类型，并确定Hh信号的功能。在Aim 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信号在正常和损伤胃中的功能以及Hh信号失调在胃癌发病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.