Hedgehog signaling in upper digestive tract malignancy

上消化道恶性肿瘤中的刺猬信号传导

• 批准号: 7844985
• 负责人: ANDRZEJ A. DLUGOSZ
• 金额: $ 27.3万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-13 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7844985
• 关键词: Acute; Adenocarcinoma; Adult; Cancer Etiology; Cells; Chief Cell; Development; Dysplasia; Embryonic Development; Epithelial Cells; Epithelium; Erinaceidae; GLI2 gene; Gastric Adenocarcinoma; Gastric Intraepithelial Neoplasia; Gastric Parietal Cells; Gastric mucosa; Gastrointestinal tract structure; Gene Targeting; Genetic; Growth; Homeostasis; Human; LacZ Genes; Ligands; Literature; Maintenance; Malignant Neoplasms; Mesenchymal; Mesenchyme; Messenger RNA; Modeling; Mucous body substance; Mus; Natural regeneration; Neck; Neoplasms; Oncogenic; Organ; Pathogenesis; Pathology; Pathway interactions; Pattern; Play; Publishing; Reporter; Reporter Genes; Research Personnel; Role; Signal Transduction; Stem cells; Stomach; Stomach Neoplasms; Testing; Tissues; Tumor Biology; autocrine; base; cell type; design; injured; injury and repair; insight; malignant stomach neoplasm; mortality; mouse model; neoplastic cell; paracrine; progenitor; programs; repaired; research study; response; response to injury; smoothened signaling pathway; tool; transcription factor; tumor; tumorigenesis

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.

描述（由申请人提供）：分泌型刺猬蛋白（Hh）配体在发育过程中各种组织的生长和模式化中发挥重要作用，最近的研究发现在几种成体组织损伤和修复过程中Hh信号传导的瞬时重新激活。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期间启动，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 信号传导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 途径的细胞类型才容易发生 Hh 途径相关的肿瘤发生，但这一概念尚未经过严格测试。胃癌是全球第二大癌症死亡原因，绝大多数胃肿瘤与 Hh 信号传导活性升高有关，这归因于 Hh 配体 Sonic Hedgehog (Shh) 和/或 Indian Hedgehog (Ihh) 的异常高表达。我们通过组成性激活小鼠胃中的 Hh 信号传导，建立了一个稳健的胃腺癌模型，表明 Hh 信号传导失调在人类这些侵袭性肿瘤的发病机制中具有因果作用。然而，目前对于 Hh 信号传导异常如何导致胃肿瘤发生、哪些祖细胞产生“Hh 激活”胃癌，以及维持已形成肿瘤是否需要 Hh 信号传导，目前还知之甚少。此外，Hh信号在正常胃中的精确功能尚未确定，并且关于胃损伤和修复过程中Hh信号活性变化的信息很少，这可能导致癌症的发生。在目标 1 中，我们建议鉴定正常胃和病理改变胃中表达 Hh 通路成分的细胞类型，并确定 Hh 信号传导的功能。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功能。拟议的研究将为正常和受损胃中 Hh 信号传导的功能以及 Hh 信号传导失调在胃癌发病机制中的作用提供新的见解。