Molecular Basis of Epithelial Skin Cancer

上皮性皮肤癌的分子基础

• 批准号: 8445151
• 负责人: ANDRZEJ A. DLUGOSZ
• 金额: $ 29.24万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445151
• 关键词: Basal Cell; Basal Cell Cancer; Basal cell carcinoma; Benign; Biological; Cells; Clinic; Development; Embryo; Epithelial; Erinaceidae; Funding; Gastric Adenocarcinoma; Gene Deletion; Genes; Genetic; Goals; Grant; Growth; Hair; Hair follicle structure; Hamartoma; Human; Lead; Ligands; Location; Maintenance; Malignant Neoplasms; Malignant Peripheral Nerve Sheath Tumor; Mediating; Molecular; Mus; Nature; Neoplastic Cell Transformation; Oncogenic; Pathogenesis; Pathway interactions; Phenotype; Physiological; Play; Population; Process; Proliferating; Resistance; Rest; Role; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Neoplasms; Staging; Stem cells; Stomach; Testing; Work; Wound Healing; base; beta catenin; cancer type; cell type; chromatin remodeling; inhibitor/antagonist; insight; keratinocyte; medulloblastoma; mouse model; neoplastic cell; novel strategies; prevent; progenitor; public health relevance; receptor; regenerative; response; smoothened signaling pathway; stem cell niche; tissue regeneration; tumor; tumor initiation; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Cancer development is associated with reactivation of several 'embryonic' signaling pathways, including the Hedgehog pathway, and our long-term goal in this grant has been to gain insight into how deregulated Hedgehog signaling contributes to tumor development. Our previous studies have been focused on basal cell carcinoma, a common skin tumor, and several other cancers associated with deregulated Hedgehog signaling. Activation of the Hedgehog (Hh)/Gli pathway in skin leads to formation of benign tumors called follicular hamartomas, basal cell carcinomas, or other follicular tumors. Both follicular hamartomas and basal cell carcinomas express multiple Wnt ligands, leading in both cases to activation of the canonical Wnt/beta-catenin pathway. While it has been shown that follicular hamartomas are strictly dependent on canonical Wnt/beta-catenin signaling for their formation, it is not known whether Wnt signaling plays a similarly important role in basal cell carcinomas and other malignant tumors driven by the Hh/Gli pathway. Although basal cell carcinoma tumor progenitors reside within the epithelial stem cell niche of the hair follicle, called the bulge, mobilization to form a transit amplifying cell population (a Wnt-mediated process) is required for tumorigenesis, underscoring the importance of a regenerative response in tumor development. We hypothesize that the phenotype of epithelial tumors arising in skin is determined by the nature of the oncogenic alteration(s), crosstalk with other signaling pathways, the location of potential tumor progenitors within their lineage, and tumor-promoting effects associated with tissue regeneration, either physiological (e.g., cyclical hair follicle growth) or pathological (wound-healing). We propose to begin exploring these relationships using state-of-the-art mouse models and a pharmacological inhibitor of Wnt signaling. In Aim 1 of this proposal, we will test the importance of canonical Wnt/beta-catenin signaling in the pathogenesis of basal cell carcinoma using genetic and pharmacological approaches. In Aim 2, we will determine the contribution of specific hair follicle cell compartments to Hedgehog/Gli-driven tumorigenesis, and assess the role of tissue regeneration in this process. In Aim 3, we will investigate the contribution of differentiated cell types to Hedgehog/Gli- and Ras-driven tumorigenesis in skin. These studies will yield new insights into the mechanisms underlying skin tumorigenesis, and are likely to lead to new approaches to the treatment of malignancies in which functionally relevant interactions exist between the Hh/Gli and Wnt pathways.

描述（由申请人提供）：癌症的发展与几种“胚胎”信号通路的重新激活有关，包括刺猬信号通路，我们的长期目标是深入了解不受管制的刺猬信号通路如何促进肿瘤的发展。我们之前的研究主要集中在基底细胞癌（一种常见的皮肤肿瘤）和其他几种与Hedgehog信号失调相关的癌症。皮肤中Hedgehog (Hh)/Gli通路的激活可导致称为滤泡错构瘤、基底细胞癌或其他滤泡肿瘤的良性肿瘤的形成。滤泡错构瘤和基底细胞癌均表达多种Wnt配体，导致典型Wnt/ β -连环蛋白通路的激活。虽然有研究表明滤泡错构瘤的形成严格依赖于典型的Wnt/ β -catenin信号，但尚不清楚Wnt信号是否在基底细胞癌和其他由Hh/Gli途径驱动的恶性肿瘤中发挥类似的重要作用。尽管基底细胞癌的肿瘤祖细胞存在于毛囊的上皮干细胞壁龛中，称为突起，但动员形成转运扩增细胞群（wnt介导的过程）是肿瘤发生所必需的，这强调了再生反应在肿瘤发展中的重要性。我们假设皮肤上皮肿瘤的表型是由致瘤改变的性质、与其他信号通路的相互作用、潜在肿瘤祖细胞在其谱系中的位置以及与组织再生相关的肿瘤促进作用决定的，无论是生理性的（例如，周期性毛囊生长）还是病理性的（伤口愈合）。我们建议使用最先进的小鼠模型和Wnt信号的药理学抑制剂开始探索这些关系。在本提案的目的1中，我们将使用遗传学和药理学方法测试典型Wnt/ β -连环蛋白信号在基底细胞癌发病机制中的重要性。在Aim 2中，我们将确定特定毛囊细胞区室对Hedgehog/ glis驱动的肿瘤发生的贡献，并评估组织再生在这一过程中的作用。在Aim 3中，我们将研究分化细胞类型对皮肤中Hedgehog/Gli和ras驱动的肿瘤发生的贡献。这些研究将对皮肤肿瘤发生的机制产生新的见解，并可能导致治疗恶性肿瘤的新方法，其中Hh/Gli和Wnt通路之间存在功能相关的相互作用。