Molecular Basis of Epithelial Skin Cancer

上皮性皮肤癌的分子基础

• 批准号: 7917941
• 负责人: ANDRZEJ A. DLUGOSZ
• 金额: $ 32.06万
• 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/7917941
• 关键词: Arts; 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. PUBLIC HEALTH RELEVANCE: Basal cell cancer is a type of skin cancer, and it is the most common type of cancer in humans. The work we are proposing in this grant will help us understand how these cancers are formed and what regulates their growth. This information should lead to new ways to treat or prevent these common cancers.

描述（由申请人提供）：癌症的发展与几个“胚胎”信号通路的重新激活有关，包括Hedgehog通路，我们在这项资助中的长期目标是深入了解解除管制的Hedgehog信号通路如何有助于肿瘤的发展。我们以前的研究主要集中在基底细胞癌，一种常见的皮肤肿瘤，以及其他几种与Hedgehog信号失调相关的癌症。皮肤中Hedgehog（Hh）/Gli通路的激活导致称为滤泡性错构瘤、基底细胞癌或其他滤泡性肿瘤的良性肿瘤的形成。滤泡性错构瘤和基底细胞癌均表达多种Wnt配体，导致经典Wnt/β-连环蛋白途径的激活。虽然已经表明滤泡性错构瘤的形成严格依赖于经典的Wnt/β-连环蛋白信号传导，但尚不清楚Wnt信号传导是否在基底细胞癌和由Hh/Gli通路驱动的其他恶性肿瘤中发挥类似的重要作用。尽管基底细胞癌肿瘤祖细胞位于毛囊的上皮干细胞龛（称为隆突）内，但形成转运扩增细胞群（Wnt介导的过程）的动员是肿瘤发生所需的，这强调了再生反应在肿瘤发展中的重要性。我们假设皮肤中产生的上皮肿瘤的表型由致癌改变的性质、与其他信号传导途径的串扰、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，无论是生理性的（例如，周期性毛囊生长）或病理性（伤口愈合）。我们建议开始探索这些关系使用国家的最先进的小鼠模型和药理学抑制剂的Wnt信号。在本提案的目标1中，我们将使用遗传学和药理学方法测试经典Wnt/β-连环蛋白信号传导在基底细胞癌发病机制中的重要性。在目标2中，我们将确定特定毛囊细胞隔室对Hedgehog/Gli驱动的肿瘤发生的贡献，并评估组织再生在此过程中的作用。在目标3中，我们将研究分化细胞类型对Hedgehog/Gli和Ras驱动的皮肤肿瘤发生的贡献。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。 基底细胞癌是皮肤癌的一种，也是人类最常见的癌症类型。我们在这项资助中提出的工作将帮助我们了解这些癌症是如何形成的，以及是什么调节了它们的生长。这些信息应该会导致治疗或预防这些常见癌症的新方法。