Characterization of RAS-Driven Human Epidermal Neoplasia

RAS 驱动的人类表皮肿瘤的特征

• 批准号: 7257268
• 负责人: PAUL KHAVARI
• 金额: $ 34.05万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-04 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257268
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Adhesions; Antibodies; Appearance; Architecture; Basal cell carcinoma; Basement membrane; CDK4 gene; Cancer Model; Cell Death; Cells; Clinical; Collagen; Collagen Type VI; Collagen Type VII; Collagen Type XVII; Dermal; Development; Epidermis; Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica; Funding; Future; Genes; Genetic; Goals; Growth; Hemidesmosomes; Histology; Human; Incidence; Individual; Integrins; Invasive; MEKs; Malignant Neoplasms; Mediating; Medical; Membrane Proteins; Modeling; Molecular Target; Mus; Mutate; Neoplasms; Oncogene Proteins; Oncogenic; Organ; Pathway interactions; Patients; Process; Protein Overexpression; Proteins; Relative (related person); Research Design; Research Personnel; Role; Signal Transduction; Site; Skin; Skin Cancer; Squamous cell carcinoma; Stratum Basale; Tertiary Protein Structure; Testing; Tissues; Tumorigenicity; angiogenesis; base; cancer therapy; carcinogenesis; cell growth; cohesion; design; extracellular; human tissue; insight; keratinocyte; laminin-5; mutant; protein expression; ral Guanine Nucleotide Exchange Factor; restraint; skin squamous cell carcinoma; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): CHARACTERIZATION OF RAS-DRIVEN HUMAN EPIDERMAL NEOPLASIA. The 2 most common cancers in the U.S., including cutaneous squamous cell carcinoma (SCC), arise from the epidermis. RAS, among the most commonly mutated genes in human cancer, has been implicated in SCC development in mice. The medical relevance of murine studies of SCC and other cancers, however, is limited by major differences between mouse and human skin and by the greater ease of transformation of murine tissues. Recently, we have demonstrated that Ras and CDK4 are induced in a subset of human SCC and that coexpressing Ras with CDK4 induces invasive human epidermal neoplasia indistinguishable from SCC at all levels studied. The overall goal of this proposal is to characterize the mechanistic basis for Ras-driven human epidermal neoplasia as a means of enhancing our understanding of human tissue tumorigenesis. First, we plan to characterize the function of the 3 major proximal Ras effector pathways, Raf, PI3K and RalGEF, in tumorigenesis with CDK4. These effectors can trigger changes found in many cancers, such as proliferation, inhibition of differentiation, angiogenesis and invasion. Ras mutants selective for these pathways as well as the effectors themselves will be used to define their relative contributions to Ras-driven human neoplasia. These studies are designed to define the impacts of individual Ras effector pathways and the degree to which they are necessary and sufficient for initiation of epidermal tumorigenesis. Second, we plan to define the necessity of specific epidermal adhesion proteins in Ras-driven human epidermal neoplasia. Among such adhesion proteins, BP180 and type VI/ collagen are required for epidermal-dermal cohesion in humans and are overexpressed in SCC, however, their potential roles in epidermal cancer are unknown. To address this, will use BP180 and collagen VII-deficient primary human keratinocytes from patients with epidermolysis bullosa _B) in our Ras-driven epidermal cancer model. Determining whether epidermal tumorigenesis can proceed in the absence of BP180 and collagen VII as well as defining the degree to which specific domains of these proteins influence this process will help define their role in human epidermal neoplasia. At the end of the proposed funding period, we hope to have characterized Ras-driven human epidermal neoplasia as a basis for insight into human tissue tumorigenesis and for development of future targeted molecular therapies for cancers of the skin and other organs.

描述（由申请人提供）：RAS 驱动的人类表皮肿瘤的特征。在美国，两种最常见的癌症，包括皮肤鳞状细胞癌 (SCC)，都起源于表皮。 RAS 是人类癌症中最常见的突变基因之一，与小鼠鳞状细胞癌的发展有关。然而，小鼠鳞状细胞癌和其他癌症研究的医学相关性受到小鼠和人类皮肤之间的重大差异以及小鼠组织更容易转化的限制。最近，我们证明 Ras 和 CDK4 在人类 SCC 的子集中被诱导，并且 Ras 与 CDK4 共表达会诱导侵袭性人类表皮肿瘤，在所有研究水平上与 SCC 无法区分。该提案的总体目标是描述 Ras 驱动的人类表皮瘤形成的机制基础，作为增强我们对人类组织肿瘤发生的理解的一种手段。首先，我们计划表征 3 个主要近端 Ras 效应通路 Raf、PI3K 和 RalGEF 在 CDK4 肿瘤发生中的功能。这些效应器可以触发许多癌症中发现的变化，例如增殖、分化抑制、血管生成和侵袭。对这些途径具有选择性的 Ras 突变体以及效应子本身将用于确定它们对 Ras 驱动的人类肿瘤的相对贡献。这些研究旨在确定各个 Ras 效应通路的影响以及它们对于表皮肿瘤发生的必要性和充分性的程度。其次，我们计划确定特定表皮粘附蛋白在 Ras 驱动的人类表皮瘤形成中的必要性。在这些粘附蛋白中，BP180和VI型/胶原蛋白是人类表皮-真皮粘合所必需的，并且在鳞状细胞癌中过度表达，然而，它们在表皮癌中的潜在作用尚不清楚。为了解决这个问题，我们将在 Ras 驱动的表皮癌模型中使用来自大疱性表皮松解症患者的 BP180 和缺乏胶原蛋白 VII 的原代人类角质形成细胞_B)。确定表皮肿瘤发生是否可以在没有 BP180 和胶原蛋白 VII 的情况下进行，以及确定这些蛋白质的特定结构域影响这一过程的程度，将有助于确定它们在人类表皮肿瘤中的作用。在拟议的资助期结束时，我们希望将 Ras 驱动的人类表皮瘤形成的特征作为深入了解人类组织肿瘤发生和开发未来皮肤癌和其他器官癌的靶向分子疗法的基础。