Characterization of RAS-Driven Human Epidermal Neoplasia

RAS 驱动的人类表皮肿瘤的特征

• 批准号: 6680460
• 负责人: PAUL KHAVARI
• 金额: $ 38.87万
• 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/6680460
• 关键词: SCID mouse; basosquamous cell carcinoma; biological signal transduction; cell differentiation; cell proliferation; clinical research; cyclin dependent kinase; epidermal growth factor; epidermolysis bullosa; gene expression; growth factor receptors; guanine nucleotide binding protein; human tissue; keratinocyte; neoplasm /cancer genetics; neoplastic growth; phosphatidylinositol 3 kinase; skin neoplasms; tissue /cell culture

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驱动的人表皮瘤变的特征。美国最常见的两种癌症，包括皮肤鳞状细胞癌（SCC），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SCC的发生有关。然而，小鼠研究SCC和其他癌症的医学相关性受到小鼠和人类皮肤之间的主要差异以及小鼠组织更容易转化的限制。最近，我们已经证明Ras和CDK4在人类SCC的一个亚群中被诱导，并且Ras与CDK4的共表达诱导侵袭性人表皮瘤变，在所有研究水平上与SCC没有区别。本提案的总体目标是表征ras驱动的人类表皮瘤变的机制基础，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个主要的近端Ras效应通路Raf、PI3K和RalGEF在CDK4肿瘤发生中的功能。这些效应物可以引发在许多癌症中发现的变化，如增殖、分化抑制、血管生成和侵袭。选择这些通路的Ras突变体以及效应体本身将用于确定它们对Ras驱动的人类肿瘤的相对贡献。这些研究旨在确定单个Ras效应通路的影响，以及它们对表皮肿瘤发生起始的必要和充分程度。其次，我们计划确定特异性表皮粘附蛋白在ras驱动的人表皮瘤变中的必要性。在这些粘附蛋白中，BP180和VI型/胶原蛋白是人类表皮-真皮内聚所必需的，并且在鳞状细胞癌中过表达，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，我们将在我们的ras驱动的表皮癌模型中使用来自大疱性表皮松解症(b)患者的BP180和vii型胶原蛋白缺陷原代人角质形成细胞。确定在缺乏BP180和胶原VII的情况下表皮肿瘤发生是否可以进行，以及确定这些蛋白的特定结构域对这一过程的影响程度，将有助于确定它们在人类表皮瘤变中的作用。在拟议的资助期结束时，我们希望能够描述ras驱动的人类表皮瘤变，作为深入了解人类组织肿瘤发生的基础，并为未来针对皮肤和其他器官癌症的靶向分子疗法的发展奠定基础。