Laminin-332 and its Receptors in Carcinoma Progression

Laminin-332 及其受体在癌症进展中的作用

• 批准号: 7507715
• 负责人: Matt Peter Marinkovich
• 金额: $ 33万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7507715
• 关键词: Affect; Antibodies; Antibody Therapy; Basement membrane; Binding; Carcinoma; Cell Proliferation; Cell Surface Receptors; Cell surface; Collagen; Collagen Type VII; Data; Deposition; Dermal; Development; Disease; Disruption; Epidermal Growth Factor Receptor; Event; Extracellular Matrix; Funding; Genetic; Homeostasis; Human; Incidence; Individual; Integrins; Invasive; Laminin; Learning; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Membrane Proteins; Metalloproteases; Modeling; Modification; Molecular; Normal tissue morphology; Operative Surgical Procedures; Patients; Play; Population; Process; Protein Binding; Proteins; Proteolysis; Public Health; Radiation therapy; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Skin Tissue; Squamous cell carcinoma; Testing; Work; base; chemotherapy; cohesion; comparative; computerized data processing; design; driving force; extracellular; in vivo; in vivo Model; molecular assembly/self assembly; novel; outcome forecast; receptor; response; skin squamous cell carcinoma; syndecan; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Invasive squamous cell carcinoma of the skin is a significant problem in the U.S. with over one million cases annually. With a rising incidence and with surgery and radiation therapy as the only feasible treatment options, the need for development of more specific molecular agents to combat this disease is great. Towards this end, this proposal seeks to functionally characterize important components of the dermal-epidermal junction to determine how basement membrane proteins act as a significant driving force for invasion and progression of cutaneous squamous cell carcinoma. Laminin-332 is an essential component of the epidermal basement membrane, and is required for epidermal tumorigenesis as we have shown through use of an in vivo model of human cutaneous SCC. Recent data suggest that laminin-332's proteolytic modifications, its binding to collagen VII and its interaction with a6¿4 integrin each play important roles in SCC tumorigenesis, however a unified model of laminin-332 function in SCC which incorporates all of these features is lacking. In addition to a6¿4 integrin, several other cell surface receptors interact with laminin-332, including syndecan-1, c-Met and EGFR, and these receptors may also participate in laminin-332 derived signaling during SCC tumorigenesis. How these molecules coordinate together to activate pro-tumorigenic signaling pathways in SCC remains to be fully elucidated and is the focus of this proposal. First we plan to study the contributions of individual domains of laminin-332 to this process by both genetic deletion and antibody inhibition. We will also elucidate the pro-tumorigenic signaling contributed by specific residues contained in ¿4 integrin. Second, we will examine the role of ¿4 integrin associated molecules to understand how they, with laminin-332 and ¿4 integrin, coordinate proliferation, cellular invasion, laminin-332 deposition, metalloproteinase activity and other functions essential for carcinoma progression. Finally, based on preliminary data showing specific inhibition of SCC tumorigenesis without disruption of normal skin cohesion, using an antibody against the G45 domain of laminin-332, we plan to develop and test a panel of antibodies against other laminin-332 domains as well as a collagen VII NC1 antibody. In these studies, we will functionally characterize how these antibodies act on SCC tumorigenesis, as well as normal skin. We will also determine whether combination antibody therapy can produce synergistic carcinoma inhibition. At the end of the proposed funding period, we hope to have answered fundamental questions about the role of the extracellular matrix in SCC tumorigenesis and to learn new information which has the potential for the development of novel and specific therapies for cutaneous SCC. PUBLIC HEALTH RELEVANCE: Squamous cell carcinoma (SCC) of the skin is the second most common human cancer, but effective and specific molecular therapies for this disease are lacking. This proposal focuses on understanding the critical role that the dermal-epidermal basement membrane proteins laminin-332 and a6¿4 integrin play in facilitating SCC progression and invasion. This proposal also seeks to develop novel and specific molecular therapies to inhibit the function of laminin-332 and associated molecules in SCC without disrupting normal skin tissue.

描述（由申请人提供）：皮肤的浸润性鳞状细胞癌在美国是一个严重的问题，每年有超过一百万例病例。 随着发病率的上升以及手术和放射治疗作为唯一可行的治疗选择，开发更特异性的分子药物来对抗这种疾病的需求是巨大的。 为此，该提案旨在功能上表征真皮-表皮交界处的重要组成部分，以确定基底膜蛋白如何作为皮肤鳞状细胞癌侵袭和进展的重要驱动力。 层粘连蛋白-332是表皮基底膜的重要组成部分，并且是表皮肿瘤发生所必需的，正如我们通过使用人皮肤SCC的体内模型所示。 最近的数据表明，层粘连蛋白-332的蛋白水解修饰，其与胶原VII的结合以及其与α 6 β 4整联蛋白的相互作用在SCC肿瘤发生中均起重要作用，然而，缺乏层粘连蛋白-332在SCC中的功能的统一模型，该模型包含所有这些特征。 除了a6 4整联蛋白，其他几种细胞表面受体与层粘连蛋白-332相互作用，包括syndecan-1，c-Met和EGFR，这些受体也可能参与SCC肿瘤发生过程中层粘连蛋白-332衍生的信号传导。 这些分子如何协调在一起激活促肿瘤发生的信号通路在SCC仍然是完全阐明，是这个建议的重点。 首先，我们计划通过基因缺失和抗体抑制来研究层粘连蛋白332的各个结构域对这一过程的贡献。 我们还将阐明由整合素4中所含的特定残基贡献的促肿瘤发生信号传导。 第二，我们将研究<$4整合素相关分子的作用，以了解它们如何与层粘连蛋白-332和<$4整合素协调增殖，细胞侵袭，层粘连蛋白-332沉积，金属蛋白酶活性和其他对癌症进展至关重要的功能。 最后，基于初步数据显示，使用针对层粘连蛋白-332的G45结构域的抗体，在不破坏正常皮肤凝聚力的情况下特异性抑制SCC肿瘤发生，我们计划开发和测试一组针对其他层粘连蛋白-332结构域的抗体以及胶原蛋白VII NC 1抗体。 在这些研究中，我们将从功能上表征这些抗体如何作用于SCC肿瘤发生以及正常皮肤。 我们还将确定联合抗体治疗是否可以产生协同的癌抑制作用。 在建议的资助期结束时，我们希望能够回答有关细胞外基质在SCC肿瘤发生中的作用的基本问题，并了解新的信息，这些信息有可能用于开发皮肤SCC的新型和特异性疗法。 公共卫生关系：皮肤鳞状细胞癌（SCC）是人类第二常见的癌症，但缺乏针对这种疾病的有效和特异性分子疗法。 该建议的重点是了解真皮-表皮基底膜蛋白层粘连蛋白332和α 6 <$4整合素在促进SCC进展和侵袭中的关键作用。 该提案还寻求开发新的和特异性的分子疗法，以抑制层粘连蛋白-332和相关分子在SCC中的功能，而不破坏正常皮肤组织。