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（由适用提供）：在美国，皮肤的侵入性鳞状细胞癌是一个重大问题，每年超过100万例。由于唯一可行的治疗选择，并以手术和放射疗法作为唯一可行的治疗选择，需要开发更具体的分子剂来对抗这种疾病。为此，该提案试图在功能上表征皮肤表皮连接的重要组成部分，以确定地下膜蛋白如何成为皮肤鳞状细胞癌的浸润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，正如我们通过使用人皮肤SCC的体内模型所表明的那样，表皮肿瘤发生所必需的。最近的数据表明，层粘连蛋白-332的蛋白水解修饰，与胶原蛋白的结合以及与A6¿4整合素的相互作用在SCC结核菌中扮演重要的作用，但是在SCC中的统一模型中，层层中的统一模型均缺乏所有这些特征。除了A6¿4整联蛋白外，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结核菌期间层粘连蛋白-332衍生的信号。这些分子如何将SCC中促氧化型信号通路的协调在一起尚待完全阐​​明，这是该建议的重点。首先，我们计划通过遗传缺失和抗体抑制作用研究层粘连蛋白332对此过程的贡献。我们还将阐明由€4整合素中包含的特定残差贡献的促肿瘤信号传导。其次，我们将研究€4整合素相关分子的作用，以了解它们如何使用层粘连蛋白332和4整合素，坐标增殖，细胞浸润，层粘连蛋白332沉积，金属蛋白酶活性和其他功能，其他功能是癌瘤进展所必需的。最后，基于对SCC肿瘤发生的特定抑制的初步数据，而不会破坏正常皮肤凝聚力，使用针对层粘连蛋白332的G45结构域的抗体，我们计划开发和测试针对其他层粘胶蛋白-332域的抗体小组，以及其他collagen vii vii nc1抗体。在这些研究中，我们将在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疗法是否可以产生协同癌。在拟议的融资期结束时，我们希望回答有关细胞外基质在SCC肿瘤发生中的作用的基本问题，并学习新信息，该信息有可能开发出新的和特定的皮肤SCC疗法。公共卫生相关性：皮肤的方形细胞癌（SCC）是第二常见的人类癌症，但缺乏该疾病的有效和特定的分子疗法。该提议着重于理解皮肤表皮基底膜蛋白层粘连蛋白-332和A6¿4整合素在促进SCC进展和侵袭中发挥的关键作用。该建议还试图开发新颖和特定的分子疗法，以抑制SCC中层粘连蛋白332和相关分子的功能，而不会破坏正常的皮肤组织。