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: 7895866
• 负责人: Matt Peter Marinkovich
• 金额: $ 33.01万
• 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/7895866
• 关键词: Affect; Antibodies; Antibody Therapy; Basement membrane; Binding; Carcinoma; Cell Proliferation; Cell Surface Receptors; Collagen; Collagen Type VII; Data; Deposition; Dermal; Development; Disease; Epidermal Growth Factor Receptor; Event; Extracellular Matrix; Funding; Genetic; Homeostasis; Human; Incidence; Individual; Integrins; 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; Radiation therapy; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Skin Tissue; Squamous cell carcinoma; Testing; Work; advanced disease; base; chemotherapy; cohesion; combat; comparative; computerized data processing; design; driving force; extracellular; in vivo; in vivo Model; meetings; molecular assembly/self assembly; novel; outcome forecast; public health relevance; 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）：皮肤侵袭性鳞状细胞癌是美国的一个严重问题，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，非常需要开发更具体的分子制剂来对抗这种疾病。 为此，该提案旨在从功能上表征真皮-表皮连接处的重要组成部分，以确定基底膜蛋白如何充当皮肤鳞状细胞癌侵袭和进展的重要驱动力。 Laminin-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 体内模型所证明的那样。 最近的数据表明，层粘连蛋白 332 的蛋白水解修饰、其与胶原蛋白 VII 的结合以及其与 a6¿4 整合素的相互作用在 SCC 肿瘤发生中均发挥着重要作用，然而，缺乏包含所有这些特征的层粘连蛋白 332 在 SCC 中功能的统一模型。 除了 a6¿4 整合素外，其他几种细胞表面受体也与层粘连蛋白 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鳞状细胞癌中的促肿瘤信号通路仍有待充分阐明，也是本提案的重点。 首先，我们计划通过基因删除和抗体抑制来研究层粘连蛋白 332 的各个结构域对此过程的贡献。 我们还将阐明 4 整合素中包含的特定残基所贡献的促肿瘤信号传导。 其次，我们将检查 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、金属蛋白酶活性和癌症进展所必需的其他功能。 最后，基于显示特异性抑制 SCC 肿瘤发生而不破坏正常皮肤凝聚力的初步数据，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 NC1 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鳞状细胞癌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的癌症抑制作用。 在拟议的资助期结束时，我们希望能够回答有关细胞外基质在鳞状细胞癌肿瘤发生中的作用的基本问题，并了解有潜力开发皮肤鳞状细胞癌新型和特异性疗法的新信息。 公共健康相关性：皮肤鳞状细胞癌 (SCC) 是第二常见的人类癌症，但缺乏针对这种疾病的有效且特异性的分子疗法。 该提案的重点是了解真皮表皮基底膜蛋白 laminin-332 和 a6¿4 整合素在促进鳞状细胞癌进展和侵袭中发挥的关键作用。 该提案还寻求开发新颖且特定的分子疗法，以抑制 SCC 中层粘连蛋白 332 和相关分子的功能，而不破坏正常皮肤组织。