Laminin-332 and its Receptors in Carcinoma Progression

Laminin-332 及其受体在癌症进展中的作用

基本信息

批准号：
7686297
负责人：
Matt Peter Marinkovich
金额：
$ 33万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
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/7686297
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

项目摘要

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）：在美国，侵袭性鳞状细胞癌是一个严重的问题，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，需要开发新的治疗方法。为此，该提案旨在从功能上表征真皮-表皮连接的重要组成部分，以确定基底膜蛋白如何作为皮肤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 体内模型所表明的那样，Laminin-332 的蛋白水解修饰及其作用。与胶原蛋白 VII 的结合及其与 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，层粘连蛋白 332 功能的统一模型在SCC 缺乏包含所有这些特征的细胞，除了 a6¿4 整合素外，其他几种细胞表面受体也与 laminin-332 相互作用，包括 syndecan-1、c-Met 和 EGFR，并且这些受体也可能参与 laminin-332。鳞状细胞癌肿瘤发生过程中这些分子如何协调一致以激活鳞状细胞癌中的促肿瘤信号传导途径仍有待充分阐明，这也是本提案的重点。通过基因缺失和抗体抑制研究层粘连蛋白-332的各个结构域对该过程的贡献，我们还将阐明由 ¿ 中包含的特定残基所贡献的促肿瘤信号传导。 4 整合素其次，我们将研究 ¿ 的作用。 4 个整合素相关分子，了解它们如何与层粘连蛋白-332 和 ¿最后，基于初步数据显示，使用针对 G45 结构域的抗体可以特异性抑制 SCC 肿瘤发生，而不破坏正常皮肤的凝聚力。层粘连蛋白 332 的结构域，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，我们将对功能进行表征。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作用的基本问题。皮肤鳞状细胞癌 (SCC) 是第二常见的人类癌症，但该疾病缺乏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。新颖且特定的分子疗法可抑制 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。