The Roles of Tumor Microenvironment in Neurofibroma Development and Therapeutics

肿瘤微环境在神经纤维瘤发展和治疗中的作用

• 批准号: 8634746
• 负责人: Lu Le
• 金额: $ 32万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-28 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634746
• 关键词: 3-Dimensional; Affect; Benign; Binding; Cancerous; Cell Communication; Cell Differentiation process; Cells; Clinical; Complex; Complication; Cutaneous; Data; Dermal; Dermal Neoplasm; Dermis; Development; Disease; Elements; Embryo; Endocrine Glands; Endothelial Cells; Environment; Event; Evolution; Exhibits; Fibroblasts; GTPase-Activating Proteins; Genetic; Goals; Growth; Hereditary Disease; Hormonal; Hormones; Human; In Vitro; Individual; Inflammatory Infiltrate; Laboratories; Lead; Link; Malignant - descriptor; Malignant Neoplasms; Malignant Peripheral Nerve Sheath Tumor; Mediating; Methods; Modeling; Molecular; Molecular Probes; Mus; Mutation; NF1 gene; NF1 tumor suppressor; Nerve; Nerve Fibers; Nerve Plexus; Nervous system structure; Neurofibromatoses; Neurofibromatosis 1; Neurons; Operative Surgical Procedures; Pathogenesis; Patients; Peripheral Nerve Sheath Neoplasm; Phase; Physiological; Pigments; Play; Plexiform Neurofibroma; Population; Pre-Clinical Model; Predisposition; Proliferating; Property; Reagent; Research; Role; Schwann Cells; Signal Transduction; Skin; Staging; Stem cells; Testing; Therapeutic; Time; Tumor Suppressor Genes; Work; base; bone; cancer prevention; cancer therapy; cell behavior; cell type; dermal neurofibroma; effective therapy; extracellular; eye blood vessel; in vitro Model; in vivo; inhibitor/antagonist; innovation; insight; mast cell; mouse model; neoplastic; neoplastic cell; nerve stem cell; neurofibroma; new therapeutic target; novel; paracrine; pre-clinical; prevent; progenitor; research study; stem; steroid hormone; therapeutic development; tumor; tumor microenvironment; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The human tumor predisposition disease von Recklinghausen's neurofibromatosis type I (NF1) is one of the most common genetic disorders of the nervous system, affecting 1 in 3000 individuals worldwide. It is caused by mutation in the NF1 tumor suppressor gene, which encodes a GTPase Activating Protein (GAP) that negatively regulates p21-RAS signaling. Dermal and plexiform neurofibromas, as well as malignant peripheral nerve sheath tumors and other malignant tumors are serious complications of NF1. Neurofibromas are complex tumors and composed mainly of abnormal local cells including: Schwann cells, nerves, endothelial cells, fibroblasts and additionally a large number of infiltrating inflammatory mast cells. However, little is known about the molecular mechanisms mediating the initiation and progression of these complex tumors, or the identity of the specific cell type that gives rise to cutaneous neurofibromas. Recent work in our laboratory has identified a novel population of neural stem cells residing in the dermis termed skin-derived precursors (SKPs) as the cell of origin of dermal neurofibroma and generated the first mouse model for this complex cutaneous tumor. These studies also provide evidences that additional signals from non-neoplastic cells in the tumor microenvironment play essential roles in neurofibroma formation. The emerging evidence points to mast cell, neurons and steroid hormone, as crucial early contributors to tumorigenesis. Based upon our preliminary data, we hypothesize that inhibitors to these specific tumor constituents will be able to prevent or delay neurofibroma development. The objectives of this proposal are to systematically examine the role of non-neoplastic cells in the tumor microenvironment in the initiation and progression of dermal neurofibromas. These studies aim to identify potential therapeutic windows that can target these tumors at the earliest stages. Specifically, we will (1) define early, initiating geneic and tumor microenvironmental events that dictate dermal neurofibroma development and (2) determine phenotypic consequences of inhibition of these specific constituents in the tumor microenvironment during early phases of neurofibroma development. This research plans are novel because we have uncovered unique paracrine interactions between the neoplastic cells (the Schwann cells) and their microenvironment that are required for tumor formation. Moreover, this proposal not only will provide important insights into the molecular and cellular pathogenesis of neurofibroma, but also could lead directly to new and potentially effective therapies aimed at delaying or preventing tumor formation in NF1 patients, where none exist today. In addition, while focused on neurofibroma, this work raises the exciting possibility that the surrounding non-neoplastic cells in the tumor environment may also impact the growth of other tumor types. An increased understanding of the role of non-neoplastic tumor-associated cells may lead to new directions for cancer therapy and prevention.

描述（由申请人提供）：人类肿瘤易感性疾病冯·雷克林豪森 I 型神经纤维瘤病 (NF1) 是神经系统最常见的遗传性疾病之一，全世界每 3000 人中就有 1 人受到影响。它是由 NF1 肿瘤抑制基因突变引起的，该基因编码 GTP 酶激活蛋白 (GAP)，可负向调节 p21-RAS 信号传导。真皮和丛状神经纤维瘤，以及恶性周围神经鞘瘤等恶性肿瘤是NF1的严重并发症。神经纤维瘤是复杂的肿瘤，主要由异常局部细胞组成，包括：雪旺细胞、神经、内皮细胞、成纤维细胞以及大量浸润性炎性肥大细胞。然而，人们对介导这些复杂肿瘤的发生和进展的分子机制或引起皮肤神经纤维瘤的特定细胞类型的身份知之甚少。我们实验室最近的工作发现，真皮中存在一种新的神经干细胞群，称为皮肤源性前体细胞（SKP），它们是真皮神经纤维瘤的起源细胞，并为这种复杂的皮肤肿瘤建立了第一个小鼠模型。这些研究还提供了证据，表明来自肿瘤微环境中非肿瘤细胞的额外信号在神经纤维瘤形成中发挥着重要作用。新出现的证据表明肥大细胞、神经元和类固醇激素是肿瘤发生的关键早期因素。根据我们的初步数据，我们假设这些特定肿瘤成分的抑制剂将能够预防或延缓神经纤维瘤的发展。该提案的目的是系统地研究肿瘤微环境中的非肿瘤细胞在真皮神经纤维瘤的发生和进展中的作用。这些研究旨在确定可以在最早阶段针对这些肿瘤的潜在治疗窗口。具体来说，我们将（1）定义决定真皮神经纤维瘤发展的早期起始基因和肿瘤微环境事件，以及（2）确定在神经纤维瘤发展的早期阶段抑制肿瘤微环境中这些特定成分的表型后果。这项研究计划很新颖，因为我们发现了肿瘤细胞（施万细胞）与其肿瘤形成所需的微环境之间独特的旁分泌相互作用。此外，这一提议不仅将为神经纤维瘤的分子和细胞发病机制提供重要见解，而且可能直接导致新的、潜在有效的疗法，旨在延迟或预防 NF1 患者肿瘤的形成，而目前这种疗法尚不存在。此外，在关注神经纤维瘤的同时，这项工作提出了令人兴奋的可能性，即肿瘤环境中的周围非肿瘤细胞也可能影响其他肿瘤类型的生长。对非肿瘤性肿瘤相关细胞作用的进一步了解可能会为癌症治疗和预防带来新的方向。