The Roles of Tumor Microenvironment in Neurofibroma Development and Therapeutics

描述(申请人提供)：人类肿瘤易感性疾病冯雷克林豪森的神经纤维瘤病I型(NF1)是最常见的神经系统遗传性疾病之一，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，该基因编码一种GTP酶激活蛋白(GAP)，负向调节p21-RAS信号。皮肤和丛状神经纤维瘤，以及恶性周围神经鞘瘤和其他恶性肿瘤是NF1的严重并发症。神经纤维瘤是一种复杂的肿瘤，主要由异常的局部细胞组成，包括雪旺细胞、神经、内皮细胞、成纤维细胞和大量浸润性的炎性肥大细胞。然而，对于介导这些复杂肿瘤发生和发展的分子机制，或引起皮肤神经纤维瘤的特定细胞类型的识别，人们知之甚少。我们实验室最近的工作已经确定了一种新的存在于真皮中的神经干细胞群体，称为皮源性前体(SKPs)，它是真皮神经纤维瘤的起源细胞，并建立了这种复杂皮肤肿瘤的第一个小鼠模型。这些研究还提供了证据，表明肿瘤微环境中来自非肿瘤细胞的额外信号在神经纤维瘤的形成中起着至关重要的作用。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。本研究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发展中的作用。这些研究旨在确定可以在早期阶段针对这些肿瘤的潜在治疗窗口。具体地说，我们将(1)定义决定皮肤神经纤维瘤发展的早期、启动遗传学和肿瘤微环境事件，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。这项研究计划是新颖的，因为我们发现了肿瘤形成所需的肿瘤细胞(雪旺细胞)与其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的见解，还可能直接导致旨在延缓或防止NF1患者肿瘤形成的新的、潜在有效的治疗方法，而目前尚不存在这种疗法。此外，在聚焦于神经纤维瘤的同时，这项工作提出了一种令人兴奋的可能性，即肿瘤环境中周围的非肿瘤细胞也可能影响其他类型的肿瘤的生长。提高对非肿瘤肿瘤相关细胞作用的认识可能会为癌症的治疗和预防带来新的方向。

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.