Role of Neuregulin-1 in Schwann Cell Neoplasia

描述(申请人提供)：恶性周围神经鞘瘤(MPNST)是一种高度侵袭性的雪旺细胞肿瘤，发生在1型神经纤维瘤病(NF1)患者中，NF1是影响神经系统的最常见的遗传性疾病。NF1和P53抑癌基因突变普遍存在于MPNST中，生长因子刺激等表观遗传因素可能与这些突变协同促进MPNST肿瘤的发生。我们假设神经调节蛋白-1(NRG-1)家族的生长和分化因子促进MPNST肿瘤的发生。为了验证这一假设，我们培育了在雪旺细胞中表达NRG-1异构体胶质生长因子-(3(GGF133)的转基因小鼠(P0-GGF(3只小鼠))。P0-GGF(3只小鼠表现出明显的雪旺细胞增生、周围神经节癌前病变和MPNST样雪旺细胞瘤。我们对P0-GGF(3只小鼠)中产生的MPNSTs的初步研究表明，NF1基因的产物神经纤维蛋白在这些肿瘤中不表达，它们的P53表达也发生了变化。人类MPNST同样表达多种NRG-1亚型和erb B受体，我们发现2株人MPNST细胞的增殖依赖于erb B信号。由于P0-GGF(3只小鼠)中MPNST的形成是生长因子表达变化的结果，这些小鼠代表了一个不同于之前描述的所有其他转基因模型，并提供了一个独特的机会来研究体内MPNST形成过程中表观遗传因素和肿瘤抑制因子之间的相互作用。在这项建议中，我们将P0-GGF(3)小鼠模型与小鼠和人MPNST细胞系配对，以严格检验NRG-1/erbB信号通路的结构性激活以及NF1和P53肿瘤抑制基因突变共同促进MPNST发病的假设。具体地说，我们将检验如下假设：1)特定的NRG-1亚型和erbB膜酪氨酸激酶分别是MPNST在体外增殖、存活和/或迁移所必需的，并且NRG-1/erbB信号通路的组成性激活对于MPNST体内肿瘤的形成是必要的；2)NJ7和p53抑癌基因功能的丧失与MPNST在P0-GGF中的肿瘤形成有关(3)NRG-1/erbB信号通路的结构性激活和NF1和/或p53抑癌基因的零突变协同促进了体内MPNST的肿瘤形成。这些研究将对促进MPNST形成的机制提供重要的见解，并将NRG-1/erbB信号通路确立为MPNSTs的新的治疗靶点。

DESCRIPTION (provided by applicant): Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell neoplasms that occur in patients with neurofibromatosis type 1 (NF1), the most common genetic disease affecting the nervous system. Nf1 and p53 tumor suppressor gene mutations occur commonly in MPNSTs and epigenetic factors such as stimulation by growth factors likely cooperate with these mutations to promote MPNST tumorigenesis. We hypothesized that proteins in the neuregulin-1 (NRG-1) family of growth and differentiation factors promote MPNST tumorigenesis. To test this hypothesis, we generated transgenic mice expressing the NRG-1 isoform glial growth factor-(3 (GGF133) in Schwann cells (P0-GGF(3 mice). P0-GGF(3 mice demonstrate prominent Schwann cell hyperplasia, preneoplastic lesions in peripheral ganglia and MPNST-like Schwann cell neoplasms. Our preliminary studies of MPNSTs arising in P0-GGF(3 mice indicate that neurofibromin, the product of the Nf1 gene, is not expressed in these neoplasms and that their p53 expression is also altered. Human MPNSTs likewise co express multiple NRG-1 isoforms and erbB receptors and we have found that the proliferation of 2 human MPNST cell lines is dependent on erbB signaling. As MPNST formation in P0-GGF(3 mice results from altered growth factor expression, these mice represent a transgenic model distinct from all others previously described and provide a unique opportunity to examine interactions between epigenetic factors and tumor suppressors during in vivo MPNST formation. In this proposal, we will partner the P0-GGF(3 mouse model with mouse and human MPNST cell lines to critically test the hypothesis that constitutive activation of the NRG-1/erbB signaling pathway and mutations of the Nf1 and p53 tumor suppressor genes cooperate to promote MPNST pathogenesis. Specifically, we will test the hypotheses that: 1) Specific NRG-1 isoforms and erbB membrane tyrosine kinases are individually necessary for MPNST proliferation, survival and/or migration in vitro and that constitutive activation of the NRG-1/erbB signaling pathway is necessary for MPNST tumorigenesis in vivo; 2) loss of NJ7 and p53 tumor suppressor gene function is associated with MPNST tumorigenesis in P0-GGF(3 mice and 3) constitutive activation of the NRG-1/erbB signaling pathway and null mutations of the Nf1 and/or p53 tumor suppressor genes cooperate to accelerate MPNST tumorigenesis in vivo. These studies will provide important insights into the mechanisms promoting MPNST formation and establish the NRG-1/erbB signaling pathway as a novel therapeutic target in MPNSTs.