Role of Neuregulin-1 in Schwann Cell Neoplasia

描述（由申请人提供）：恶性周围神经鞘肿瘤（MPNSTs）是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，这是影响神经系统的最常见的遗传性疾病。Nf1和p53肿瘤抑制基因突变在MPNST中常见，生长因子刺激等表观遗传因素可能与这些突变共同促进MPNST的发生。我们假设生长和分化因子的神经调节蛋白-1 （NRG-1）家族中的蛋白质促进了MPNST的肿瘤发生。为了验证这一假设，我们在雪旺细胞（P0-GGF（3只小鼠））中产生了表达NRG-1异构体胶质生长因子- 3 （GGF133）的转基因小鼠。P0-GGF(3)小鼠表现出明显的雪旺细胞增生、外周神经节瘤前病变和mpnst样雪旺细胞肿瘤。我们对P0-GGF(3)小鼠中产生的mpnst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，而且它们的p53表达也发生了改变。人类MPNST同样可以表达多种NRG-1亚型和erbB受体，我们发现2种人类MPNST细胞系的增殖依赖于erbB信号传导。由于P0-GGF(3)小鼠的MPNST形成源于生长因子表达的改变，这些小鼠代表了一种不同于先前描述的其他小鼠的转基因模型，并提供了一个独特的机会来研究表观遗传因子和肿瘤抑制因子在体内MPNST形成过程中的相互作用。在本研究中，我们将P0-GGF(3)小鼠模型与小鼠和人类MPNST细胞系进行配对，以严格验证NRG-1/erbB信号通路的组成性激活以及Nf1和p53肿瘤抑制基因的突变共同促进MPNST发病的假设。具体来说，我们将验证以下假设：1)特异性NRG-1亚型和erbB膜酪氨酸激酶是MPNST体外增殖、存活和/或迁移所必需的，NRG-1/erbB信号通路的组成性激活是MPNST体内肿瘤发生所必需的；2)在P0-GGF（3只小鼠）中，NJ7和p53肿瘤抑制基因功能的缺失与MPNST的肿瘤发生有关；3)NRG-1/erbB信号通路的组成性激活以及Nf1和/或p53肿瘤抑制基因的零突变共同加速了MPNST的体内肿瘤发生。这些研究将为MPNST的形成机制提供重要的见解，并将NRG-1/erbB信号通路作为MPNST的新治疗靶点。

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.