Keng Vincent W, Watson Adrienne L, Rahrmann Eric P, Li Hua, Tschida Barbara R, Moriarity Branden S, Choi Kwangmin, Rizvi Tilat A, Collins Margaret H, Wallace Margaret R, Ratner Nancy, Largaespada David A
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA ; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA ; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA ; Brain Tumor Program, University of Minnesota, Minneapolis, MN 55455, USA ; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.
Sarcoma. 2012;2012:620834. doi: 10.1155/2012/620834. Epub 2012 Dec 18.
The genetic mechanisms involved in the transformation from a benign neurofibroma to a malignant sarcoma in patients with neurofibromatosis-type-1- (NF1-)associated or sporadic malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. It is hypothesized that many genetic changes are involved in transformation. Recently, it has been shown that both phosphatase and tensin homolog (PTEN) and epidermal growth factor receptor (EGFR) play important roles in the initiation of peripheral nerve sheath tumors (PNSTs). In human MPNSTs, PTEN expression is often reduced, while EGFR expression is often induced. We tested if these two genes cooperate in the evolution of PNSTs. Transgenic mice were generated carrying conditional floxed alleles of Pten, and EGFR was expressed under the control of the 2',3'-cyclic nucleotide 3'phosphodiesterase (Cnp) promoter and a desert hedgehog (Dhh) regulatory element driving Cre recombinase transgenic mice (Dhh-Cre). Complete loss of Pten and EGFR overexpression in Schwann cells led to the development of high-grade PNSTs. In vitro experiments using immortalized human Schwann cells demonstrated that loss of PTEN and overexpression of EGFR cooperate to increase cellular proliferation and anchorage-independent colony formation. This mouse model can rapidly recapitulate PNST onset and progression to high-grade PNSTs, as seen in sporadic MPNST patients.
1型神经纤维瘤病（NF1）相关或散发性恶性外周神经鞘瘤（MPNST）患者中，从良性神经纤维瘤转变为恶性肉瘤所涉及的遗传机制仍不清楚。据推测，转变过程涉及许多基因变化。最近研究表明，磷酸酶和张力蛋白同源物（PTEN）及表皮生长因子受体（EGFR）在周围神经鞘瘤（PNST）的发生中均起重要作用。在人类MPNST中，PTEN表达常降低，而EGFR表达常被诱导。我们测试了这两个基因在PNST演变过程中是否协同作用。构建了携带条件性Pten基因敲除等位基因的转基因小鼠，并在2'，3'-环核苷酸3'-磷酸二酯酶（Cnp）启动子及驱动Cre重组酶转基因小鼠（Dhh-Cre）的沙漠刺猬（Dhh）调控元件控制下表达EGFR。雪旺细胞中Pten完全缺失和EGFR过表达导致了高级别PNST的发生。使用永生化人类雪旺细胞进行的体外实验表明，PTEN缺失和EGFR过表达协同作用可增加细胞增殖及非锚定依赖性集落形成。这种小鼠模型能够快速重现PNST的发病及进展为高级别PNST的过程，就像散发性MPNST患者那样。
