Pathological and molecular progression of astrocytomas in a GFAP:: 12V=Ha-Ras mouse astrocytoma model
Pathological and molecular progression of astrocytomas in a GFAP:: 12V=Ha-Ras mouse astrocytoma model
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DOI：
10.1016/s0002-9440(10)62057-3
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发表时间：
2005-09-01
影响因子：
6
通讯作者：
Guha, A
中科院分区：
文献类型：
--
作者：
Shannon, P;Sabha, N;Guha, A
我们之前描述了一种基因工程小鼠星形细胞瘤模型，该模型具有胚胎星形胶质细胞特异性、激活的 V-12-Ha-RAS (GFAP-RAS) 转基因。 GFAP-RAS 系 Ras-B8 在出生时表现正常，但 50% 的小鼠在 4 个月内死于低级别和高级别星形细胞瘤。我们检查了 Ras-B8 基因工程小鼠中星形细胞瘤的发生和进展。在胚胎第 16.5 天 (E16.5)，除了转基因表达之外，与对照同窝仔鼠相比，没有任何病理学差异。弥漫性星形胶质细胞增生是 1 周龄 Ras-B8 小鼠的第一个显着特征；然而，这些星形胶质细胞在体外或体内均未发生转化。从3周到8周，低级别星形细胞瘤的发病率逐渐增加，12周龄小鼠中85%患有低级别或高级别星形细胞瘤，后者的特点是增殖增加、核异型性和血管生成。在两种级别的星形细胞瘤中均检测到 Tp53 突变，高级别星形细胞瘤表达表皮生长因子受体和血管内皮生长因子水平升高，同时 PTEN 和 p16 水平降低，与人类星形细胞瘤相似。我们假设星形胶质细胞前体中 V-12-Ha-RAS 的表达会诱导星形胶质细胞增生，但转化和随后的进展需要由异常激活的 p21-RAS 引起的额外分子改变。有趣的是，许多这些获得性改变发生在人类星形细胞瘤中，进一步验证了 GFAP-RAS 作为研究星形细胞瘤发生和进展的有用模型。
We previously characterized a genetically engineered mouse astrocytoma model with embryonic astrocyte-specific, activated V-12-Ha-RAS (GFAP-RAS) transgenesis. The GFAP-RAS line Ras-B8 appears normal at birth, but 50% of mice die by 4 months from low- and high-grade astrocytomas. We examined the development and progression of astrocytomas in the Ras-B8 genetically engineered mouse. At embryonic day 16.5 (E16.5), there were no pathological differences compared to control littermates, aside from transgene expression. Diffuse astroglial hyperplasia was the first distinguishing feature in the 1-week-old Ras-B8 mice; however, these astrocytes were not transformed in vitro or in vivo. From 3 to 8 weeks the incidence of low-grade astrocytomas progressively increased with 85% of 12-week-old mice harboring low- or high-grade astrocytomas, the latter characterized by increased proliferation, nuclear atypia, and angiogenesis. Tp53 mutations were detected in both astrocytoma grades, with high-grade astrocytomas expressing elevated levels of epidermal growth factor receptor and vascular endothelial growth factor, plus decreased levels of PTEN and p16, similar to human astrocytomas. We postulate that expression of V-12-Ha-RAS in astroglial precursors induces astroglial hyperplasia, but transformation and subsequent progression requires additional molecular alterations resulting from aberrant activated p21-RAS. Of interest, many of these acquired alterations occur in human astrocytomas, further validating GFAP-RAS as a useful model for studying astrocytoma development and progression.