Zhu Yuan, Guignard Frantz, Zhao Dawen, Liu Li, Burns Dennis K, Mason Ralph P, Messing Albee, Parada Luis F
Center for Developmental Biology and Kent Waldrep Foundation Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Cancer Cell. 2005 Aug;8(2):119-30. doi: 10.1016/j.ccr.2005.07.004.
Malignant astrocytoma, the most prevalent primary brain tumor, is resistant to all known therapies and frequently harbors mutations that inactivate p53 and activate Ras signaling. We have generated mouse strains that lack p53 and harbor a conditional allele of the NF1 tumor suppressor that negatively regulates Ras signaling. The mice develop malignant astrocytomas with complete penetrance. The majority of tumors display characteristics of glioblastoma multiforme with concomitant alteration of signaling pathways previously described in the human counterparts of this neoplasm. We find that the sequence of tumor suppressor inactivation influences tumorigenicity and that earliest evidence of tumor formation localizes to regions of the brain that contain a multipotent stem cell population capable of in vivo differentiation into neurons and glia.
恶性星形细胞瘤是最常见的原发性脑肿瘤，对所有已知疗法均有抗性，且经常携带使p53失活并激活Ras信号传导的突变。我们已培育出缺乏p53并携带NF1肿瘤抑制基因条件性等位基因的小鼠品系，该基因对Ras信号传导起负调控作用。这些小鼠会完全显性地发展出恶性星形细胞瘤。大多数肿瘤表现出多形性胶质母细胞瘤的特征，同时伴有该肿瘤人类对应物中先前描述的信号通路改变。我们发现肿瘤抑制基因失活的顺序会影响致瘤性，并且肿瘤形成的最早证据定位于大脑中含有能够在体内分化为神经元和神经胶质的多能干细胞群体的区域。
