Hemmati Houman D, Nakano Ichiro, Lazareff Jorge A, Masterman-Smith Michael, Geschwind Daniel H, Bronner-Fraser Marianne, Kornblum Harley I
Division of Biology 139-74, California Institute of Technology, Pasadena, CA 91125, USA.
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15178-83. doi: 10.1073/pnas.2036535100. Epub 2003 Nov 26.
Pediatric brain tumors are significant causes of morbidity and mortality. It has been hypothesized that they derive from self-renewing multipotent neural stem cells. Here, we tested whether different pediatric brain tumors, including medulloblastomas and gliomas, contain cells with properties similar to neural stem cells. We find that tumor-derived progenitors form neurospheres that can be passaged at clonal density and are able to self-renew. Under conditions promoting differentiation, individual cells are multipotent, giving rise to both neurons and glia, in proportions that reflect the tumor of origin. Unlike normal neural stem cells, however, tumor-derived progenitors have an unusual capacity to proliferate and sometimes differentiate into abnormal cells with multiple differentiation markers. Gene expression analysis reveals that both whole tumors and tumor-derived neurospheres express many genes characteristic of neural and other stem cells, including CD133, Sox2, musashi-1, bmi-1, maternal embryonic leucine zipper kinase, and phosphoserine phosphatase, with variation from tumor to tumor. After grafting to neonatal rat brains, tumor-derived neurosphere cells migrate, produce neurons and glia, and continue to proliferate for more than 4 weeks. The results show that pediatric brain tumors contain neural stem-like cells with altered characteristics that may contribute to tumorigenesis. This finding may have important implications for treatment by means of specific targeting of stem-like cells within brain tumors.
小儿脑肿瘤是发病和死亡的重要原因。据推测，它们源自自我更新的多能神经干细胞。在此，我们测试了不同的小儿脑肿瘤，包括髓母细胞瘤和胶质瘤，是否含有具有与神经干细胞相似特性的细胞。我们发现肿瘤衍生的祖细胞形成了神经球，这些神经球可以以克隆密度传代并能够自我更新。在促进分化的条件下，单个细胞具有多能性，能产生神经元和神经胶质细胞，其比例反映了肿瘤的起源。然而，与正常神经干细胞不同的是，肿瘤衍生的祖细胞具有异常的增殖能力，有时还会分化为具有多种分化标志物的异常细胞。基因表达分析表明，整个肿瘤和肿瘤衍生的神经球都表达许多神经和其他干细胞特有的基因，包括CD133、Sox2、musashi - 1、bmi - 1、母体胚胎亮氨酸拉链激酶和磷酸丝氨酸磷酸酶，不同肿瘤之间存在差异。将肿瘤衍生的神经球细胞移植到新生大鼠脑内后，它们会迁移、产生神经元和神经胶质细胞，并持续增殖超过4周。结果表明，小儿脑肿瘤含有特性改变的神经干细胞样细胞，这些细胞可能有助于肿瘤发生。这一发现可能对通过特异性靶向脑肿瘤内的干细胞样细胞进行治疗具有重要意义。
