Konopka G, Bonni A
Department of Pathology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Curr Mol Med. 2003 Feb;3(1):73-84. doi: 10.2174/1566524033361609.
The astrocytomas represent the most common primary tumors of the brain. Despite efforts to improve the treatment of astrocytomas, these tumors and in particular the high-grade astrocytoma termed glioblastoma multiforme still carry a poor prognosis. In recent years, there has been an intensive effort to gain an understanding of the cellular and molecular mechanisms that contribute to the pathogenesis of astrocytomas as a first step toward the development of better treatments for these devastating tumors. Here, we will review our current understanding of the signaling pathways that underlie glial transformation. Studies of astrocytomas have led to the identification of two major groups of signaling proteins whose abnormalities contribute to gliomagenesis: the cell cycle pathways and the growth factor-regulated signaling pathways. Among the cell cycle proteins, the p16-cdk4-pRb and ARF-MDM2-p53 cell cycle arrest pathways play a prominent role in glial transformation. In addition, deregulation of polypeptide growth factors acting via receptor tyrosine kinases (RTKs) and of intracellular signals, including the lipid phosphatase PTEN, that regulate cellular responses to RTKs plays a critical role in gliomagenesis. In addition to the identification of the signaling proteins targeted in glial transformation, the cell-of-origin of astrocytomas has been investigated. Genetic modeling of astrocytomas in mice suggests that neuroepithelial precursor cells represent preferred cellular substrates of gliomas or that either astrocytes or precursor cells constitute potential cells-of-origin of astrocytomas. During normal brain development, neuroepithelial precursor cells, including neural stem cells, differentiate into astrocytes. As the mechanisms that control gliogenesis during normal brain development become better understood, it will be important to determine if deregulation of these mechanisms might contribute to the pathogenesis of astrocytomas. The elucidation of the molecular underpinnings of astrocytomas holds the promise of improved treatment options for patients with these devastating brain tumors.
星形细胞瘤是最常见的原发性脑肿瘤。尽管人们努力改善星形细胞瘤的治疗方法，但这些肿瘤，尤其是被称为多形性胶质母细胞瘤的高级别星形细胞瘤，预后仍然很差。近年来，人们进行了深入研究，试图了解导致星形细胞瘤发病机制的细胞和分子机制，这是朝着开发更好的治疗这些毁灭性肿瘤的方法迈出的第一步。在这里，我们将回顾目前对神经胶质细胞转化所涉及的信号通路的理解。对星形细胞瘤的研究已导致鉴定出两大类信号蛋白，其异常有助于胶质瘤的发生：细胞周期通路和生长因子调节的信号通路。在细胞周期蛋白中，p16-cdk4-pRb和ARF-MDM2-p53细胞周期阻滞通路在神经胶质细胞转化中起重要作用。此外，通过受体酪氨酸激酶（RTK）起作用的多肽生长因子以及调节细胞对RTK反应的细胞内信号（包括脂质磷酸酶PTEN）的失调在胶质瘤发生中起关键作用。除了鉴定神经胶质细胞转化中靶向的信号蛋白外，还对星形细胞瘤的起源细胞进行了研究。小鼠星形细胞瘤的基因模型表明，神经上皮前体细胞是胶质瘤的首选细胞底物，或者星形胶质细胞或前体细胞构成星形细胞瘤的潜在起源细胞。在正常脑发育过程中，神经上皮前体细胞，包括神经干细胞，会分化为星形胶质细胞。随着对正常脑发育过程中控制神经胶质细胞生成机制的了解越来越深入，确定这些机制的失调是否可能导致星形细胞瘤的发病机制将变得很重要。阐明星形细胞瘤的分子基础有望为患有这些毁灭性脑肿瘤的患者提供更好的治疗选择。
