Department of Pediatrics, Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA.
PLoS One. 2010 May 26;5(5):e10849. doi: 10.1371/journal.pone.0010849.
Recent publications have described an important role for cross talk between PI-3 kinase and sonic hedgehog signaling pathways in the pathogenesis of medulloblastoma.
METHODOLOGY/PRINCIPAL FINDINGS: We crossed mice with constitutive activation of Smoothened, SmoA1, with Pten deficient mice. Both constitutive and conditional Pten deficiency doubled the incidence of mice with symptoms of medulloblastoma and resulted in decreased survival. Analysis revealed a clear separation of gene signatures, with up-regulation of genes in the PI-3 kinase signaling pathway, including downstream activation of angiogenesis in SmoA1+/-; Pten +/- medulloblastomas. Western blotting and immunohistochemistry confirmed reduced or absent Pten, Akt activation, and increased angiogenesis in Pten deficient tumors. Down-regulated genes included genes in the sonic hedgehog pathway and tumor suppressor genes. SmoA1+/-; Pten +/+ medulloblastomas appeared classic in histology with increased proliferation and diffuse staining for apoptosis. In contrast, Pten deficient tumors exhibited extensive nodularity with neuronal differentiation separated by focal areas of intense staining for proliferation and virtually absent apoptosis. Examination of human medulloblastomas revealed low to absent PTEN expression in over half of the tumors. Kaplan-Meier analysis confirmed worse overall survival in patients whose tumor exhibited low to absent PTEN expression.
CONCLUSIONS/SIGNIFICANCE: This suggests that PTEN expression is a marker of favorable prognosis and mouse models with activation of PI-3 kinase pathways may be important tools for preclinical evaluation of promising agents for the treatment of medulloblastoma.
最近的出版物描述了 PI-3 激酶和 Sonic Hedgehog 信号通路之间的串扰在成神经管细胞瘤发病机制中的重要作用。
方法/主要发现：我们将 Smoothened 组成性激活的小鼠与 Pten 缺陷型小鼠进行了杂交。组成性和条件性 Pten 缺失使患有成神经管细胞瘤症状的小鼠的发病率增加了一倍，并导致生存率降低。分析显示基因特征明显分离，PI-3 激酶信号通路中的基因上调，包括 SmoA1+/-中的血管生成下游激活；Pten +/-成神经管细胞瘤。Western blot 和免疫组织化学证实 Pten 减少或缺失，Akt 激活，以及 Pten 缺陷肿瘤中血管生成增加。下调的基因包括 Sonic Hedgehog 通路和肿瘤抑制基因。SmoA1+/-；Pten +/+成神经管细胞瘤在组织学上表现为经典，增殖增加，凋亡弥漫染色。相比之下，Pten 缺陷肿瘤表现为广泛的结节状，神经元分化，由增殖强烈染色的局灶区域隔开，凋亡几乎不存在。对人类成神经管细胞瘤的检查显示，超过一半的肿瘤中 PTEN 表达低至缺失。Kaplan-Meier 分析证实，肿瘤中 PTEN 表达低至缺失的患者总生存率较差。
结论/意义：这表明 PTEN 表达是预后良好的标志物，激活 PI-3 激酶途径的小鼠模型可能是评估治疗成神经管细胞瘤有前途药物的临床前评价的重要工具。
