Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma.

摘要: The formation of human malignant gliomas is thought to involve the accumulation multiple genetic alterations. To define function specific alterations in glioma formation, we serially introduced functionally equivalent those noted into normal astrocytes (NHAs). We then monitored ability each these contribute growth otherwise genetically stable NHAs intracranial gliomas. Using this model, show that expression telomerase catalytic component (hTERT), but not E7-mediated inactivation pRb or E6/E7-mediated p53/pRb, was sufficient initiate tumorigenic process by circumventing cellular senescence astrocytes. hTERT expression, even combination with did transform These together, however, cooperated ras pathway activation (initiated mutant H-Ras), phosphatidylinositol 3-kinase myristoylated Akt) epidermal factor receptor activation, allow for tumors strongly resembling p53/pRb pathway-deficient, telomerase-positive, ras-activated grade III anaplastic astrocytomas. results identify four pathways as key development