Selective destruction of glioblastoma cells by interference with the activity or expression of ATF5.

Glioblastoma multifome is the most common and most aggressive primary brain tumor with no current curative therapy. We found expression of the bZip transcription factor ATF5 in all 29 human glioblastomas and eight human and rat glioma cell lines assessed. ATF5 is not detectably expressed by mature brain neurons and astrocytes, but is expressed by reactive astrocytes. Interference with ATF5 function or expression in all glioma cell lines tested causes marked apoptotic cell death. In contrast, such manipulations do not affect survival of ATF5-expressing cultured astrocytes or of several other cell types that express this protein. In a proof-of-principle experiment, retroviral delivery of a function-blocking mutant form of ATF5 into a rat glioma model evokes death of the infected tumor cells, but not of infected brain cells outside the tumors. The widespread expression of ATF5 in glioblastomas and the selective effect of interference with ATF5 function/expression on their survival suggest that ATF5 may be an attractive target for therapeutic intervention in such tumors.

Pattern of mutant p53 expression in human astrocytomas suggests the existence of alternate pathways of tumorigenesis.

BACKGROUND: Clinical observations suggest that malignant astrocytomas may arise from well-differentiated, low-grade tumors that have undergone anaplastic progression or may develop de novo. Mutations that alter the function of the p53 gene product are thought to play a critical role in astrocytoma tumorigenesis. The authors studied the pattern of mutant p53 expression in astrocytomas to define its role in the formation of malignant tumors by these different pathways. METHODS: Tissues from 44 astrocytomas corresponding to Grades I-IV of the World Health Organization (WHO) classification were analyzed for the presence of mutations in exons 5, 7, and 8 of the p53 gene using single strand conformation polymorphism (SSCP) and sequence analysis of DNA amplified by the polymerase chain reaction. Immunostaining for mutant p53 proteins was performed on tissues fixed in formaldehyde solution and embedded in paraffin; the tissues were from these 44 astrocytomas and another 103 astrocytomas obtained from archival material. RESULTS: Tumors with mutant p53 genes were reliably identified by immunostaining for mutant p53 proteins. A higher percentage of astrocytomas of histologic Grades II-IV stained positively for p53 than were identified by mutational analysis. The average ages of patients with Grade III/IV astrocytomas with prominent (> 10%) p53 staining and those with sparse (< 10%) or no p53 staining were 44.5, 64.3, and 67.9 years, respectively (P < 0.0001). CONCLUSIONS: The pattern of mutant p53 expression is consistent with a role in driving the progression of low-grade astrocytomas to more malignant tumors. These results provide a genetic basis for the clinical observation that malignant astrocytomas resulting from anaplastic progression occur in a younger patient population than do malignant astrocytomas arising de novo.