Identifying candidate genes involved in brain tumor formation.

Malignant primary brain tumors, gliomas, often overexpress both platelet-derived growth factor (PDGF) ligands and receptors providing an autocrine and/or paracrine boost to tumor growth. Glioblastoma multiforme (GBM) is the most frequent glioma. Its aggressive and infiltrative growth renders it extremely difficult to treat. Median survival after diagnosis is currently only 12-14 months. The present review describes the use of retroviral tagging to identify candidate cancer-causing genes that cooperate with PDGF in brain tumor formation. Newborn mice injected intracerebrally with a Moloney murine leukemia retrovirus carrying the sis/PDGF-B oncogene and a replication competent helper virus developed brain tumors with many characteristics of human gliomas. Analysis of proviral integrations in the brain tumors identified almost 70 common insertion sites (CISs). These CISs were named brain tumor loci and harbored known but also putative novel cancer-causing genes. Microarray analysis identified differentially expressed genes in the mouse brain tumors compared to normal brain. Known tumor genes and markers of immature cells were upregulated in the tumors. Tumors developed 13-42 weeks after injection and short latency tumors were further distinguished as fast growing and GBM-like. Long latency tumors resembled slow-growing oligodendrogliomas and contained significantly less integrations as compared to short latency tumors. Several candidate genes tagged in this retroviral screen have known functions in neoplastic transformation and oncogenesis. Some candidates with a previously unknown function in tumorigenesis were found and their putative role in brain tumor formation will be discussed in this review. The results show that proviral tagging may be a useful tool in the search for candidate glioma genes.