Retroviral insertional mutagenesis: tagging cancer pathways.

Slow transforming retroviruses, such as the Moloney murine leukemia virus (M-MuLV), induce tumors upon infection of a host after a relatively long latency period. The underlying mechanism leading to cell transformation is the activation of proto-oncogenes or inactivation of tumor suppressor genes as a consequence of proviral insertions into the host genome. Cells carrying proviral insertions that confer a selective advantage will preferentially grow out. This means that proviral insertions mark genes contributing to tumorigenesis, as was demonstrated by the identification of numerous proto-oncogenes in retrovirally induced tumors in the past. Since cancer is a complex multistep process, the proviral insertions in one clone of tumor cells also represent oncogenic events that cooperate in tumorigenesis. Novel advances, such as the launch of the complete mouse genome, high-throughput isolation of proviral flanking sequences, and genetically modified animals have revolutionized proviral tagging into an elegant and efficient approach to identify signaling pathways that collaborate in cancer.