Retroviruses earned their notoriety by inducing a broad range of tumors in vertebrates. Whereas some retroviruses carry oncogenes in their genome, the vast majority of retroviruses do not encode such elements and thus, must integrate near cellular proto-oncogenes and up-regulate them to induce tumors. Many cellular genes involved in tumorigenesis were first identified as viral oncogenes (v-onc) or genes up-regulated upon retroviral insertion. They are now known to be involved in various types of spontaneous tumors in humans. Up-regulation of cellular protooncogenes via insertional mutagenesis or insertion of v-oncs constitutes a necessary step for tumor induction. However, up-regulation of an oncogene alone is not sufficient for tumor induction and other events are required for tumor development. Therefore, similarly to tumors of other etiologies, retrovirally-induced tumors are developed as a multistep process and thus, represent a valuable system to address questions related to mechanisms of cancer induction and promotion. Initially, we set out to address the role of commensal bacteria (microbiota) in transmission of Murine Leukemia Virus (MuLV) which unlike other retroviruses can spread highly efficiently as an oral and as a blood- borne pathogen. Accordingly, we re-derived susceptible BALB/cJ mice as germ-free (GF, sterile) and found that these animals were capable of transmitting infectious virus. However, to our surprise, infected GF mice never developed virally-induced disease - lymphoma or leukemia. Association of the GF mice with a defined group of commensal bacteria (Altered Schaedler Flora or ASF) and with a single Propionibacterium acnes (P. acnes) but not with proteobacterium `similar to E. coli and Shigella' (SECS) reversed the tumor- resistant phenotype, establishing the requirement for specific microbial input in leukemia development. Gene- expression analysis suggested that microbiota-dependent mechanism of leukemia progression could be mediated by pro-inflammatory cytokines, in particular interleukin 6 (IL6) and granulocyte macrophage colony- stimulating factor (GM-CSF). Although the gut microbiota has been implicated in the progression of colon and liver cancers, the requirement of the gut microbiota for leukemia development is a new discovery. Therefore, our model is a powerful tool for identifying leukemia-inducing pathways activated by commensal bacteria. Chronic inflammation contributes to a multitude of cancers. As inflammation is often associated with microbial products, we think that our findings will provide valuable new insights into cancer prevention and treatment.
After the initial somatic mutation, tumor development requires a series of genetic and epigenetic changes. Our preliminary data suggest that the gut commensal bacteria serve as an epigenetic factor that contributes to leukemia development. Using well-defined animal models, this application will address the previously unappreciated contribution of the commensal microbiota to the process of leukemogenesis.
