Vaccination against a hit-and-run viral cancer

Department of Pathology, University of Cambridge, UK.
Journal of General Virology (Impact Factor: 3.18). 09/2010; 91(Pt 9):2176-85. DOI: 10.1099/vir.0.023507-0
Source: PubMed


Cancers with viral aetiologies can potentially be prevented by antiviral vaccines. Therefore, it is important to understand how viral infections and cancers might be linked. Some cancers frequently carry gammaherpesvirus genomes. However, they generally express the same viral genes as non-transformed cells, and differ mainly in also carrying oncogenic host mutations. Infection, therefore, seems to play a triggering or accessory role in disease. The hit-and-run hypothesis proposes that cumulative host mutations can allow viral genomes to be lost entirely, such that cancers remaining virus-positive represent only a fraction of those to which infection contributes. This would have considerable implications for disease control. However, the hit-and-run hypothesis has so far lacked experimental support. Here, we tested it by using Cre-lox recombination to trigger transforming mutations in virus-infected cells. Thus, 'floxed' oncogene mice were infected with Cre recombinase-positive murid herpesvirus-4 (MuHV-4). The emerging cancers showed the expected genetic changes but, by the time of presentation, almost all lacked viral genomes. Vaccination with a non-persistent MuHV-4 mutant nonetheless conferred complete protection. Equivalent human gammaherpesvirus vaccines could therefore potentially prevent not only viral genome-positive cancers, but possibly also some cancers less suspected of a viral origin because of viral genome loss.

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    • "Hit-and-run oncogenesis is most frequently considered in the context of virally induced cancers.28 The idea that cancer progression can persist in the absence of initiating viral oncoprotein expression is supported by laboratory models in which a transformed cellular phenotype persists despite loss of viral oncoprotein expression for adenoviruses,29,30 herpesviruses,31,32 and the polyomavirus Simian virus 40 (SV40) large T antigen (TAg).33–37 Hit-and-run–mediated pathophysiology has been suggested as a pathway for polyomavirus in human brain tumors and mesotheliomas,38–40 JC virus in colorectal cancer,41 papillomaviruses in Schneiderian inverted papillomas,42 and Hepatitis B in hepatomas.43 "
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    ABSTRACT: In a medical sense, biomodulation could be considered a biochemical or cellular response to a disease or therapeutic stimulus. In cancer pathophysiology, the initial oncogenic stimulus leads to cellular and biochemical changes that allow cells, tissue, and organism to accommodate and accept the oncogenic insult. In epithelial cell cancer development, the process of carcinogenesis is frequently characterized by sequential cellular and biochemical adaptations as cells transition through hyperplasia, dysplasia, atypical dysplasia, carcinoma in situ, and invasive cancer. In some cases, the adaptations may persist after the initial oncogenic stimulus is gone in a type of "hit-and-run" oncogenesis. These pathophysiological changes may interfere with cancer prevention therapies targeted solely to the initial oncogenic insult, perhaps contributing to resistance development. Characterization of these accommodating adaptations could provide insight for the development of cancer preventive regimens that might more effectively biomodulate preneoplastic cells toward a more normal state.
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    ABSTRACT: Evaluation of: Stevenson PG, May JS, Connor V, Efstathiou S: Vaccination against a hit-and-run viral cancer. J. Gen. Virol. 91, 2176-2185 (2010). Viral hit-and-run oncogenesis scenarios suggest that transient acquisition of viral genomes can induce a permanent change in the gene expression pattern of the host cell, resulting in malignant conversion. Stevenson et al. developed an in vivo model system based on the introduction of a Cre-recombinase positive murid herpesvirus into genetically engineered mice. They demonstrated that the Cre recombinase could switch on a silent oncogene and inactivate a tumor suppressor gene resulting in sarcomagenesis. However, some of the tumors lacked herpesvirus genomes, suggesting a hit-and-run type oncogenesis. The authors also observed that vaccination could prevent sarcomagenesis in their model.
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