Despite not being considered oncogenic, cytomegalovirus (CMV) has been detected in an increasing number of malignancies. However, recent studies have suggested mechanisms through which CMV may modulate the tumor environment, encouraging its study as a positive modifier of tumorigenesis. In this study, we investigated the effects of CMV infection in Trp53 heterozygous mice. Animals were infected with murine CMV (MCMV) after birth at 2 days (P2) or 4 weeks of age via intraperitoneal injection and then monitored for tumor formation. Additional control cohorts were mock-infected (saline vehicle) or infected with HSV-1, a similar herpes virus. Following MCMV infection, widespread systemic infection ensued followed by immune clearance of the virus resulting in seroconversion. Mice infected at P2 developed tumors at a high frequency (43%) by 9 months of age. In contrast, only 3% of mock-infected or mice infected at 4 weeks developed tumors. The majority of tumors from P2 MCMV-infected mice were pleomorphic rhabdomyosarcomas (RMS) as evidenced by MyoD1, Desmin, and Myogenin staining. Importantly, MCMV-infected tumors contained MCMV DNA, RNA, and protein. An examination of clinical cases revealed that human RMS (embryonal, alveolar, and pleomorphic) harbored human CMV IE1 and pp65 protein as well as viral RNA. All of the cases (n=18) tested positive for CMV genetic material. CMV protein was found throughout the tumor including pleomorphic cells. Additionally, perivascular areas demonstrated intense staining consistent with other reports of linking CMV with angiogenesis. To confirm the selective presence of HCMV DNA in human RMS, quantitative PCR analysis showed that tumors expressed an average of 81.1 copies/ng of HCMV-UL83 and of 22.2 copies/ng of HCMV-UL146 compared to 0 and 0.49 copies/ng in normal muscle, respectively. The amplified products’ nucleotide sequence was greater than 95% identical to that of a clinical strain Taken together, our findings offer support for the hypothesis that CMV contributes to the development of pleomorphic RMS in the context of Trp53 mutation, a situation which occurs with high frequency in human RMS.

Citation Format: Richard L. Price, Katherine Bingmer, Lualhati Harkins, Hans Iwenofu, Chang-Hyuk Kwon, Charles Cook, Christopher Pelloski, E Antonio Chiocca. Cytomegalovirus infection leads to pleomorphic rhabdomyosarcomas in Trp53 +/- mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4777. doi:10.1158/1538-7445.AM2013-4777

©2013 American Association for Cancer Research
2013