Abstract
Infection of human cancer xenografts in mice with murine leukemia viruses (MLVs) is a long-standing observation, but the likelihood of infection in vivo and its biological consequences are poorly understood. We therefore conducted a prospective study in commonly used xenograft recipient strains. From BALB/c nude mice engrafted with MCF7 human mammary carcinoma cells, we isolated a virus that was virtually identical to Bxv1, a locus encoding replication-competent xenotropic MLV (XMLV). XMLV was detected in 9/17 (53%) independently isolated explants. XMLV was not found in primary leukemias or in THP1 leukemia cells grown in Bxv1-negative NSG (NOD/SCID/γCnull) mice, although MCF7 explants harbored replication-defective MLV proviruses. To assess the significance of infection for xenograft behavior in vivo, we examined changes in growth and global transcription in MCF7 and the highly susceptible Raji Burkitt lymphoma cell line chronically infected with XMLV. Raji cells showed a stronger transcriptional response that included up-regulation of chemokines and effectors of innate antiviral immunity. In conclusion, the risk of de novo XMLV infection of xenografts is high in Bxv1 positive mice, while infection can have positive or negative effects on xenograft growth potential with significant consequences for interpretation of many xenograft studies.
Highlights
The potential for acquisition of endogenous murine retrovirus infection by human cells grown as xenografts was first reported many years ago, prior to the advent of molecular cloning and sequence-based classification of these viruses [1,2]
To assess the likelihood of acquiring de novo infection with murine leukemia virus we used the MCF7 mammary carcinoma cell line [17], a well-established xenograft model which we had previously found to be highly susceptible to infection with another gamma-retrovirus, feline leukemia virus (FeLV)
In this study we have shown that there is a substantial risk of acquiring de novo infection of human xenografts with xenotropic MLV (XMLV)
Summary
The potential for acquisition of endogenous murine retrovirus infection by human cells grown as xenografts was first reported many years ago, prior to the advent of molecular cloning and sequence-based classification of these viruses [1,2]. This phenomenon and its relevance to research on human disease were largely ignored until reports of XMRV (xenotropic murine leukemia virus-related virus) as a potential human pathogen brought these issues back into the limelight. Our results show that there is a very significant risk of acquiring XMLV in human breast cancer-derived MCF7 xenografts grown in BALB/c nude mice, a commonly used recipient strain
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