The viral tropism of two distinct oncolytic viruses, reovirus and myxoma virus, is modulated by cellular tumor suppressor gene status

• Published in: Oncogene Vol. 29; no. 27; pp. 3990 - 3996
• Main Authors: Kim, M, Williamson, C T, Prudhomme, J, Bebb, D G, Riabowol, K, Lee, P W K, Lees-Miller, S P, Mori, Y, Rahman, M M, McFadden, G, Johnston, R N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08-07-2010; Nature Publishing Group
• Subjects: 631/67/581; 692/699/67; 692/700/565/1331; Adenovirus; AKT protein; Animals; Antiviral activity; Apoptosis; Apoptosis - genetics; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Cancer; Carcinogenesis; Care and treatment; Cell Biology; Cell Cycle Proteins - genetics; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Cellular signal transduction; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; Fundamental and applied biological sciences. Psychology; Gene Deletion; Gene expression; Gene Knockdown Techniques; Genes, Tumor Suppressor; Genetic aspects; Genomic instability; Health aspects; Human Genetics; Humans; Internal Medicine; Medicine; Medicine & Public Health; Mice; Molecular and cellular biology; Myxoma; Myxoma virus; Myxoma virus - physiology; Neoplasms - genetics; Neoplasms - pathology; Neoplasms - virology; Oncology; Oncolysis; Oncolytic Viruses - physiology; p53 Protein; Physiological aspects; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Proteins; Reoviridae - physiology; Reovirus; Reoviruses; Retinoblastoma Protein - deficiency; Retinoblastoma Protein - genetics; short-communication; Signal transduction; Tropism; Tumor suppressor genes; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; Viral Tropism; Viruses; Canada; South Korea; myxoma virus; anticancer therapy; tumor suppressor; reovirus; oncolytic virus; Virus; Chordopoxvirinae; Poxviridae; anticancer tnerapy; Myxoma virus; Leporipoxvirus; Carcinogenesis; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.137

Replication-competent oncolytic viruses hold great potential for the clinical treatment of many cancers. Importantly, many oncolytic virus candidates, such as reovirus and myxoma virus, preferentially infect cancer cells bearing abnormal cellular signaling pathways. Reovirus and myxoma virus are highly responsive to activated Ras and Akt signaling pathways, respectively, for their specificity for viral oncolysis. However, considering the complexity of cancer cell populations, it is possible that other tumor-specific signaling pathways may also contribute to viral discrimination between normal versus cancer cells. Because carcinogenesis is a multistep process involving the accumulation of both oncogene activations and the inactivation of tumor suppressor genes, we speculated that not only oncogenes but also tumor suppressor genes may have an important role in determining the tropism of these viruses for cancer cells. It has been previously shown that many cellular tumor suppressor genes, such as
p53
,
ATM
and
Rb
, are important for maintaining genomic stability; dysfunction of these tumor suppressors may disrupt intact cellular antiviral activity due to the accumulation of genomic instability or due to interference with apoptotic signaling. Therefore, we speculated that cells with dysfunctional tumor suppressors may display enhanced susceptibility to challenge with these oncolytic viruses, as previously seen with adenovirus. We report here that both reovirus and myxoma virus preferentially infect cancer cells bearing dysfunctional or deleted
p53
,
ATM
and
Rb
tumor suppressor genes compared to cells retaining normal counterparts of these genes. Thus, oncolysis by these viruses may be influenced by both oncogenic activation and tumor suppressor status.