title: Herpesvirus saimiri-mediated delivery of the adenomatous polyposis coli tumour suppressor gene reduces proliferation of colorectal cancer cells.
abstract: Colorectal cancer (CRC) is a major cause of cancer-related mortality. A contributing factor to the progression of this disease is sporadic or hereditary mutation of the adenomatous polyposis coli (APC) gene, a negative regulator of the Wnt signalling pathway. Inherited mutations in APC cause the disorder familial adenomatous polyposis (FAP), which leads to CRC development in early adulthood. However, the gene is also disrupted in some 60% of sporadic cancers. Restoration of functional APC may slow the growth of CRC by negatively regulating proliferation-associated genes such as c-myc. Therefore, we have cloned the cDNA of the APC tumour suppressor gene into a replication competent Herpesvirus saimiri (HVS)-based vector to assess APC gene delivery in SW480 and SW620 CRC cell lines. Our results demonstrate that full length APC protein was efficiently expressed from the HVS vector and that transgene expression inhibited proliferation of both the SW480 and the metastatic SW620 cancer cell lines. Moreover, a sustained effect could be observed for at least 8 weeks after initial infection in SW480 cells. In addition, monolayer wounding assays showed a marked reduction in proliferation and migration in HVS-GFP-APC infected cells. We believe that this is the first instance of infectious delivery and APC cDNA expression from a virus-based vector.
authors.affiliation: Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Macnab
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Turrell
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.forename: Alex F
authors.initials: AF
authors.lastname: Markham
authors.forename: P Louise
authors.initials: PL
authors.lastname: Coletta
authors.forename: Adrian
authors.initials: A
authors.lastname: Whitehouse
mesh_terms: D000818:Animals; D016645:Aotidae; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D023061:Gene Order; D018014:Gene Transfer Techniques; D017491:Genes, APC; D005822:Genetic Vectors / Q000235:genetics*; D045325:HCT116 Cells; D006567:Herpesvirus 2, Saimiriine / Q000235:genetics*; D006801:Humans; D014161:Transduction, Genetic; D019076:Transgenes