Abstract
Oncolytic virotherapy is a distinctive antitumor therapy based on the cancer-cell-specific infectivity and killing activity of viruses, which exert a considerable antitumor effect with only a few treatments. Because colorectal cancer cells often acquire resistance to the molecular-targeted therapies and alternative treatments are called for, in this study, we evaluated the oncolytic activity against colorectal cancer cells of a recombinant measles virus (rMV-SLAMblind), which is blind to signaling lymphocytic activation molecule (SLAM) and infects target cells via nectin-4/poliovirus receptor-related 4 protein. We examined 10 cell lines including 8 cell lines that were resistant to epidermal-growth-factor-receptor (EGFR) targeted therapy. rMV-SLAMblind infected and lysed the nectin-4-positive cell lines dependently on nectin-4 expression, in spite of mutation in EGFR cascade. Tumour progression in xenograft models was also abrogated by the virus, and the infection of cancer cells in vivo by the virus was demonstrated with both flow cytometry and a histological analysis. Therefore, rMV-SLAMblind is considered a novel therapeutic agent for colorectal cancers, including those resistant to molecular-targeted therapies.
Highlights
Oncolytic virotherapy is a promising approach to the eradication of cancers[10,11], because it takes advantage of the natural or acquired characteristics of a virus to target cancer cells[10,11]
We analysed the expression of these receptors and observed that all the cell lines tested were negative for signaling lymphocytic activation molecule (SLAM) and positive for CD46 (Fig. 1a)
Higher expression of nectin-4 messenger RNA (mRNA) was observed in the cells that were positive for nectin-4 in the flow-cytometric analysis than in those that were nectin-4-negative on flow cytometry (Fig. 1a,b)
Summary
Oncolytic virotherapy is a promising approach to the eradication of cancers[10,11], because it takes advantage of the natural or acquired characteristics of a virus to target cancer cells[10,11]. We recently demonstrated that genetically modified recombinant measles virus (rMV), which is derived from a wild-type MV (HL strain) but is blind to the signaling lymphocyte activation molecule (SLAM/CD150) protein (rMV-SLAMblind), selectively infected and killed breast cancer cells in a nectin-4/poliovirus receptor-related 4-dependent manner[13]. Both SLAM and nectin-4 have been shown to be MV receptors[14,15,16]. SLAM expression is observed in a wide range of immune cells[17], and www.nature.com/scientificreports/. We examined the antitumor effects of rMV-SLAMblind on colorectal cancer cells to investigate whether rMV-SLAMblind is an effective agent for treatment of colorectal cancer, especially with resistance to molecular targeted therapies
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