Abstract
Stem cell-like colon cancer cells (SCCs) pose a major challenge in colon cancer treatment because of their resistance to chemotherapy and radiotherapy. Oncolytic virus-based therapy has shown promising results in uncured cancer patients; however, its effects on SCCs are not well studied yet. Here, we engineered a cancer-favoring oncolytic vaccinia virus (CVV) as a potent biotherapeutic and investigated its therapeutic efficacy in terms of killing SCCs. CVV is an evolved Wyeth strain vaccinia virus (EVV) lacking the viral thymidine kinase. SCC models were established using human or mouse colon cancer spheres, which continuously expressed stemness markers. The cancer-favoring characteristics and different cytotoxic pathways for killing cancer cells successfully overrode general drug resistance, thereby killing colon cancer cells regardless of the presence of SCCs. Subcutaneously injected HT29 spheres showed lower growth in CVV-treated models than in 5-Fu-treated models. Intraperitoneally injected CT26 spheres induced tumor masses in the abdominal region. CVV-treated groups showed higher survival rates and smaller tumor mass formation, compared to 5-Fu-treated groups. Interestingly, the combined treatment of CVV with 5-Fu showed improved survival rates and complete suppression of tumor mass. The CVV developed in this study, thus, effectively suppresses SCCs, which can be synergistically enhanced by simultaneous treatment with the anticancer drug 5-Fu. Our novel CVV is highly advantageous as a next-generation therapeutic for treating colon cancer.
Highlights
Cancer is one of the leading causes of death, with a mortality rate of approximately 14% worldwide
cancer-favoring oncolytic vaccinia virus (CVV) was generated by replacing the viral thymidine kinase (vTK) gene from a naturally evolved cancer-favoring Wyeth strain vaccinia virus (EVV) strain [19] with the green fluorescence protein gene (Figure 1A)
evolved Wyeth strain vaccinia virus (EVV) was constructed from the Wyeth strain of vaccinia virus to achieve the cancer-favoring property and isolated and characterized by repeated replication and tumor tissue lysis [19]
Summary
Cancer is one of the leading causes of death, with a mortality rate (deaths per 1,000 individuals per year) of approximately 14% worldwide. Despite advances in anticancer drug development, most CRCs are resistant to conventional cancer therapy. This poor responsiveness to chemo- and/or radiotherapy might be attributed to stem cell-like colon cancer cells (SCCs) [3]. It is generally accepted that cancer stem cells (CSCs) are capable of self-renewal and have the exclusive ability to reproduce malignant tumors even though CSCs constitute a minor population in tumors. Drug resistance and tumor recurrence after the initial response to chemo- or radiotherapy may be due to the survival of CSCs within the original tumor. SCCs pose a considerable challenge and are considered the target in colon cancer treatment
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