Abstract
Muscle-invasive bladder cancer (MIBC) is associated with low survival and high recurrence rates even in cases in which patients receive systemic treatments, such as surgery and chemotherapy. Here, we found that a naturally existing alphavirus, namely, M1, selectively kills bladder cancer cells but not normal cells, findings supported by our observations of changes in viral replication and MIBC and patient-derived MIBC cell apoptosis. Transcriptome analysis revealed that interferon-stimulated genes (ISGs) are expressed at low levels in sensitive bladder cancer cells and high levels in resistant cells. Knocking down ZC3HAV1 (ZAP), an antiviral factor in ISGs, restores M1 virus reactivity in resistant cells, and overexpressing ZAP partially reverses M1 virus-induced decreases in cell viability in sensitive cells. In orthotopic MIBC mice, tail vein injections of M1 significant inhibit tumor growth and prolong survival period, antitumor effects of M1 are stronger than those of the first-line chemotherapy agent cisplatin (CDDP). Treated tumors display enhanced cleaved-caspase-3 signals, which are representative of cell apoptosis, and decreased Ki-67 signals, which are representative of cell proliferation. Moreover, tissue microarray (TMA) analyses of clinical tumor specimens revealed that up to 45.6% of cases of MIBC presented with low ZAP expression, a finding that is prevalent in advanced MIBC. Our results indicate that the oncolytic virus M1 is a novel agent capable of functioning as a precise and effective therapy for MIBC.
Highlights
Bladder cancer is the most common malignancy of the urinary system[1], approximately one-quarter of bladder cancers are muscle-invasive bladder cancers (MIBCs)[2], whose incidence and mortality are elevated in China[3]
We compared the antitumor effects of M1 on two bladder cancer cell lines (T24 and UM-UC-3) and a normal cell line (SV-HUC-1) with those of conventional chemotherapy drugs, we found that the cell viability was lower after the treatment of M1 in bladder cancer T24 and UM-UC-3 cells, higher in normal bladder cell SVHUC-1 compared with cisplatin (Fig. 1c)
Surgery and chemotherapy remain the only treatments for MIBC; the post-surgery complication rate is high[20]
Summary
Bladder cancer is the most common malignancy of the urinary system[1], approximately one-quarter of bladder cancers are muscle-invasive bladder cancers (MIBCs)[2], whose incidence and mortality are elevated in China[3]. Radical cystectomy and cisplatin (cis-diamminedichloridoplatinum (CDDP))-based chemotherapy remain the standard first-line treatments for MIBC. Radical cystectomy and urinary diversion facilitate total removal of the primary tumor, affected patients must subsequently endure multiple reconstructive surgeries, and the 5-year survival rate among patients receiving these treatments is only 40–60%5. Cisplatin-based chemotherapy has been reported to yield a 6-year progression-free survival rate of 3.7%6, this regimen is highly toxic to patients and is even associated with a mortality rate of approximately 4%7. Comprehensive assessments of the benefits, risks, and side effects of cisplatin-based chemotherapy indicate that this therapy is not appropriate for part of post-surgery patients or patients with end-stage disease[8]. New approaches to the treatment of Official journal of the Cell Death Differentiation Association
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