Abstract
To properly evaluate the biological effects of immunotherapy, it is critical to utilize a model of cancer in immune-competent mice. Currently, MBT-2 is the most common murine bladder cancer cell line used in orthotopic bladder cancer models, even though this cell type often has an inappropriate genetic mutation landscape. In these models, after tumors are detected with in vivo imaging, the mouse usually dies within two to three weeks due to post-renal azotemia caused by the rapidly growing mass. This event prohibits the evaluation of tumor behavior upon intravesical drug treatment. We explored whether an shRNA-induced decrease in the expression of the c-myc oncogene in MBT-2 cells could slow down their in vitro proliferation and in vivo tumor growth. We transduced MBT-2 cells with shRNA lentiviruses that bound c-myc, established MBT2.cMYCshRNA and confirmed the retardation of the growth of tumors implanted in C3H/He mice. Accordingly, this study suggests that this novel orthotopic bladder cancer model in immune-competent mice may be more appropriate for the analysis of the effects of the intravesical instillation of immunotherapeutic agents.
Highlights
Non-muscle-invasive bladder cancer (NMIBC) accounts for > 70% of all newly diagnosed cases of bladder cancer
To prevent recurrence and progression, intravesical Bacillus Calmette-Guerin (BCG) immunotherapy or intravesical chemotherapy are used as adjuvant therapies; a substantial number of patients do not complete this therapy owing to refractory disease or intolerance [1]
To effectively evaluate the effect of intravesical therapy in bladder cancer, an animal model must meet several requirements: 1) the tumor is of urothelial origin, with different stages of disease progression; 2) the tumor grows intravesically and can be directly exposed to antineoplastic drugs; and 3) it mimics the clinical course of human urinary bladder cancer
Summary
Non-muscle-invasive bladder cancer (NMIBC) accounts for > 70% of all newly diagnosed cases of bladder cancer. After the bladder tumors are detected with non-invasive in vivo imaging, such as MRI or bioluminescence imaging, the mouse dies within two to three weeks due to azotemia [5] This outcome makes it impossible to observe long-term tumor responses after intravesical immunotherapeutic treatments. We explored whether the moderate siRNA-induced down-regulation of c-myc expression in MBT-2 cells decreases cell proliferation and tumor growth in an orthotopic model of bladder cancer. These results may help facilitate the establishment of an appropriate murine bladder tumor model
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