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Updated: May 3, 2026
An Orthotopic Bladder Tumor Model and the Evaluation of Intravesical saRNA Treatment
Published on: July 28, 2012
Metformin as an anti-cancer agent against bladder cancer acts via PD-L1 downregulation in an orthotopic mouse model
Chang-Ching Yeh1, Pei-Chu Tsai1, Yung-Deng Song1
1National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
Background:
PD-L1 is a crucial immune checkpoint protein that limits the effectiveness of antitumor immunity. Blocking the PD-L1/PD-1 pathway has shown promise in cancer treatment, but low response rates to checkpoint inhibitors highlight the need for alternative therapeutic strategies. Metformin, a drug primarily used for diabetes, has gained attention as a potential cancer treatment due to its effects on PD-L1 expression, the tumor microenvironment, and its ability to inhibit the proliferation of tumor cells. Meta-analyses suggest that metformin may reduce the incidence and improve the prognosis of bladder cancer in patients with type 2 diabetes, but the exact mechanisms by which it exerts its effects remain unclear.
Materials:
This study employed a syngeneic orthotopic bladder cancer model with immunocompetent C57BL/6 mice to evaluate metformin's therapeutic effects. Safe dosage was established through a maximum tolerated dose (MTD) test, identifying 150 mg/kg/day as suitable. Tumor size, body weight, survival, and PD-L1 expression were measured, while a tetrazolium-based assay assessed bladder cancer cell proliferation in vitro.
Results:
Findings revealed elevated PD-L1 gene and protein expression in mouse bladder cancer tissues. In vitro, metformin inhibited PD-L1 expression and proliferation of MB49 mouse bladder cancer cells. In vivo, metformin reduced cancer cachexia, tumor size, and improved survival at 150 mg/kg/day. Importantly, metformin attenuated tumor-induced PD-L1 upregulation in a dose-dependent manner.
Conclusion:
Overall, this study suggests that bladder tumors can increase PD-L1 expression to promote PD-L1-mediated intrinsic tumor growth pathways, and metformin effectively downregulates PD-L1 expression, suppresses bladder cancer cell proliferation, and prolongs survival in an orthotopic bladder cancer mouse model.
Insights
Metformin, a diabetes drug, shows promise in treating bladder cancer by reducing programmed death-ligand 1 (PD-L1) expression and inhibiting tumor cell growth. This study demonstrates metformin
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Programmed death-ligand 1 (PD-L1) is an immune checkpoint protein that can limit anti-tumor immunity.
- While PD-L1/PD-1 pathway blockade shows cancer treatment promise, low response rates necessitate alternative strategies.
- Metformin, a diabetes drug, is being investigated for cancer treatment due to its potential to modulate the tumor microenvironment and inhibit cancer cell proliferation.
Purpose of the Study:
- To investigate the therapeutic effects of metformin on bladder cancer.
- To evaluate metformin's impact on PD-L1 expression and tumor cell proliferation in an orthotopic bladder cancer mouse model.
Main Methods:
- A syngeneic orthotopic bladder cancer model using C57BL/6 mice was established.
- Metformin's maximum tolerated dose (MTD) was determined to be 150 mg/kg/day.
- Tumor size, survival, body weight, and PD-L1 expression were assessed; in vitro proliferation was measured using a tetrazolium-based assay.
Main Results:
- Metformin inhibited PD-L1 gene and protein expression in mouse bladder cancer cells in vitro.
- In vivo, metformin (150 mg/kg/day) reduced tumor size, alleviated cancer cachexia, and improved survival.
- Metformin dose-dependently attenuated tumor-induced PD-L1 upregulation.
Conclusions:
- Bladder tumors can upregulate PD-L1 to promote intrinsic growth pathways.
- Metformin effectively downregulates PD-L1 expression in bladder cancer.
- Metformin suppresses bladder cancer cell proliferation and prolongs survival in a preclinical model.
