Skip to main content
  • Poster presentation
  • Open access
  • Published:

Metformin inhibits urothelial tumorigenesis in the UPII-mutant Ha-ras transgenic mouse model

Background

Bladder cancer occurs mainly in older people and is expensive to manage. As the population continues to age, bladder cancer may remain to be a major public health burden. Therefore, we hypothesized that an agent, like metformin, with anti-aging property could have preventive activity against the development and progression of human urinary bladder cancer.

Materials and methods

The UPII mutant Ha-ras transgenic mouse model mimics human papillary transitional urothelial cell carcinoma and exhibits enhanced mTOR activity in tumor tissues. Homozygous UPII mutant Ha-ras transgenic mice were identified through genotyping using the Southern blotting method. Genotyped Ha-ras mice were then fed orally with normal drinking water or 0.1% or 0.05% metformin in drinking water starting at 6 weeks of age and ending at 6 months of age. Death rate, body weight, tumor burden, and proliferative and apoptotic indices at the end of treatments will be evaluated by pathological and statistical analyses.

Results

About 62% of male, homozygous mutant Ha-ras transgenic mice which drank normal water died of urinary tract obstruction and hydronephrosis within 6 months of age, while only about 11% or 15% of mice which drank 0.1% or 0.05% metformin containing water died. Drinking metformin dramatically increased the survival of mutant Ha-ras tumor bearing mice by 51 to 47% (Ps<0.01). Metformin drinking also significantly decreased the mean bladder weights of male, homozygous mutant Ha-ras transgenic mice by up to 62%. Histological analysis of H&E stained bladder sections from metformin treated mice demonstrated more differentiated tumors compared to those in control groups. The in vivo mechanisms of metformin’s action are associated with anti-proliferation, reduction of phospho-mTOR and 4E-BP1 expression and induction of TSC2 expression in bladder tissues.

Conclusions

Our results demonstrated strong in vivo anti-urothelial tumorigenesis activity of metformin drinking in the UPII-mutant H-ras model via inhibition of the mTOR pathway. These results suggested the potential of metformin in preventing recurrence of clinical bladder cancer and in improving quality of life for patients.

Author information

Authors and Affiliations

Authors

Rights and permissions

Open Access  This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.

The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Z., Yokoyama, N., Pollak, M. et al. Metformin inhibits urothelial tumorigenesis in the UPII-mutant Ha-ras transgenic mouse model. Cancer Metab 2 (Suppl 1), P90 (2014). https://doi.org/10.1186/2049-3002-2-S1-P90

Download citation

  • Published:

  • DOI: https://doi.org/10.1186/2049-3002-2-S1-P90

Keywords