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  • Original Paper
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Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation

Oncogene volume 20, pages 1973–1980 (2001)Cite this article

Abstract

Urothelial tumors develop along two distinctive phenotypic pathways (superficial papillary non-invasive tumors versus flat carcinoma in situ lesions), with markedly different biological behavior and prognosis. Although multiple genetic alterations have been identified in human bladder cancer, their cause–effect relationship with the two pathways has not been firmly established. Using a urothelium-specific promoter of the uroplakin II gene, we showed earlier in transgenic mice that the urothelial expression of SV40T antigen, which inactivates p53 and pRb, induced carcinoma in situ and invasive and metastatic bladder cancer. In striking contrast, we demonstrate here that the urothelial expression of an activated Ha-ras in transgenic mice caused urothelial hyperplasia and superficial papillary non-invasive bladder tumors. These results provide strong, direct experimental evidence that the two phenotypical pathways of bladder tumorigenesis are caused by distinctive genetic defects. Our results indicate that Ha-ras activation can induce urothelial proliferation in vivo; and that urothelial hyperplasia is a precursor of low-grade, superficial papillary bladder tumors. Our transgenic models provide unique opportunities to study the detailed molecular events underlying different types of bladder neoplasms, and can serve as useful preclinical models for evaluating the in vivo efficacy of preventive and therapeutic agents that act on various signaling pathways in bladder cancer.

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Acknowledgements

We wish to thank Dr Herbert Lepor for his continued support and encouragement for this work. The current study was supported in part by a Merit Review grant from Veterans Administration Research Service to X-R Wu, and by NIH grants to X-R Wu (DK52206 and DK56903), A Pellicer (DK52206) and T-T Sun (DK52206, DK39753, DK57269).

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Authors and Affiliations

  1. Department of Urology, New York University School of Medicine, New York, 10016, NY, USA

    Zhong-Ting Zhang, Hong-Ying Huang, Ellen Shapiro, Tung-Tien Sun & Xue-Ru Wu

  2. Department of Microbiology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, 10016, NY, USA

    Xue-Ru Wu

  3. Department of Pathology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, 10016, NY, USA

    Angel Pellicer

  4. Department of Dermatology, New York University School of Medicine, New York, 10016, NY, USA

    Tung-Tien Sun

  5. Department of Pharmacology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, 10016, NY, USA

    Tung-Tien Sun

  6. The Department of Veterans Affairs Medical Center, New York, 10010, NY, USA

    Joanne Pak & Xue-Ru Wu

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Zhang, ZT., Pak, J., Huang, HY. et al. Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation. Oncogene 20, 1973–1980 (2001). https://doi.org/10.1038/sj.onc.1204315

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