Urothelial tumor initiation requires deregulation of multiple signaling pathways: Implications in target-based therapies

Haiping Zhou, Hong Ying Huang, Ellen Shapiro, Herbert Lepor, William C. Huang, Moosa Mohammadi, Ian Mohr, Moon Shong Tang, Chuanshu Huang, Xue Ru Wu

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Although formation of urothelial carcinoma of the bladder (UCB) requires multiple steps and proceeds along divergent pathways, the underlying genetic and molecular determinants for each step and pathway remain undefined. By developing transgenic mice expressing single or combinatorial genetic alterations in urothelium, we demonstrated here that overcoming oncogene-induced compensatory tumor barriers was critical for urothelial tumor initiation. Constitutively active Ha-ras (Ras*) elicited urothelial hyperplasia that was persistent and did not progress to tumors over a 10 months period. This resistance to tumorigenesis coincided with increased expression of p53 and all pRb family proteins. Expression of a Simian virus 40 T antigen (SV40T), which disables p53 and pRb family proteins, in urothelial cells expressing Ras* triggered early-onset, rapidly-growing and high-grade papillary UCB that strongly resembled the human counterpart (pTaG3). Urothelial cells expressing both Ras* and SV40T had defective G. 1/S checkpoint, elevated Ras-GTPase and hyperactivated AKT-mTOR signaling. Inhibition of the AKT-mTOR pathway with rapamycin significantly reduced the size of high-grade papillary UCB but hyperactivated mitogen-activated protein kinase (MAPK). Inhibition of AKT-mTOR, MAPK and STAT3 altogether resulted in much greater tumor reduction and longer survival than did inhibition of AKT-mTOR pathway alone. Our studies provide the first experimental evidence delineating the combinatorial genetic events required for initiating high-grade papillary UCB, a poorly defined and highly challenging clinical entity. Furthermore, they suggest that targeted therapy using a single agent such as rapamycin may not be highly effective in controlling high-grade UCB and that combination therapy employing inhibitors against multiple targets are more likely to achieve desirable therapeutic outcomes.

Original languageEnglish (US)
Pages (from-to)770-780
Number of pages11
JournalCarcinogenesis
Volume33
Issue number4
DOIs
StatePublished - 2012
Externally publishedYes

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Urinary Bladder
Papillary Carcinoma
Simian virus 40
Viral Tumor Antigens
Sirolimus
Neoplasms
Mitogen-Activated Protein Kinases
Carcinoma
Therapeutics
ras Proteins
Urothelium
Oncogenes
Transgenic Mice
Hyperplasia
Molecular Biology
Carcinogenesis
Proteins
Survival

ASJC Scopus subject areas

  • Cancer Research

Cite this

Zhou, H., Huang, H. Y., Shapiro, E., Lepor, H., Huang, W. C., Mohammadi, M., ... Wu, X. R. (2012). Urothelial tumor initiation requires deregulation of multiple signaling pathways: Implications in target-based therapies. Carcinogenesis, 33(4), 770-780. https://doi.org/10.1093/carcin/bgs025

Urothelial tumor initiation requires deregulation of multiple signaling pathways : Implications in target-based therapies. / Zhou, Haiping; Huang, Hong Ying; Shapiro, Ellen; Lepor, Herbert; Huang, William C.; Mohammadi, Moosa; Mohr, Ian; Tang, Moon Shong; Huang, Chuanshu; Wu, Xue Ru.

In: Carcinogenesis, Vol. 33, No. 4, 2012, p. 770-780.

Research output: Contribution to journalArticle

Zhou, H, Huang, HY, Shapiro, E, Lepor, H, Huang, WC, Mohammadi, M, Mohr, I, Tang, MS, Huang, C & Wu, XR 2012, 'Urothelial tumor initiation requires deregulation of multiple signaling pathways: Implications in target-based therapies', Carcinogenesis, vol. 33, no. 4, pp. 770-780. https://doi.org/10.1093/carcin/bgs025
Zhou, Haiping ; Huang, Hong Ying ; Shapiro, Ellen ; Lepor, Herbert ; Huang, William C. ; Mohammadi, Moosa ; Mohr, Ian ; Tang, Moon Shong ; Huang, Chuanshu ; Wu, Xue Ru. / Urothelial tumor initiation requires deregulation of multiple signaling pathways : Implications in target-based therapies. In: Carcinogenesis. 2012 ; Vol. 33, No. 4. pp. 770-780.
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