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

Zhang, Zhong Ting; Pak, Joanne; Huang, Hong; Shapiro, Ellen; Sun, Tung‐Tien; Pellicer, A.; Wu, Xue-Ru

doi:10.1038/sj.onc.1204315

Cited by 142 publications

(128 citation statements)

References 44 publications

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“…Finally, we found a significant association of the impaired DNp63 expression with reduced b-catenin expression that relates to a worse prognosis of bladder cancer patients (Garcia del Muro et al, 2000;Shimazui et al, 1996). Recently, experimental studies on transgenic mice have provided strong evidences that different genetic defects are responsible for the two distinctive pathways of urothelial tumorigenesis (Zhang et al, 1999(Zhang et al, , 2001). Activation of Ha-ras alone, which plays a central role in mitogenic signal transduction, induces urothelial hyperplasia and papillary noninvasive tumours but not invasive carcinomas (Zhang et al, 2001), indicating that increased cell proliferation alone can lead to development of the papillary noninvasive urothelial tumour.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, experimental studies on transgenic mice have provided strong evidences that different genetic defects are responsible for the two distinctive pathways of urothelial tumorigenesis (Zhang et al, 1999(Zhang et al, , 2001). Activation of Ha-ras alone, which plays a central role in mitogenic signal transduction, induces urothelial hyperplasia and papillary noninvasive tumours but not invasive carcinomas (Zhang et al, 2001), indicating that increased cell proliferation alone can lead to development of the papillary noninvasive urothelial tumour. On the other hand, inactivation of p53 and pRb by SV40 large T antigen induces CIS, invasive carcinoma, and metastatic disease (Zhang et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

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Impaired ΔNp63 expression associates with reduced β-catenin and aggressive phenotypes of urothelial neoplasms

et al. 2003

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p63, a homologue of the p53 gene, is considered to be essential for the normal development of stratified epithelia including urothelium. To examine possible roles of p63 in urothelial tumorigenesis, p63 expression was systematically examined in normal urothelium, low-grade papillary noninvasive (LPN) urothelial tumours, and high-grade or invasive carcinomas, using either an isoformnonspecific or a DN-isoform-specific antibody. Expression profiles of p63 were also analysed in cultured cells. Immunoreactivity with the two antibodies was virtually identical in tissue samples examined. Basal and intermediate cell layers of normal urothelium showed intense nuclear p63 immunostaining. This normal staining pattern was preserved in a majority of LPN tumours, whereas it was frequently impaired in high-grade or muscle-invasive carcinomas. At the mRNA level, DNp63 expression predominated over TAp63, and amounts of DNp63 mRNA correlated with p63 immunoreactivity, confirming that DNp63 accounts for p63 expressed in urothelial tissues. In cultured cells, DNp63 was also expressed in low-grade tumour cells as well as normal urothelial cells, but undetectable in high-grade aggressive carcinoma cells. Interestingly, impaired DNp63 expression significantly associated with reduced b-catenin expression that was possibly related to progression of urothelial neoplasms. Thus, impaired DNp63 expression characterises aggressive phenotypes of urothelial neoplasms.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impaired ΔNp63 expression associates with reduced β-catenin and aggressive phenotypes of urothelial neoplasms

et al. 2003

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“…This promoter exhibits several properties that are important for transgenesis: (1) it functions in a strictly urothelium-specific manner; (2) it is active in all mouse urothelial layers, including the basal layer that is more susceptible to oncogenic transformation; and (3) its expression persists even after malignant transformation (Lin et al, 1995;Zhang et al, 1999). Using this promoter to develop transgenic mouse models, we found that urothelial expression of an activated Ha-ras can induce urothelial hyperplasia and low-grade, superficial papillary tumors (Zhang et al, 2001). The onset of the bladder tumors depends on the dosage of the uroplakin II-Ha-ras transgene, as mice harboring 30-50 copies of the transgene develop tumors at 4-5 months of age and mice harboring 1-2 copies of the transgene develop only urothelial hyperplasia before 10 months of age, after which 63% of the mice develop the bladder tumors (Zhang et al, 2001).…”

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p53 deficiency provokes urothelial proliferation and synergizes with activated Ha-ras in promoting urothelial tumorigenesis

et al. 2004

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Mutation and deletion of the p53 tumor suppressor gene are arguably the most prevalent among the multiple genetic alterations found in human bladder cancer, but these p53 defects are primarily associated with the advanced diseases, and their roles in bladder tumor initiation and in synergizing with oncogenes in tumor progression have yet to be defined. Using the mouse uroplakin II gene promoter, we have targeted into urothelium of transgenic mice a dominant-negative mutant of p53 that lacks the DNA-binding domain but retains the tetramerization domain. Urothelium-expressed p53 mutant binds to and stabilizes the endogenous wild-type p53, induces nuclear abnormality, hyperplasia and occasionally dysplasia, without eliciting frank carcinomas. Concurrent expression of the p53 mutant with an activated Ha-ras, the latter of which alone induces urothelial hyperplasia, fails to accelerate tumor formation. In contrast, the expression of the activated Ha-ras in the absence of p53, as accomplished by crossing the activated Ha-ras transgenic mice with the p53 knockout mice, results in early-onset bladder tumors that are either low-grade superficial papillary or high grade in nature. These results provide the first in vivo experimental evidence that p53 deficiency predisposes the urothelium to hyperproliferation, but is insufficient for bladder tumorigenesis; that the mere reduction of p53 dosage, as produced in transgenic mice expressing the dominant-negative p53 or in heterozygous p53 knockouts, is incapable of synergizing with Ha-ras to induce bladder tumors; and that the complete loss of p53 is a prerequisite for collaborating with activated Ha-ras to promote bladder tumorigenesis.

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“…These "superficial" tumors are therefore rarely lethal, but their high recurrence rates coupled with patient longevity make them the most expensive solid tumors to treat and therefore a significant public health burden. Superficial tumors are thought to be driven by Ras pathway activation (2), most often (in up to 65% of cases) via the accumulation of activating mutations in the type 3 fibroblast growth factor receptor (3) and less often via mutations in phosphoinositide 3-kinase (4) or Ras itself. The second progression track involves the inactivation of major tumor suppressors [p53, Rb, and phosphatase and tensin homologue (PTEN); refs.…”

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The Molecular, the Bad, and the Ugly: Preventing Bladder Cancer via mTOR Inhibition

McConkey

Dinney

2009

Cancer Prevention Research

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This perspective on Seager et al. (beginning on p. 1008) considers an important advance in the effort to control bladder cancer. Frontline therapy for superficial transitional cell carcinoma of the bladder involves instillation of the crude immunomodulatory bacterial extract Bacillus Calmette-Guérin directly into the organ. Seager et al. now show that local administration of a chemical inhibitor of mammalian target of rapamycin strongly suppressed growth in a novel preclinical mouse model that develops carcinoma in situ, a particularly problematic form of transitional cell carcinoma of the bladder. The results not only support the clinical evaluation of mammalian target of rapamycin inhibitors in this setting, they open the door for the evaluation of additional molecular local therapies as well.It is well established that bladder cancer develops along two major molecular tracks (1). The first track is characterized by the development of papillary lesions that rarely become invasive or metastatic but almost always recur (1). These "superficial" tumors are therefore rarely lethal, but their high recurrence rates coupled with patient longevity make them the most expensive solid tumors to treat and therefore a significant public health burden. Superficial tumors are thought to be driven by Ras pathway activation (2), most often (in up to 65% of cases) via the accumulation of activating mutations in the type 3 fibroblast growth factor receptor (3) and less often via mutations in phosphoinositide 3-kinase (4) or Ras itself. The second progression track involves the inactivation of major tumor suppressors [p53, Rb, and phosphatase and tensin homologue (PTEN); refs. 1, 4, 5], and it produces tumors that are highly invasive and metastatic. Although ∼50% of these muscle-invasive tumors respond well to cisplatin-based therapies (6, 7), the other half is highly refractory to all current regimens and leads to rapid mortality.Although superficial and muscle-invasive bladder cancers are considered distinct diseases, there is a form of superficial (non-muscle-invasive) cancer, which is called carcinoma in situ (CIS), that often does appear to progress to muscleinvasive disease (8). This form of bladder cancer is characterized by the presence of flat, dysplastic lesions that can involve the whole bladder mucosa via the "field effect." Current frontline therapy for CIS involves intravesical therapy with the immunomodulator Bacillus Calmette-Guérin (BCG), which produces responses in a majority of patients (9). However, BCG has significant negative side effects, responsive patients recur at a high rate, and there are no effective treatment options for patients who develop BCG-refractory disease. Therefore, it would be of great value to identify less toxic, effective strategies to prevent CIS progression.Abate-Shen's laboratory recently showed that nearly 100% of 6-to 8-week-old animals undergoing conditional inactivation of p53 and PTEN via adenoviral Cre delivery to the urothelium develop muscle-invasive tumors by the time...

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

Cited by 142 publications

References 44 publications

Impaired ΔNp63 expression associates with reduced β-catenin and aggressive phenotypes of urothelial neoplasms

Impaired ΔNp63 expression associates with reduced β-catenin and aggressive phenotypes of urothelial neoplasms

p53 deficiency provokes urothelial proliferation and synergizes with activated Ha-ras in promoting urothelial tumorigenesis

The Molecular, the Bad, and the Ugly: Preventing Bladder Cancer via mTOR Inhibition

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