Genetic alterations in urothelial bladder carcinoma

Mhawech‐Fauceglia, Paulette; Cheney, Richard; Schwaller, Juerg

doi:10.1002/cncr.21743

Cited by 79 publications

(48 citation statements)

References 88 publications

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“…This is evident for prostate carcinoma, which does not occur with an elevated frequency in patients with Cowden's disease but nevertheless a high frequency of PTEN defects (70-80% of primary tumors) is observed in sporadic prostate carcinoma (52). Similarly, bladder cancer, which does not occur with an increased frequency in tuberous sclerosis patients, has been reported to have TSC1 defects in a significant proportion of sporadic tumors (18).…”

Section: Discussionmentioning

confidence: 97%

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Loss of Tuberous Sclerosis Complex-2 Function and Activation of Mammalian Target of Rapamycin Signaling in Endometrial Carcinoma

Dave

et al. 2008

Clinical Cancer Research

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Purpose: The involvement of phosphatase and tensin homologue deleted on chromosome ten (PTEN) in endometrial carcinoma has implicated phosphatidylinositol 3-kinase signaling and mammalian target of rapamycin (mTOR) activation in this disease. Understanding the extent of mTOR involvement and the mechanism responsible for activation is important, as mTOR inhibitors are currently being evaluated in clinical trials for endometrial carcinoma. Although tuberous sclerosis complex 2 (TSC2) is the ''gatekeeper'' for mTOR activation, little is known about defects in the TSC2 tumor suppressor or signaling pathways that regulate TSC2, such as LKB1/AMPactivated protein kinase, in the development of endometrial carcinoma. Experimental Design: We determined the frequency of mTOR activation in endometrial carcinoma (primary tumors and cell lines) and investigated PTEN, LKB1, and TSC2 defects as underlying cause(s) of mTOR activation, and determined the ability of rapamycin to reverse these signaling defects in endometrial carcinoma cells. Results: Activation of mTOR was a consistent feature in endometrial carcinomas and cell lines. In addition to PTEN, loss of TSC2 and LKB1 expression occurred in a significant fraction of primary tumors (13% and 21%, respectively). In tumors that retained TSC2 expression, phosphorylation of tuberin at S939 was observed with a high frequency, indicating that mTOR repression by TSC2 had been relieved via AKT phosphorylation of this tumor suppressor. In PTEN-null and LKB1-null endometrial carcinoma cell lines with functional inactivation of TSC2, phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 were able to inhibit AKT and mTOR signaling and reverseTSC2 phosphorylation. In contrast, although rapamycin inhibited mTOR signaling, it did not relieve phosphorylation of TSC2 at S939. Conclusions: Inactivation ofTSC2 via loss of expression or phosphorylation occurred frequently in endometrial carcinoma to activate mTOR signaling. High-frequency mTOR activation supports mTOR as a rational therapeutic target for endometrial carcinoma. However, whereas rapamycin and its analogues may be efficacious at inhibiting mTOR activity, these drugs do not reverse the functional inactivation of TSC2 that occurs in these tumors.

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Section: Discussionmentioning

confidence: 97%

“…Although not as well studied as either PTEN or LKB1, there is little evidence for the involvement of TSC1 or TSC2 in the development of sporadic tumors other than a subset of bladder carcinomas (TSC1; ref. 18), angiomyolipoma (19), and astrocytomas (20).…”

mentioning

confidence: 99%

Loss of Tuberous Sclerosis Complex-2 Function and Activation of Mammalian Target of Rapamycin Signaling in Endometrial Carcinoma

Dave

et al. 2008

Clinical Cancer Research

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“…Approximately 80% of urothelial carcinomas are of noninvasive type, these often being multifocal or recurrent (ϳ70%) but with limited muscle invasion (ϳ15%) and a good prognosis. 5 This type of tumor is often preceded by simple and nodular papillary urothelial hyperplasia and harbors frequent mutations in ras (30 to 40%) and fibroblast growth factor receptor 3 (ϳ70%) genes, 6,7 suggesting primary involvement of activation of receptor tyrosine kinase and oncogenic ras. In contrast, high-grade and muscle invasive cancers progress to local and distant metastases despite radical cystectomy or systemic chemotherapy.…”

mentioning

confidence: 99%

c-Jun NH2 Terminal Kinase Activation and Decreased Expression of Mitogen-Activated Protein Kinase Phosphatase-1 Play Important Roles in Invasion and Angiogenesis of Urothelial Carcinomas

Shimada

Nakamura

Ishida

et al. 2007

The American Journal of Pathology

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We here examined whether c-Jun NH 2 terminal kinase (JNK) might be involved in the progression of urothelial carcinomas. In vitro and in vivo invasion assays using Matrigel and chick embryo chorioallantoic membrane approaches showed constitutive activation of JNK to significantly increase two processes, invasion and angiogenesis, in the human urothelial carcinoma cell line kU-7, this being suppressed by a JNK inhibitor, SP600125, or cell-permeable peptides. In addition, we found that mitogen-activated protein kinase phosphatase (

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“…LGUD is commonly seen in patients with bladder neoplasia. In patients without urothelial neoplasia the risk of developing cancer has been estimated to only 19% in an 8-year mean follow-up when LUGD are present, while observed from 32 to 83% of patients when associated to Cis (19,20). One possible explanation is the coexistence of two main molecular pathways of bladder tumor progression involving p53 (from flat dysplasia to Cis) or loss of heterozygosity on chromosome 9 (from dysplasia to low-grade papillary carcinoma but no Cis), with common interactions and overlapping (19).…”

Section: Low Grade Urothelial Dysplasia (Lgud)mentioning

confidence: 99%

Fluorescence diagnosis and flat lesions of urothelium: New challenges for pathologists and urologists (Review)

Compérat¹

2009

Oncol Rep

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Abstract. Bladder cancer is a common malignancy. Recurrence rate and progression vary greatly depending on factors such as tumor multiplicity, size, previous recurrence rates, tumor stage, tumor grade and the presence of carcinoma in situ. Treatment is expensive, recent studies demonstrated that superficial bladder cancer is a major economic burden. It is necessary to establish new kinds of techniques to improve diagnosis, therapy and follow-up, such as fluorescence diagnosis, without adding significant risk of complications. As urologists have a better sight of bladder lesions with fluorescence diagnosis, pathologists will be asked in the future to evaluate more frequently flat lesions, which up to now would not have been a matter of concern. For several reasons it is very important to have accurate and precise definitions of these flat lesions. First to permit uniform treatment of large groups of patients and second to see in large cohorts the evolution and natural history of several flat lesions, not always well known up to now. The aim of the study was to review the most important flat lesions, to demonstrate the difficulty of classifying several lesions, to introduce to urologists the new problems linked to FD and to suggest new models for accurate analysis. How far can we go in our answer as pathologists and how will it change the patient management?

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Genetic alterations in urothelial bladder carcinoma

Cited by 79 publications

References 88 publications

Loss of Tuberous Sclerosis Complex-2 Function and Activation of Mammalian Target of Rapamycin Signaling in Endometrial Carcinoma

Loss of Tuberous Sclerosis Complex-2 Function and Activation of Mammalian Target of Rapamycin Signaling in Endometrial Carcinoma

c-Jun NH2 Terminal Kinase Activation and Decreased Expression of Mitogen-Activated Protein Kinase Phosphatase-1 Play Important Roles in Invasion and Angiogenesis of Urothelial Carcinomas

Fluorescence diagnosis and flat lesions of urothelium: New challenges for pathologists and urologists (Review)

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