Molecular pathogenesis of bladder cancer

Knowles, Margaret A.

doi:10.1007/s10147-008-0812-0

Cited by 107 publications

(110 citation statements)

References 98 publications

(94 reference statements)

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“…In superficial Ta bladder tumours, activation of Ras signalling is caused by gain-of-function mutations in HRAS, KRAS, NRAS and FGFR3. Although these mutations are less frequent in T 2 -T 4 bladder cancers, the RAS pathway seems to be affected in highstage tumours as well as by amplification/overexpression of different RTKs, including ERBB2 and ERBB1 (Knowles, 2008;Mitra and Cote, 2009). Two levels of Fra-1 upregulation via the RAS pathway, transcriptional and protein stabilisation, have been described previously (Casalino et al, 2003;.…”

Section: Discussionmentioning

confidence: 96%

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

et al. 2011

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Fos-related antigen 1 (Fra-1) is a Fos family member overexpressed in several types of human cancers. Here, we report that Fra-1 is highly expressed in the muscleinvasive form of the carcinoma of the bladder (80%) and to a lesser extent in superficial bladder cancer (42%). We demonstrate that in this type of cancer Fra-1 is regulated via a C-terminal instability signal and C-terminal phosphorylation. We show that manipulation of Fra-1 expression levels in bladder cancer cell lines affects cell morphology, motility and proliferation. The gene coding for AXL tyrosine kinase is directly upregulated by Fra-1 in bladder cancer and in other cell lines. Importantly, our data demonstrate that AXL mediates the effect of Fra-1 on tumour cell motility but not on cell proliferation. We suggest that AXL may represent an attractive therapeutic target in cancers expressing high Fra-1 levels.

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Section: Discussionmentioning

confidence: 96%

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

et al. 2011

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“…TCCs represent the absolute majority of bladder tumors and are divided into two types, non-muscle invasive (ϳ70%) and muscle invasive (15). In many cases, muscle invasive TCC manifest metastatic features that represent a major cause of death.…”

Section: E Pithelial Mesenchymal Transition (Emt) Is a Genetic Programmentioning

confidence: 99%

SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer

Sayan

Griffiths

Pal

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

170

163

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The epithelial-mesenchymal transition (EMT) contributes to cancer metastasis. Two ZEB family members, ZEB1 and ZEB2(SIP1), inhibit transcription of the E-cadherin gene and induce EMT in vitro. However, their relevance to human cancer is insufficiently studied. Here, we performed a comparative study of SIP1 and ZEB1 proteins in cancer cell lines and in one form of human malignancy, carcinoma of the bladder. Whereas ZEB1 protein was expressed in all E-cadherin-negative carcinoma cell lines, being in part responsible for the high motility of bladder cancer cells, SIP1 was hardly ever detectable in carcinoma cells in culture. However, SIP1 represented an independent factor of poor prognosis (P ‫؍‬ 0.005) in a series of bladder cancer specimens obtained from patients treated with radiotherapy. In contrast, ZEB1 was rarely expressed in tumor tissues; and E-cadherin status did not correlate with the patients' survival. SIP1 protected cells from UV-and cisplatin-induced apoptosis in vitro but had no effect on the level of DNA damage. The anti-apoptotic effect of SIP1 was independent of either cell cycle arrest or loss of cell-cell adhesion and was associated with reduced phosphorylation of ATM/ATR targets in UV-treated cells. The prognostic value of SIP1 and its role in DNA damage response establish a link between genetic instability and metastasis and suggest a potential importance for this protein as a therapeutic target. In addition, we conclude that the nature of an EMT pathway rather than the deregulation of E-cadherin per se is critical for the progression of the disease and patients' survival. E pithelial mesenchymal transition (EMT) is a genetic program controlling cell migration during embryonic development and in wound healing (1, 2). Aberrant activation of EMT programs occurs in cells of epithelial tumors and contributes to the formation of cancer stem cells and metastasis (1-4). EMT is characterized by the loss of epithelial and the acquisition of mesenchymal features. EMT programs are controlled by several master regulators including TWIST, SNAIL (SNAI1 and SNAI2), and ZEB (ZEB1/␦EF1/TCF8 and SIP1/ZEB2) protein family members. These proteins act downstream in EMTinducing signal transduction pathways activated by growth factors, integrin engagement and hypoxia (1-3). Their expression is tightly regulated at the posttranscriptional level. Recent reports highlighted the importance of miR-200 microRNA family in the regulation of ZEB1 and SIP1 protein expression (5). ZEB proteins bind proximal E-boxes within the E-cadherin gene (cdh1) promoter and repress transcription by recruiting corepressor complexes (6). Likewise, they directly repress numerous genes encoding components of the epithelial junctional complex and cell polarity factors (7,8). The relevance of ZEB proteins to tumor progression has been studied in several forms of human cancer. Expression of ZEB1 correlated with the aggressive phenotype in various histological types of endometrial carcinoma and was detected in sarcomatous compartment of endometri...

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“…29 Me sa ne kan se riy le iliş-ki li çe şit li on ko gen ler ve tü mör bas kı la yı cı gen ler ile çe şit li kro mo zom böl ge le ri tes pit edil miş tir (Tab lo 1). 5 İkin ci grup ta bu lu nan tü mör bas kı la yı cı genler se on ko gen le rin ter si ne hüc re ço ğal ma sı nı in hibe edi ci özel lik te dir. Bu gen ler, kan ser ge li şi mi ne et ki le ri ba kı mın dan re se sif özel lik te dir ler.…”

Section: Me Sa Ne Kan Se Ri̇ Ni̇n Eti̇ Yo Lo Ji̇ Si̇unclassified

The Role of Molecular Mechanisms in the Development of Bladder Carcinoma: Review

Altayli¹,

Güneş²

2011

Turkiye Klinikleri J Med Sci

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Ö ÖZ ZE ET T Kanser türleri içinde önemli bir yer tutan mesane kanseri, Batı ülkelerinde yapılan çalışmalara göre sıklık sıralamasında erkeklerde dördüncü sırayla tüm kanserlerin %5-10'unu, kadınlardaysa sekizinci sıradaki yeriyle % 4'ünü oluşturmaktadır. Mesane kanserinin etiyolojisi, büyük oranda bilinmemekle birlikte, çevresel, demografik ve genetik faktörlerin etkili olduğu düşünülmektedir. Mesane kanserinin gelişiminde rol oynayan çevresel faktörler; sigara, mesleki karsinojenler, şistozomiyazis, kronik sistit, tedavi amaçlı siklofosfamid kullanımı ve pelvik radyoterapidir. Mesane kanserinin gelişiminde rol oynayan demografik faktörler cinsiyet, ırk ve yaştır. Mesane kanserinin gelişiminde çok sayıda onkogenlerin ve tümör süpresör genlerin çeşitli seviyelerdeki mutasyonları önemli rol oynamaktadır. Onkogenler, hücresel seviyede dominant etkiye sahip genlerdir; yani aktive edildiklerinde veya ekspresyon seviyeleri arttığında tek bir mutant allel, bir hücreyi normal fenotipten malign fenotipe dönüştürmeye yetebilir. Mesane kanseriyle ilişkili en iyi bilinen onkogenler; H-ras, erb-B2 ve c-myc'dir. Tümör baskılayıcı genlerse onkogenlerin tersine hücre çoğalmasını inhibe edici özelliktedir. Tümör baskılayıcı genlerin, kanser gelişiminde etkili olabilmesi için her iki allelinin fonksiyonunu yitirmesi gerekir ve dolayısıyla bu genler, kanser gelişimindeki etkileri bakımından resesif özelliktedirler. Kromozom 13q'daki retinoblastoma geni (Rb) ve kromozom 17p'deki p53 geni, en iyi çalışılmış tümör baskılayıcı gendir. Kanserin ilerlemesinde anjiyogenez gelişimi, hücre dışı matriks ve hücre adezyon moleküllerindeki çeşitli anormallikler etkili olmaktadır. Ayrıca mesane kanserinin gelişiminde ve ilerlemesinde, mikrosatellit kararsızlığıyla çeşitli epigenetik faktörlerin de etkili olduğu gösterilmiştir. Mesane kanserinin gelişiminde ve ilerlemesinde rol oynayan karmaşık mekanizmaların anlaşılması için yeni çalışmalara ihtiyaç vardır.A An na ah h t ta ar r K Ke e l li i m me e l le er r: : Mesane tümörleri; onkojenler; genler, tümör baskılayıcı; karsinojenler; mutasyon; hücre yapışma molekülleri; çok biçimlilik, genetik A AB BS S T TR RA AC CT T Studies performed in Western countries has proven that the bladder carcinoma, which occupies an important place among all cancers, constitutes 5-10% of all male cancers and is the fourth most common cancer in males, while it is eighth most common cancer in females and constitutes 4% of all female cancers. Although etiology of bladder carcinoma is not clearly known, environmental, demographic and genetic factors are thought to be influential. The environmental factors that play role in the development of bladder carcinoma are smoking, occupational carcinogens, schistosomiasis, chronic cystitis, administration of cyclophosphamide for therapeutic purposes and pelvic radiotherapy. Demographic factors that play a role in the development of bladder carcinoma are gender, race and age. The mutations on the different levels of tumor suppressor genes and oncogenes have an important role in...

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Molecular pathogenesis of bladder cancer

Cited by 107 publications

References 98 publications

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer

The Role of Molecular Mechanisms in the Development of Bladder Carcinoma: Review

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