Urinary Bladder Transitional Cell Carcinogenesis Is Associated with Down-Regulation of NF1 Tumor Suppressor Gene in Vivo and in Vitro

Aaltonen, Vesa; Boström, Peter J.; Söderström, Karl‐Ove; Hirvonen, Outi; Tuukkanen, Juha; Nurmi, Martti; Laato, Matti; Peltonen, Juha

doi:10.1016/s0002-9440(10)65322-9

Cited by 35 publications

(32 citation statements)

References 44 publications

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“…The absence of the NF1 inhibitory effect will favor increased cell proliferation, as found in the superficial tumor compartments of muscle-invasive TCC (Blanes et al, 1999). Likewise, Aaltonen et al (1999) have reported a decreased NF1 mRNA and protein levels in high-grade TCC, suggesting that alterations in NF1 gene expression may be involved in bladder carcinogenesis. On the other hand, we found TP53 abnormalities in 29 of 43 informative cases (67.4%), after screening two introns.…”

Section: Diaz-cano Et Almentioning

confidence: 97%

Molecular Evolution and Intratumor Heterogeneity by Topographic Compartments in Muscle-Invasive Transitional Cell Carcinoma of the Urinary Bladder

Díaz‐Cano

Blanes²,

Rubio³

et al. 2000

Laboratory Investigation

122

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SUMMARY:Superficial transitional cell carcinomas (TCC) of the urinary bladder have been shown to be monoclonal. However, no combined study of clonality and tumor suppressor genes (TSG) is available to date for muscle-invasive TCC. Forty-four muscle-invasive TCC of the urinary bladder selected from women were included in this study. Tumor cells located above and below the muscularis mucosa zone were systematically microdissected and used for DNA extraction. Hha-I digested and undigested samples were used to study the methylation pattern of androgen receptor alleles and undigested samples were used for microsatellite analysis of TSG (TP53, RB1, WT1, and NF1). Both loss of heterozygosity (LOH) and single nucleotide polymorphism (SNP) analyses were performed using optimized denaturing gradient gel electrophoresis. The expression of p53, pRB, and p21 WAF1 was assessed by immunohistochemistry. Appropriate controls were run in every case. All except two TCC showed a monoclonal pattern with the same allele inactivated in both compartments. Microsatellite analysis of TSG revealed the same LOH/SNP pattern in both tumor compartments in 30 cases (involving more than 1 TSG locus in 8) and genetic heterogeneity in 14 cases. From the latter group, 9 cases expressed more genetic changes in the deep compartment (involving TP53 gene in all cases, WT1 gene in 2, and NF1 in 1), whereas in 4 cases the superficial compartment showed more genetic changes (three involving NF1 and one involving both RB and TP53). No statistical difference in the immunoexpression was detected, although it tended to be higher in the superficial compartment than in the deep compartment. These concordant data in polymorphic DNA regions indicate that bladder-muscle-invasive TCC are monoclonal proliferations with homogeneous tumor cell selection. Heterogeneous tumor cell selection by topography defined two different genetic compartments: superficial, NF1-defective, and deep, TP53-defective. No differences in the immunohistochemical expression were observed, precluding a more extensive clinical application. (Lab Invest 2000, 80:279-289).

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Section: Diaz-cano Et Almentioning

confidence: 97%

Molecular Evolution and Intratumor Heterogeneity by Topographic Compartments in Muscle-Invasive Transitional Cell Carcinoma of the Urinary Bladder

Díaz‐Cano

Blanes²,

Rubio³

et al. 2000

Laboratory Investigation

122

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“…34,35 RNA was extracted from cultured cells using either Nucleospin RNA II total RNA isolation kit (Macherey-Nagel Inc., Easton, PA) or RNAzol B reagent (TelTest Inc., Friendswood, TX) according to manufacturer's instructions. RNA samples were treated with 5 U of DNase I (Roche) to eliminate possible contaminating DNA.…”

Section: Rna Extraction and Cdna Synthesismentioning

confidence: 99%

Regulation of prostate cell collagen receptors by malignant transformation

Mirtti

Nylund

Lehtonen

et al. 2005

Intl Journal of Cancer

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Cell adhesion receptors, including the integrin-type collagen receptors (a 1 b 1 , a 2 b 1 , a 10 b 1 and a 11 b 1 ) participate in cancer progression and invasion. Quantitative RT-PCR indicated that all 4 receptors are abundantly expressed in sarcoma-derived cell lines, whereas most carcinoma-derived cells express a 1 b 1 and a 2 b 1 only. This was surprising because a 11 b 1 has been connected previously to the progression of lung adenocarcinomas. To test the hypothesis that a 11 expression may not persist in cultured cancer cells we analyzed fresh tissue samples of 104 total prostatectomies, keeping in mind that prostate cancer cell lines showed negligible a 11 mRNA levels. In prostate a 2 expression was significantly lower in poorly differentiated carcinomas when compared to benign lesions (p 5 0.0331). In immunohistochemistry the protein levels of a 2 integrin decreased significantly (p 5 0.0001) and the protein levels of a 11 subunit increased significantly (p 5 0.029) with the increasing grade of carcinoma. Thus a 11 b 1 may replace a 2 b 1 during tumor progression. Our observations support the idea that a 11 b 1 may be expressed in tumors but the corresponding cell lines may lose the expression of this integrin. Previous studies have shown that in cell culture androgen receptor (AR) controls a 2 b 1 expression. We measured AR mRNA levels and the number of AR positive nuclei in the prostate samples and the results showed a significant correlation between a 2 b 1 and AR. Androgen receptors may control the mechanisms regulating integrin expression in prostate. ' 2005 Wiley-Liss, Inc.Key words: integrins; collagen; prostate; cancer; cell linesIntegrins are adhesion molecules that act in cell-cell and cellextracellular matrix interactions. They comprise of 2 subunits called a and b, which can form at least 24 different non-covalently linked a/b-heterodimers.1 Four collagen receptors form a specific subclass of integrins because they all contain an inserted domain (I domain) in their a subunit. These a subunits form heterodimers with b 1 subunit only.The most abundant integrin-type collagen receptors are a 1 b 1 and a 2 b 1 . Integrin a 1 b 1 is predominantly expressed in mesenchyme and the highest expression levels are on smooth muscle cells.2,3 Integrin a 2 b 1 is expressed abundantly on epithelial cells but it is also present on many mesenchymal cells, such as fibroblasts, chondrocytes and osteoblasts. [4][5][6] The newest members of the collagen receptor integrins, a 10 b 1 and a 11 b 1 , were found more recently 7,8 and their expression patterns are less well-known. 9,10Integrins have been shown to regulate cell growth, differentiation and survival, as well as malignant transformation, cancer cell invasion and metastasis.11 When malignant tumors and cancer cells have been analyzed, the expression and function of a 2 b 1 has been connected to invasion of malignant melanoma 12 as well as to prostatic, gastric and ovarian carcinomas, 13-15 whereas a 1 b 1 integrin is the collagen receptor of T cell derived ...

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“…5,6 Furthermore, the levels of NF1 protein and/or messenger RNA have been reported to be altered in certain proliferative diseases, such as transitional cell carcinoma and psoriasis. 13,14 On the other hand, neurofibromas have been described to develop on locations of previous mechanical trauma. 7,8 Interestingly, recent results demonstrate up-regulation of NF1 gene expression in response to tissue trauma and suggest that a "second hit" in a form of somatic mutations in lesional neurofibromatosis cells is not necessarily a prerequisite for the development of neurofibromas.…”

Section: Commentmentioning

confidence: 99%

Occult Neurofibroma and Increased S100 Protein in the Skin of Patients With Neurofibromatosis Type 1

Karvonen¹,

Kallioinen²,

Ylä‐Outinen³

et al. 2000

Arch Dermatol

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Urinary Bladder Transitional Cell Carcinogenesis Is Associated with Down-Regulation of NF1 Tumor Suppressor Gene in Vivo and in Vitro

Cited by 35 publications

References 44 publications

Molecular Evolution and Intratumor Heterogeneity by Topographic Compartments in Muscle-Invasive Transitional Cell Carcinoma of the Urinary Bladder

Molecular Evolution and Intratumor Heterogeneity by Topographic Compartments in Muscle-Invasive Transitional Cell Carcinoma of the Urinary Bladder

Regulation of prostate cell collagen receptors by malignant transformation

Occult Neurofibroma and Increased S100 Protein in the Skin of Patients With Neurofibromatosis Type 1

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