ras Oncogene p21 expression is increased in premalignant lesions and high grade bladder carcinoma.

Viola, Michael V.; Fromowitz, Frank B.; Oravez, Sheila; Deb, Sumitra; Schlom, Jeffrey

doi:10.1084/jem.161.5.1213

Cited by 158 publications

(65 citation statements)

References 17 publications

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“…The maintenance of the noninvasive phenotype of the control pSV2neo-transfected pooled parental line RT-4 and of the RT-4-cr-3 and RT-4-mr-7 plus the acquisition of an invasive phenotype by RT-4-cr-1 and RT4-mr-10 was clear and striking. This modulation of the invasive phenotype by manipulation of the level of HRAS appears to be consistent with clinical data showing correlations of enhanced invasion with greater degrees of p21 expression (8). In addition, it is consistent with a model postulating possible mutations in the promoter (13) or in the coding regions (14) of the HRAS gene as "second hits," inducing tumor cell invasion.…”

Section: Discussionsupporting

confidence: 71%

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Overexpression of normal and mutated forms of HRAS induces orthotopic bladder invasion in a human transitional cell carcinoma.

Theodorescu

Cornil

Fernandez

et al. 1990

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

104

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Recent studies have shown that orthotopic (transurethral) transplantation of human bladder cancer cell lines into nude mice permits tumor growth that accurately reflects their clinical malignant status in the original host. Thus, such a system allows a unique opportunity to analyze the genetic events involved in the conversion of low-grade bladder cancer, the vast majority of which are curable, to the highgrade life-threatening form of the disease. Since 5-10% of transitional cell carcinomas (TCCs) have been shown to contain a mutated HRAS gene, and protein expression levels of all forms ofHRAS have been correlated with TCC progression, we chose to study the contribution of the HRAS oncogene in bladder tumor progression. We evaluated the effects of transfection of normal or mutated HRAS genes into a human TCC, called , that behaves as a superficial noninvasive papillary tumor after transurethral orthotopic inoculation into athymic nude mice. We found that overexpression of either transfected normal or mutated HRAS genes converted RT-4 cells to express an invasive phenotype remarkably similar in nature to the clinical behavior of high-grade bladder carcinomas. These results suggest a role for overexpressed normal or mutated RAS genes in human bladder carcinoma progression, and highlight the importance of using orthotopic inoculation systems for evaluation of the contribution of oncogenes to malignant tumor progression.Dominantly acting cellular transforming genes belonging to the RAS family of oncogenes have been detected in a wide spectrum of animal and human cancers by DNA-mediated gene transfer experiments in which immortalized nonneoplastic cells are used as recipients (1)(2)(3). By employing such assays in combination with gene cloning and sequencing analysis, it has been estimated that 5-10% of human transitional cell carcinomas (TCCs) contain activated/mutated RAS oncogenes (3-5). Moreover, of the three known RAS family members, by far the most common found to be mutated in urothelial malignancies is HRAS (4-6). TCCs can be broadly classified in two forms: superficial and invasive. Moreover, although the majority of superficial bladder carcinomas are curable, 2-25% progress to the invasive lifethreatening form of the disease (7). This raises the question of whether the presence of activated RAS oncogenes is causally associated with the degree of invasiveness of such tumors. The various studies cited above suggest that based on prevalence comparisons of TCCs with mutated RAS and invasive TCCs this is probably not the case (4-6). However, in view of the low frequency of occurrence of activated RAS genes combined with the relatively small number of bladder tumors analyzed, it is difficult to rule out the possibility that patients having tumors with an activated RAS oncogene constitute a distinct clinical subgroup of invasive tumors.The possible relationship of RAS gene expression to bladder cancer development and progression has also been analyzed by immunohistochemical techniques. These studies have,...

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Section: Discussionsupporting

confidence: 71%

“…These studies have, in the main, concentrated on estimating the level of the RAS gene protein product, p21, in tumors of various stages (8). The results have shown that in general, there is a correlation between levels of p21 and the degree of tumor invasiveness similar to what has been observed in some other types of tumor (9)(10)(11).…”

Section: Introductionmentioning

confidence: 63%

Overexpression of normal and mutated forms of HRAS induces orthotopic bladder invasion in a human transitional cell carcinoma.

Theodorescu

Cornil

Fernandez

et al. 1990

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

104

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“…The usual techniques for studying oncogene structure and/or function include blotting studies of DNA or of its RNA message and investigation of the biochemical function of protein products. Immunoblotting studies indicate that ras genes are probably involved in (normal) growth control (Shih & Weeks, 1984;McGrath et al, 1984;Sweet et al, 1984;Bar-Sagi, 1989) and that their alteration plays a role in causing several types of human haematological and solid tumours (Viola et al, 1985;Thoret et al, 1984;Lundy et al, 1986;Thein et al, 1986;Liu et al, 1987;Bos et al, 1987;Senn et al, 1988;Pedersen-Bjegard et al, 1988;Hirai et al, 1988).…”

Section: Resultsmentioning

confidence: 99%

Ras oncogene expression and DNA content in plasma cell dyscrasias: a flow cytofluorimetric study

Danova

Riccardi²,

Ucci³

et al. 1990

Br J Cancer

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“…Newer potential prognostic factors may be utilized to select patients who are potentially suitable for organ conservation (60)(61)(62)(63)(64)(65)(66)(67)(68). There has been a proliferation of studies concerning markers of drug resistance, D N A content, expression of epidermal growth factor receptor, chromosome abnormalities, and oncogene expression, and angiogenesis.…”

Section: Prognostic Factors For Bladder Preservationmentioning

confidence: 99%

Bladder Preservation—a Prospect for Patients with Urinary Bladder Cancer

Sternberg¹

1995

Acta Oncologica

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ras Oncogene p21 expression is increased in premalignant lesions and high grade bladder carcinoma.

Cited by 158 publications

References 17 publications

Overexpression of normal and mutated forms of HRAS induces orthotopic bladder invasion in a human transitional cell carcinoma.

Overexpression of normal and mutated forms of HRAS induces orthotopic bladder invasion in a human transitional cell carcinoma.

Ras oncogene expression and DNA content in plasma cell dyscrasias: a flow cytofluorimetric study

Bladder Preservation—a Prospect for Patients with Urinary Bladder Cancer

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