Expression of<i>ras</i>Oncogene p21 in Prostate Cancer

Viola, Michael V.; Fromowitz, Frank B.; Oravez, Sheila; Deb, Sumitra; Finkel, Gerald C.; Lundy, Joel; Hand, Patricia Horan; Thor, Ann D.; Schlom, Jeffrey

doi:10.1056/nejm198601163140301

Cited by 246 publications

(68 citation statements)

References 33 publications

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“…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). Detailed staining for p21 in normal bladder tissue has revealed that the basal (progenitor) cells of the multilayered transitional epithelium stain with the highest intensity whereas more superficial (differentiated) compartments stain to a much lesser degree (12).…”

Section: Introductionmentioning

confidence: 79%

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.

103

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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: Introductionmentioning

confidence: 79%

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.

103

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“…An overexpression of c-ras, c-myc and c-sis oncogenes has been reported (Fleming et al, 1986;Viola et al, 1986;Buttyan et al, 1987), but ras mutations are rare (Gumerlock et al, 1991;Moul et al, 1992). A role of HER-2/neu is not certain (Kuhn et al, 1993;Sadasivan et al, 1993).…”

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confidence: 99%

Loss of heterozygosity (LOH), malignancy grade and clonality in microdissected prostate cancer

Hügel

Wernert

1999

Br J Cancer

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SummaryThe aim of the present study was to find out whether increasing malignancy of prostate carcinoma correlates with an overall increase of loss of heterozygosity (LOH), and whether LOH typing of microdissected tumour areas can help to distinguish between multifocal or clonal tumour development. In 47 carcinomas analysed at 25 chromosomal loci, the overall LOH rate was found to be significantly lower in grade 1 areas (2.2%) compared with grade 2 (9.4%) and grade 3 areas (8.3%, P = 0.007). A similar tendency was found for the mean fractional allele loss (FAL, 0.043 for grade 1, 0.2 for grade 2 and 0.23 for grade 3, P = 0.0004). Of 20 tumours (65%) with LOH in several microdissected areas, 13 had identical losses at 1-4 loci within two or three areas, suggesting clonal development of these areas. Markers near RB, DCC, BBC1, TP53 and at D13S325 (13q21-22) showed higher loss rates in grades 2 and 3 (between 25% and 44.4%) compared with grade 1 (0-6.6%). Tumour-suppressor genes (TSGs) near these loci might, thus, be important for tumour progression. TP53 mutations were detected in 27%, but BBC1 mutations in only 7%, of samples with LOH. Evaluation of all 25 loci in every tumour made evident that each prostate cancer has its own pattern of allelic losses.

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“…Expression of ras gene product (molecular weight; 21, 000) has been widely studied in human malignancies of various organs (14,17,21,26,29,30). The point mutation of c-ras genes was also recognized in some organs and cell lines (27).…”

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confidence: 99%

Immunohistochemical analysis of the expression of ras oncogenes in human renal cell carcinomas.

Moriyama

Kuzumaki

Honda

et al. 1992

Acta Histochem. Cytochem

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Fifty-one cases of human renal cell carcinoma were investigated for immunohistochemical localization of ras oncogenes and their products. The immunohistochemical results were evaluated comparatively with the histological grade, stage and progression of the tumor. The ras p21 oncogene product was positive mainly in the plasma membrane of the renal cell carcinomas. The tissues from normal kidneys were limitedly stained in the cytoplasm of the proximal convoluted tubule cells. Five of 28 (17.9%) frozen specimens of renal cell carcinoma revealed the positive staining for ras mRNA by means of in situ hybridization as well as the strongly positive staining for ras p21 gene products. These 5 cases were all grade 2 and pT2b in TNM classification. However, there was no point mutation on exon 1(corresponding to codons 12 and 13) and exon 2 (corresponding to codon 61), where point mutations are reported in several human tumors. Positive staining cases for ras p21 (survival rate of 81.2% at 5 years) showed the tendency to decrease the survival rate compared to the ras p21 negative staining cases. There was a significant correlation of ras p21 positive staining and the pathological extent of the primary tumor (pT) (p<0.05).Our immunohistochemical study revealed that the expression of ras p21 is one of the parameters related to the prognosis of renal cell carcinomas.

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Expression ofrasOncogene p21 in Prostate Cancer

Cited by 246 publications

References 33 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.

Loss of heterozygosity (LOH), malignancy grade and clonality in microdissected prostate cancer

Immunohistochemical analysis of the expression of ras oncogenes in human renal cell carcinomas.

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