Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel 21-kDa protein (p21) was isolated from auto-immune complexes, found in sera of 14 patients with malignant urogenital tumors and isolated on Protein A-Sepharose. Isolated complexes were analyzed in 15% polyacrylamide-SDS minigels. After staining with Coomassie blue R, the bands were scanned with a clinical densitometer. The level of p21 in sera of cancer patients was 3 times higher than that found in normal individuals. An attempt was made to correlate consecutive levels of p21 in the sera of these cancer patients with the clinical course. In 4 cases a significant decrease (57-75%) in the level of p21 was observed in parallel with response to treatment. In 9 of 10 cases where no response or tumor progression was observed, the relative abundance of p21 increased or remained unchanged. Thus, the level of p21 was indicative of progression or regression of the disease in 13 out of 14 patients. Similar high levels of p21 in sera were also found in 22 patients with benign hyperplasia of prostate. The p21 protein was not immunoreactive with known anti-ras antibodies such as Y13-259, 142-24E05 and anti-rap1. Partial amino acid analysis of this protein showed no complete homology to any known protein, but a partial homology to known bacterial proteins involved in DNA replication or transcription was observed. Monitoring of the novel p21 levels before and after treatment may be useful in follow-up of cancer patients, providing evidence of response to treatment.
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PMID:A novel 21-kDa protein as a serum marker for benign and malignant urogenital tumors: preliminary communication. 195 89

Steady-state levels of c-Ha-ras mRNA were measured in eight sublines of the Dunning R3327 rat prostatic adenocarcinoma. As a control, normal dorsal prostate tissue was studied. Increased expression of c-Ha-ras is associated with tumor progression in one lineage of the Dunning R3327 system (H to AT1 to MAT-Lu and MAT-Ly-Lu). Here ras mRNA increases as the tumor advances from androgen dependence and a high degree of differentiation to an anaplastic aneuploid phenotype with high metastatic potential. However, in the other Dunning lineage (H to HI to HI-F to AT3), expression of c-Ha-ras is variable and does not correlate with tumor progression. Immunocytochemistry showed that levels of the c-Ha-ras p21 protein paralleled steady-state mRNA levels in variants. Transfection assays, using NIH/3T3 cells, suggested that the ras loci were not activated in the R3327 tumors. Levels of c-Ki-ras mRNA were also measured in the Dunning tumors; these did not correlate with tumor progression in either lineage. Expression of N-ras mRNA was not detected in the Dunning tumors.
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PMID:Expression of ras proto-oncogenes in the Dunning R3327 rat prostatic adenocarcinoma system. 306 50

Activation of the cellular oncogene ras has been implicated in many types of human malignancies. In this study, the relative levels of p21 protein product of ras (p21ras) in primary and metastatic colon tumors were compared to those in adjacent normal tissues. Nine of the 17 primary tumors had substantially elevated levels of p21ras with respect to adjacent normal tissues. Eight of these tumors were from Dukes' B and C stages. Four of the five tumors classified as "D" stage (in which distant metastases are present) did not show elevated levels of p21ras. In metastases from primary colon tumors, nine of nine were considerably reduced in p21ras expression regardless of the site of metastasis. These data suggest that elevation of p21ras may be a common event in early stages of colon tumors, and tumor progression may lead to a more autonomous population of cells in which other growth factors supplant the role of this protein.
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PMID:Expression of p21ras in fresh primary and metastatic human colorectal tumors. 388 18

Ras oncogenes owe their transforming properties to single point mutations in the sequence coding for the active site of the p21 protein. These mutations lead to changes in cellular proliferation and induce tumorigenic properties. Point mutations represent a well-defined target for antisense oligonucleotides that can specifically suppress the translation of the targeted mutant mRNA. We show that the stability and cellular disponibility of antisense oligonucleotides can be markedly improved by adsorption to polyalkylcyanoacrylate nanoparticles. Nanoparticle-adsorbed antisense oligonucleotides directed to a point mutation (G-->U) in codon 12 of the Ha-ras mRNA selectively inhibited the proliferation of cells expressing the point-mutated Ha-ras gene at a concentration 100 times lower than free oligonucleotides. In addition they markedly inhibited Ha-ras-dependent tumor growth in nude mice after subcutaneous injection. These experiments show that inhibition of ras oncogenes by antisense oligonucleotides can block tumor development even though ras oncogenic activation might be an early event in tumor progression.
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PMID:Antisense oligonucleotides adsorbed to polyalkylcyanoacrylate nanoparticles specifically inhibit mutated Ha-ras-mediated cell proliferation and tumorigenicity in nude mice. 793 75

After receiving 500 p.p.m. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in their drinking water for an initial 10 weeks, rats were given a single i.p. injection of N-methyl-N-nitrosourea (MNU) at a dose of 50 mg/kg body wt at week 20 (at a stage when bladder tumor development had already occurred), and then maintained until they were killed at week 40. Three and six hours after the MNU injection, the DNA methylation adducts, O6-methyldeoxyguanine (O6-medG) and 7-methyldeoxyguanine (7-medG), were immunohistochemically revealed to be markedly more frequent in urothelial preneoplasias or neoplasias than in normal cells. These adducts were rapidly repaired, and although 7-dmeG in tumor cells still persisted after 72 h, they appeared essentially to have returned to normal levels. At the termination, conversion of transitional cell carcinomas (TCC) to squamous cell carcinomas (SCC) of the urinary bladder was significantly increased in the BBN+MNU group. The extent of invasion was also significantly greater with the additional MNU treatment. Expression of p21 protein, detected by immunohistochemistry, was comparable between the groups. Mutations in the H-ras gene were observed in one case each of the BBN and BBN+MNU groups, and both cases showed a G:C to A:T transition at codon 12. The present study thus suggested that while an additional single treatment with MNU of rats bearing BBN-induced bladder neoplasias is associated with significant, possibly mutation-dependent tumor progression, H-ras mutations are not necessary events.
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PMID:DNA methylation adduct formation and H-ras gene mutations in progression of N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder tumors caused by a single exposure to N-methyl-N-nitrosourea. 800 Dec 65

Many genes participate in the regulation of cell cycle progression from G1 to S phase. Functional loss of one or more of these genes has been reported to be associated with carcinogenesis and/or tumor progression and poor prognosis in many cancers. In a series of 126 patients with hepatocellular carcinoma (HCC), we immunohistochemically evaluated tumor expression of the cell cycle-related gene protein products of Rb, p21 (WAF1), and p53. Positive immunostaining for Rb, p21, and mutant p53 protein was detected in 58%, 33%, and 37% of the tumors, respectively. The proportion of HCCs exhibiting aberrant p53 protein expression increased significantly with advancing stage of disease (p < 0.001), poorer histological classification of differentiation (p < 0.01), and increasing tumor size (p < 0.01). A decrease in the proportion of HCCs expressing p21 protein was also associated with advancing clinical stage of disease (p < 0.01), and larger tumor size (p < 0.05). The only clinicopathological feature found to be associated with Rb status, was intrahepatic metastasis, which occurred with a higher frequency in HCCs exhibiting positive immunoreactivity for Rb protein expression (p < 0.05). Multivariate survival analysis revealed that, amongst the protein products of the different genes evaluated, only positive immunostaining for aberrant p53 protein expression served as an independent prognostic indicator, being significantly associated with worse survival in patients with HCC (p = 0.023). Analysis for relationships between gene products showed an inverse correlation between expression of aberrant p53 protein and p21 protein (p < 0.01), and also an inverse correlation between p21 protein and Rb protein expression (p < 0.05) in these cases of HCC. These findings demonstrate that positive immunostaining for mutant p53 protein expression is a significant indicator of tumor progression and poor prognosis, confirm that p21 protein expression is induced in a p53-dependent manner, and suggest that Rb protein expression may be regulated to some extent by p21 in HCC.
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PMID:Protein expression of p53, p21WAF1, and Rb as prognostic indicators in patients with surgically treated hepatocellular carcinoma. 956 77

The cyclin-dependent kinase inhibitor p21/waf1 is regulated by p53-dependent and p53-independent pathways. In addition, mdm2 is an oncogene which forms an auto-regulatory loop with the normal p53 protein and its role has been implicated in oncogenesis. To determine whether a correlation exists between the expression of these gene products, tumor differentiation, tumor staging and radiation therapy, we investigated the expression of p21, p53 and mdm2, and cellular proliferation by Ki-67 (MIB1) labeling index using immunohistochemistry in 88 human oral squamous cell carcinoma (SCC) samples from 56 patients. Tumor expression of all nuclear proteins was scored according to the percentage of positive cancer nuclei, both with the cancer tissue as a whole as well as in different epithelial compartments of differentiation. Positive p21, p53, mdm2 and MIB1 staining was present in 82.4, 67.8, 25.9 and 98.8% of the SCC samples. The staining in different epithelial compartments of differentiation varied: those of p21 and mdm2 present predominantly in suprabasal and upper regions of the tumors: those of p53 and MIB1 in basal and suprabasal regions. Higher levels of p21 expression were seen in actively proliferating tumors (P = 0.025). p21 expression positively correlated with mdm2 expression but not with p53 expression. Moreover, the level of p21 expression was higher in older patients (P = 0.024) and female patients (P = 0.008). There was no significant association among p53, mdm2 and MIB1. Expression of p53 was higher in tumors with poorer cellular differentiation and in younger patients (P = 0.038 and 0.028). There was no association between tumor stage by TNM classification and the expression of any of these gene products or proliferation index. Radiation therapy did not alter the expression of any of these. To conclude, p21 protein was overexpressed in oral SCCs, and this overexpression was related to cell proliferation index and mdm2 expression but independent of p53 protein alteration. Overexpression of p21 alone appeared to be insufficient to suppress tumor progression.
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PMID:Expression of p21/waf1 in oral squamous cell carcinomas--correlation with p53 and mdm2 and cellular proliferation index. 1021 12

Tumour growth is regulated by a balance between proliferation, growth arrest and programmed cell death (apoptosis). Until recently, the majority of the studies dealing with oncogenesis has been focused on the regulation of cell proliferation. There is now growing understanding that control of growth arrest and apoptosis play key roles in the development of human cancer and in cancer treatment. Some of the more heavily studied proteins of importance for the control of growth arrest and apoptosis are p53, p21, bcl-2 and bax. Alterations in the p53 protein may lead to malignant transformation and defect therapy response, most likely as a result of defective p53-dependent apoptosis. In addition, p21 (WAF1/CIP1) is involved in cell-cycle arrest and probably in induction of p53-dependent apoptosis. Proteins belonging to the bcl-2 family are also important for normal apoptosis. Overexpression of bcl-2 protein is thought to reduce the apoptotic capacity, while bax protein seems to be necessary for induction of apoptosis. In this study, we have immunostained tissues from 93 primary colon carcinomas and have examined the expression of p53, p21 (WAF1/CIP1), bcl-2 bax, pRb and cyclin D1 for evaluation of their roles in colon-cancer progression. A highly significant association between p53 accumulation and downregulation of p21 (WAF1/CIP1) was seen. We also found a strong association between reduced/absent p21 and the development of metastases and death due to cancer disease. Cyclin D1, bcl-2 and bax protein failed to have independent prognostic impacts. Bcl-2 and bax protein levels showed an inverse relationship. The results of the present study indicate that reduced p21 protein levels play an important role in progression of colon cancer. We concluded that evaluation of p21 expression in primary colon carcinomas at the time of surgery might be a valuable tool in defining patients with a high risk of developing metastases.
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PMID:Protein expression of p53, p21 (WAF1/CIP1), bcl-2, Bax, cyclin D1 and pRb in human colon carcinomas. 1078 80

Prior reports suggest that p53 protein status may influence the response to gene transduction with wild-type (wt) p53. Adenoviral vectors containing the p53 gene were administered to normal keratinocytes, to squamous cell carcinoma (SCC) lines with varied p53 protein status (absent, mutant, wt, or degraded by papillomavirus), as well as to tumors formed in severe combined immunodeficient mice. The percentage of cells undergoing apoptosis, G1 growth arrest, WAF1/p21 induction, and in vivo tumor progression were studied after wt p53 gene transduction. Apoptosis developed first in normal keratinocytes, next in SCCs lacking p53 protein, and last in SCCs with mutant or degraded p53 protein. All of the cell lines studied demonstrated an increase in WAF1/p21 protein, but only those lacking p53 protein showed G1 arrest. Tumors lacking p53 protein were more susceptible to p53 overexpression than those containing mutant or degraded p53 protein. The endogenous p53 protein status of SCCs appears to influence the outcome of p53 gene transduction.
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PMID:Endogenous p53 gene status predicts the response of human squamous cell carcinomas to wild-type p53. 1083 Jul 22

Dysregulation of apoptosis plays an important role in tumor development. Mutations of the p53 gene have been reported in adenocarcinomas arising from Barrett's metaplasia. The p53 gene is important in the regulation of cell growth and apoptosis, with the loss of wild-type activity associated with uncontrolled cell-cycle progression and tumor formation. P21 is a cyclin-dependent kinase inhibitor that is activated by p53. Bax is a member of the bcl-2 family whose function is that of cell-death promoter. We investigated the hypothesis that there are significant alterations in the levels of apoptotic protein as well as p21 protein expression in the neoplastic progression associated with Barrett's metaplasia.
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PMID:Barrett's esophagus, apoptosis and cell cycle regulation: correlation of p53 with Bax, Bcl-2 and p21 protein expression. 1095 6


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