UMLS:C0178874 - FACTA Search

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunoreactivity of p21WAF1/CIP1 and cyclin D1 proteins was assessed in a cohort of 207 patients with superficial (pTa-pT1) bladder cancer followed up for a mean of 4.9 years. The results of the immunostainings were compared with T category, WHO grade, tumor cell proliferation rate (MIB-1 score), the expressions of p53 and bcl-2 as well as survival. Sixty-eight percent and 75% of the tumors were p21WAF1/CIP1 positive (> or = 5% of cells positive) and cyclin D1 positive (> or = 10% of cells positive), respectively. The p21WAF1/CIP1 expression was related to cyclin D1 immunolabelling (P < 0.001) but not to the other variables studied. The expression of cyclin D1 was inversely associated with T category (P = 0.001), WHO grade (P = 0.006), MIB-1 score (P = 0.014), p53 expression (P = 0.001), and bcl-2 (P = 0.011) immunoreactivity. In univariate analysis, T category (P = 0.0001), WHO grade (P < 0.0001), MIB-1 score (P < 0.0001), bcl-2 (P = 0.0092), p53 (P = 0.0016) and p21WAF1/CIP1 (P = 0.009) expressions were significant prognostic factors with regard to tumor progression, whereas cyclin D1 was without any prognostic significance (P = 0.1). Out of 123 p21 positive tumors 21 progressed, whereas only 2 out of 58 p21 negative tumors progressed. In multivariate analysis, the MIB-1 score was the only independent predictor of cancer-specific survival (P = 0.03), whereas tumor grade (P = 0.002) and cyclin D1 expression (P = 0.04) were independent predictors of tumor recurrence. Only the WHO grade (P = 0.04) retained its prognostic value indicating the risk of progression. We suggest that in superficial bladder cancer p21WAF1/CIP1 and cyclin D1 immunohistochemistry provide no additional prognostic information compared with already established prognostic factors for predicting the risk of progressive disease.
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PMID:Evaluation of p21WAF1/CIP1 and cyclin D1 expression in the progression of superficial bladder cancer. Finbladder Group. 1112 4

The tumor suppressor p53 transcriptionally regulates a large number of target genes that may affect cell growth and cell death pathways. To better understand the role of p53 loss in tumorigenesis, we have developed a mouse mammary cancer model, the Wnt-1 TG/p53 model. Wnt-1 transgenic females that are p53-/- develop mammary adenocarcinomas that arise sooner, grow faster, appear more anaplastic, and have higher levels of chromosomal instability than their Wnt-1 transgenic p53+/+ counterparts. In this study, we used several assays to determine whether the presence or absence of p53 affects gene expression patterns in the mammary adenocarcinomas. Most of the differentially expressed genes are increased in p53+/+ tumors and many of these represent known target genes of p53 (p21WAF/C1P1, cyclin G1, alpha smooth muscle actin, and cytokeratin 19). Some of these genes (cytokeratin 19, alpha smooth muscle actin, and kappa casein) represent mammary gland differentiation markers which may contribute to the inhibited tumor progression and are consistent with the more differentiated histopathology observed in the p53+/+ tumors. Several differentially expressed genes are growth regulatory in function (p21, c-kit, and cyclin B1) and their altered expression levels correlate well with the differing growth properties of the p53+/+ and p53-/- tumors. Thus, while tumors can arise and progress in the presence of functioning wild type p53, p53 may directly or indirectly regulate expression of an array of genes that facilitate differentiation and inhibit proliferation, contributing to a more differentiated, slow growing, and genomically stable phenotype.
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PMID:Differential gene expression in mouse mammary adenocarcinomas in the presence and absence of wild type p53. 1114 50

The aim of this study was to investigate the immunohistochemical expression of the proteins p53, Waf-l/p21, Rb, p16 and Ki67 in 38 cases of multiple myelomas (MM) and 4 cases of solitary extramedullary plasmacytomas in relation to the tumor histological grade and stage. In bone marrow (BM) biopsies from MM, overexpression of p53 and p21 proteins, in comparison to plasma cell infiltrates in non-pathological bone marrow, was detected in 13 out of 38 and 21 out of 38 cases, respectively. The combined immunoexpression of p53 and p21 proteins in the 38 cases of MM showed the following patterns: a) p53+/p21+ (13 cases) b) p53-/p21+ (8 cases) and c) p53-/p21- (17 cases). Rb, p16 and Ki67 proteins were detected in tumor cells in all 38 cases and their expression increased proportionally to tumor grade. The 4 cases of solitary extramedullary plasmacytomas showed the p53+/p21+ pattern in 2 cases and the p53-/p21+ pattern in 2 cases, all of them displaying Rb, p16 and Ki67 expression in tumor cells. The pattern p53+/p21+ might represent cases with wild-type p53 able to induce p21 expression. However, in previous studies p53 mutations were reported in about 3-10% of MM, and they were strongly associated with advanced disease. Thus, in some p53+/p21+ cases associated with high p53 expression and advanced disease, p53 gene cannot be excluded and up-regulation of p21 expression may be p53- independent. P53 overexpression correlated with increased tumor grade (p < 0.005), advanced histological stage (p < 0.001) and Ki67 expression in more than 10% of tumor cells (p < 0.001). Since increase in Ki67 expression also correlated with increased tumor grade (p < 0.001) and advanced histological stage (p < 0.001), these findings suggest that impairment of the p53 growth control pathway is associated with tumor progression in MM. Thus, p53 and Ki67 immunostaining in routine BM biopsies may be helpful for the detection of MM with potentially aggressive behavior. Overexpression of p21 in MM correlated with higher Ki67 expression (p < 0.005), suggesting that the p21 function of arresting cell-cycle is impaired. Ki-67 expression in MM increased in parallel with p16 (p < 0.001) and Rb expression (p < 0.001). Rb expression could represent a growth control response which, however, might not be able to induce growth arrest in view of the parallel increase in Ki67 expression and of previous findings showing that Rb protein in MM cells is expressed mostly in its phosphorylated form.
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PMID:Immunohistochemical expression of the p53, p21/Waf-1, Rb, p16 and Ki67 proteins in multiple myeloma. 1120 12

To determine if p53 abnormalities could be involved in the pathogenesis of T- or natural killer (NK)-cell lymphomas, we investigated 51 cases of these lymphomas for the expression of p53 and its relationship with p53 gene mutations, the expression of the p21 protein as well as the proliferative and apoptotic indices. Overexpression of p53 was found in 19 cases (37%), whereas mutations of the p53 gene were observed in only 5 of 28 tested cases. The analysis of immunohistochemical data showed some entity-related phenotypic profiles. Anaplastic large cell lymphomas showed a frequent overexpression of p53 (7/8 cases) and p21 (6/8 cases) proteins and rare p53 mutations (1/7 cases), suggesting accumulation of a functional wild type p53 protein able to induce p21 expression. Nodal peripheral T-cell lymphomas unspecified showed relatively frequent overexpression of p53 protein (5/7 cases), infrequent p21 expression (2/7 cases), and rare p53 gene mutations (1/6 cases). In angioimmunoblastic lymphomas, the common phenotype was p53-/p21- (15/17 cases), with only a few scattered p53-positive cells, which, on the basis of double staining results, were mostly Epstein-Barr virus-infected B cells. A p53 gene mutation was only found in 1 case (1/8 cases) of angioimmunoblastic lymphoma, which showed cytologic tumor progression. Mycosis fungoides showed p53 overexpression in 2 of 4 cases, including 1 case with p53 gene mutation and features of cytologic tumor progression. Nasal NK/T lymphomas showed p53 overexpression in 2 of 5 cases, 1 of which had a p53 gene mutation. Finally, all lymphoblastic T-cell lymphomas (5 cases) and gammadelta hepatosplenic T-cell lymphomas (3 cases) were negative for expression of p53 and p21 proteins. We conclude that p53 protein overexpression is a common finding in some entities of T- and T/NK-cell lymphomas, whereas a p53 gene mutation is a rare, sporadic, and rather late event associated with tumor progression in some instances. The p53/p21 expression pattern appears to be variable in T- and T/NK-cell lymphoma entities, reinforcing the concept of distinct, entity-related mechanisms of pathogenesis in these tumors.
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PMID:Expression of p53 protein in T- and natural killer-cell lymphomas is associated with some clinicopathologic entities but rarely related to p53 mutations. 1123 Jul 7

A physical and functional interaction between the Ca(2+)-binding protein Mts1 (S100A4) and the tumor suppressor p53 protein is shown here for the first time. We demonstrate that Mts1 binds to the extreme end of the C-terminal regulatory domain of p53 by several in vitro and in vivo approaches: co-immunoprecipitation, affinity chromatography, and far Western blot analysis. The Mts1 protein in vitro inhibits phosphorylation of the full-length p53 and its C-terminal peptide by protein kinase C but not by casein kinase II. The Mts1 binding to p53 interferes with the DNA binding activity of p53 in vitro and reporter gene transactivation in vivo, and this has a regulatory function. A differential modulation of the p53 target gene (p21/WAF, bax, thrombospondin-1, and mdm-2) transcription was observed upon Mts1 induction in tet-inducible cell lines expressing wild type p53. Mts1 cooperates with wild type p53 in apoptosis induction. Our data imply that the ability of Mts1 to enhance p53-dependent apoptosis might accelerate the loss of wild type p53 function in tumors. In this way, Mts1 can contribute to the development of a more aggressive phenotype during tumor progression.
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PMID:Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction. 1127 47

Transgenic mice expressing specific oncogenes usually develop tumors in a stochastic fashion suggesting that tumor progression is a multi-step process. To gain further understanding of the interactions between oncogenes and tumor suppressor genes during tumorigenesis, we have crossed a transgenic strain (TG.NK) carrying an activated c-neu oncogene driven by the MMTV enhancer/promoter with p53-deficient mice. c-neu transgenic mice have stochastic breast tumor formation and normal appearing salivary glands. However, c-neu mice heterozygous for a p53 deletion develop parotid gland tumors and loose their wild type p53 allele. c-neu mice with a homozygous p53 deletion have increased rates of parotid tumor onset suggesting that inactivation of p53 is required and sufficient for parotid gland transformation in the presence of activated c-neu. In contrast to the dramatic effect of p53 in parotid gland transformation, p53 loss has little effect on the rate or stochastic appearance of mammary tumors. In addition, p53 loss was accompanied by the down regulation of p21 in parotid gland tumors but not breast tumors. The parotid gland tumors were aneuploid and demonstrated increased levels of Cyclin D1 expression. These observations suggest that in c-neu transgenic mice, p53 alterations have differential tissue effects and may be influenced by the tissue specific expression of genes influencing p53 activity.
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PMID:Inactivation of p53 tumor suppressor gene acts synergistically with c-neu oncogene in salivary gland tumorigenesis. 1131 88

To identify changes in gene expression with transformation and metastasis, we investigated differential gene expression in a squamous carcinoma model established in syngeneic mice. We used mRNA differential display (DD) to detect global differences and cDNA arrays enriched for cancer-associated genes using mRNA from primary keratinocytes, transformed Pam 212 squamous carcinoma cells, and metastases of Pam 212. After DD, 72 candidate cDNAs expressed primarily in transformed and metastatic cells were selected and cloned. Fifty-seven were detected, and 32 were confirmed to be differentially expressed by Northern blot analysis. mRNA expression profiles were also generated using a mouse cDNA array composed of 4000 elements representing known genes and expressed sequence tags plus the 57 DD candidate cDNAs detected by Northern analysis to facilitate data validation. cDNA array detected 76.9% of the differentially expressed mRNAs selected from DD and confirmed by Northern blot, whereas low-abundance mRNAs did not reach the threshold for detection by the lower-sensitivity array method. Clustering analysis of DD and array results from transformed and metastatic cells identified genes that exhibited decreased or increased expression with transformation and metastasis. Alterations in the expression of several genes detected during tumor progression were consistent with their functional activities involving growth (p21, p27, and cyclin D1), resistance and apoptosis (glutathione-S-transferase, cIAP-1, PEA-15, and Fas ligand), inflammation and angiogenesis [chemokine growth-regulated oncogene 1 (also called KC)], and signal transduction (c-Met, yes-associated protein, and syk). Strikingly, 10 of 22 genes in the cluster expressed in metastases have been associated with activation of the nuclear factor (NF)-kappaB signal pathway. The NF-kappaB-inducible cytokine Gro-1 was recently shown to promote tumor growth, metastasis, and angiogenesis of squamous cell carcinomas in vivo (Loukinova et al., Oncogene, 19: 3477-3486, 2000). The results demonstrate that early response genes related to NF-kappaB contribute to metastatic tumor progression. Comparison of cell lines and tumor tissue revealed a concordance of approximately 50% by array, and 70% for Northern-confirmed, metastasis-related genes. Functional genomic approaches comparing expression among cell lines and tumor tissue may promote a better understanding of the genes expressed by malignant and host cells during tumor progression and metastasis.
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PMID:Molecular profiling of transformed and metastatic murine squamous carcinoma cells by differential display and cDNA microarray reveals altered expression of multiple genes related to growth, apoptosis, angiogenesis, and the NF-kappaB signal pathway. 1140 55

Different studies have already shown that the isolated inactivation of p21, p16, or p27 cyclin-dependent kinase inhibitors (CKIs) is associated with increased growth fraction, tumor progression, or decreased overall survival in cases of non-Hodgkin's lymphoma. In this study we linked molecular study of the p53 and p16 genes with immunohistochemical analysis of p27 expression in a group of aggressive B-cell lymphomas [large B-cell lymphomas (LBCLs) and Burkitt's lymphomas]. This was done to analyze the relationship between p53 and p16 silencing, p27 anomalous overexpression, and clinical follow-up, testing the hypothesis that the accumulation of CKI alterations could confer to the tumors a higher aggressivity. In a group of 62 patients, p53 inactivation as a result of mutation was observed in 11 cases (18%) and p16 silencing was seen in 27 cases (43.5%) as a result of methylation (20 of 62), 9p21 deletion (7 of 44), or p16 mutation (2 of 62). The simultaneous inactivation of p53 and p16 was detected exclusively in five LBCL cases. Anomalous expression of p27, which has been proven to be associated with the absence of p27/CDK2 complexes and the formation of p27/cyclin D3 complexes where p27 is inactivated, was detected in 19 of 61 cases (31%). Cases characterized by p27 anomalous expression display concurrent inactivation of p21 (provided by p53 mutations) and/or p16 CKIs in 11 of 14 LBCL cases (P = 0.040). When the relationship between the association of inactivated CKIs and overall survival was considered, a significant relationship was found between a lower overall survival probability and an increased number of inactivated CKIs in LBCL cases, with the worst prognosis for the cases displaying concurrent p53, p16, and p27 alterations. This proves that simultaneous inactivation of different tumor suppressor pathways does indeed take place, and that tumor aggressiveness takes advantage of this CKI-concerted silencing. In this same series of data, Burkitt's lymphoma patients seem to behave in a different way than LBCLs, with p53 and p16 alteration being mutually exclusive and the association with p27 anomalous expression not being clinically significant. These facts seem to support that the additive effect of the inactivation of different CKIs could be dependent of the histological type.
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PMID:Overall survival in aggressive B-cell lymphomas is dependent on the accumulation of alterations in p53, p16, and p27. 1143 67

The levels of S100 Ca(2+)-binding proteins correlate with the progression of certain tumors, but their role, if any, in carcinogenesis is still poorly understood. S100B protein associates with both the p53 oligomerization domain (residues 325-355) and the extreme C terminus of the tumor suppressor p53 (residues 367-392). Consequently, S100B inhibits p53 tetramer formation and p53 phosphorylation mediated by protein kinase C, on p53 C-terminal end. In this report, we show that the S100B protein decreases p53 DNA binding and transcriptional activity. The effect of S100B is reflected in vivo by a reduced accumulation of p53, p21, and MDM2 protein levels in co-transfection assays and in response to bleomycin. The S100B can still interact with p53 in the absence of p53 extreme C-terminal end and reduce the expression of p53 downstream effector genes. These data indicate that S100B does not require p53 extreme C-terminal end to inhibit p53 activity. Collectively, these findings imply that elevated levels of S100B in tumors such as astrocytomas and gliomas could inhibit p53 functions and contribute to cancer progression.
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PMID:Inhibition of p53 transcriptional activity by the S100B calcium-binding protein. 1145 63

PC SPES (BotanicLab, Brea, California) an herbal supplement for patients with prostate cancer, is composed of 7 highly concentrated Chinese herbs and 1 US herb. It was developed in seeking positive attributes of Chinese and Western medicine for cancer treatment. Chemical standardization of this composition showed that baicalin is the most abundant active compound. Several reports on phase 2 clinical studies of PC SPES suggest that it is a well-tolerated active treatment for androgen-independent prostate cancer. In this report, data obtained from various laboratory experiments will be presented to elucidate the in vitro mechanism. Profound biologic effects of PC SPES on prostate cancer cells were observed on both androgen-dependent (LNCap) and androgen-independent (DU-145) cell lines. These effects include the following: (1) induction of cell apoptosis and cell cycle modulation; (2) inhibition of cell proliferation; (3) downregulation of bcl-2, bcl-6, proliferating cell nuclear antigen, and prostate-specific antigen proteins; (4) downregulation of androgen receptor (AR); and (5) upregulation of p53, bax, and p21 proteins. Concurrent animal studies using 2 different models, Copenhagen rats and nude mice, confirmed a dose-dependent suppressive effect of PC SPES on tumor volumes and tumor progression. Our results show that the cytotoxic and cytostatic properties of PC SPES are not entirely dependent on the presence of AR. The antitumor mechanism of PC SPES is complex. It involves multiple metabolic pathways, such that the whole extract acts on redundant mechanisms, which otherwise will permit cell survival if a single-target agent is used.
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PMID:In vitro mechanism of PC SPES. 1150 43

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