Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of genetic changes have been documented in prostate cancer, ranging from allelic loss to point mutations and changes in DNA methylation patterns (summarized in Fig. 1). The most consistent changes seen are those of allelic loss events, with the majority of tumours examined showing loss of alleles from at least one chromosomal arm. The short arm of chromosome 8, followed by the long arm of chromosome 16, seem to be the most frequent regions of loss, suggesting the presence of novel tumour suppressor genes. Deletions of one copy of the RB and TP53 genes are less frequent as are mutations of the TP53 gene, and accumulating evidence suggests the presence of an additional tumour suppressor gene on chromosome 17p, which is frequently inactivated in prostate cancer. Alterations in the E-cadherin/alpha catenin mediated cell-cell adhesion mechanism appear to be present in almost half of all prostate cancers and may be critical to the acquisition of metastatic potential of aggressive prostate cancers. Finally, altered DNA methylation patterns have been found in the majority of prostate cancers examined, suggesting widespread alterations in methylation modulated gene expression. The presence of multiple changes in these tumours is consistent with the multistep nature of the transformation process. Finally, efforts to identify prostate cancer susceptibility loci are under way, which may elucidate critical early events in prostatic carcinogenesis.
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PMID:Molecular biology of prostate cancer progression. 762 57

A number of genetic changes have been documented in prostate cancer, ranging from allelic loss to point mutations and changes in DNA methylation patterns (summarized in Fig 1). To date, the most consistent changes are those of allelic loss events, with the majority of tumors examined showing loss of alleles from at least one chromosomal arm. The short arm of chromosome 8, followed by the long arm of chromosome 16 appear to be the most frequent regions of loss, suggesting the presence of novel tumor suppressor genes. Deletions of one copy of the Rb and p53 genes are less frequent as are mutations of the p53 gene, and accumulating evidence suggests the presence of an additional tumor suppressor gene on chromosome 17p, which is frequently inactivated in prostate cancer. Alterations in the E-cadherin/alpha catenin mediated cell-cell adhesion mechanism appear to be present in almost half of all prostate cancers, and may be critical to the acquisition of metastatic potential of aggressive prostate cancers. Finally, altered DNA methylation patterns have been found in the majority of prostate cancers examined, suggesting widespread alterations in methylation-modulated gene expression. The presence of multiple changes in these tumors is consistent with the multistep nature of the transformation process. Finally, efforts to identify prostate cancer susceptibility loci are underway and will hopefully elucidate critical early events in prostatic carcinogenesis.
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PMID:Molecular biology of prostate cancer. 793 45

The cadherins are a family of transmembrane glycoproteins responsible for calcium-dependent cell-cell adhesion. This adhesion is mediated by a group of cytoplasmic proteins, the catenins, which act inside the cell to couple the cadherin molecule to the microfilament cytoskeleton. Dysfunction of E-cadherin-dependent cell-cell adhesion has been demonstrated to contribute to the acquisition of invasive potential of malignant adenocarcinoma cells. The potential role of alterations of catenin expression in tumor cell invasion is largely unexplored. We have previously found that E-cadherin is frequently down-regulated in clinical samples of prostate cancer (Umbas, R., Schalken, J. A., Aalders, T. W., Carter, B. S., Karthaus, H. F. M., Schaafsma, H. E., Debruyne, F. M. J., and Isaacs, W. B. Cancer Res., 52: 5104-5109, 1992). In this study, we further investigate this adhesion system in both benign and malignant human prostate cells in culture. Using antibodies to E-cadherin and its cytoplasmic accessory protein, alpha-catenin, we find that 5 of 6 human prostate cancer cell lines have reduced or absent levels of one or the other or both of these molecules when compared to normal prostatic epithelial cells. Only the LNCaP prostate cancer cell line is indistinguishable from normal prostate epithelium with respect to its E-cadherin-alpha-catenin complement. Interestingly, the PC-3 line is characterized by the presence of E-cadherin, but the complete lack of alpha-catenin found at both the RNA and protein level. This lack of alpha-catenin gene expression is explained by Southern analysis, which reveals a homozygous deletion of a large portion of the alpha-catenin gene in PC-3 cells. This loss of alpha-catenin is functionally manifested by negligible Ca(2+)-dependent aggregation of these cells in vitro, when compared to LNCaP cells. These results confirm that E-cadherin-dependent cell-cell adhesion is frequently aberrant in prostate cancer cells, and suggest that in a subset of prostate cancers, this adhesion may be inactivated by loss of alpha-catenin rather than E-cadherin itself. Furthermore, these results demonstrate that mutational inactivation of the alpha-catenin gene is one mechanism responsible for the loss of normal cell-cell adhesion in prostate cancer.
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PMID:Reduction of E-cadherin levels and deletion of the alpha-catenin gene in human prostate cancer cells. 833 65

A number of genetic changes have been documented in prostate cancer, ranging from allelic loss to point mutations and changes in DNA methylation patterns. Up to now among the most consistent changes are those of allelic loss events, with the majority of tumours examined showing loss of alleles from at least one chromosomal arm. Chromosomes 8 and 13 appear to be the most frequently affected, with the former showing both loss of alleles from the short arm and gain of sequences on the long arm. Deletions of one copy of the RB gene are common, whereas deletion and/or point mutation of the TP53 gene is a less frequent event, at least in clinically localized tumours. Alterations in the E-cadherin/alpha catenin mediated cell-cell adhesion mechanism appear to be present in over one third of all prostate cancers and may be critical to the acquisition of metastatic potential of aggressive prostate cancers. In addition, altered DNA methylation patterns have been found in the majority of prostate cancers examined, suggesting an important role for methylation modulated gene expression in prostate carcinogenesis. Finally, the existence of prostate cancer susceptibility genes is suggested by study of familial clustering of prostate cancer, and it is expected that the identification of these genes will provide insight into critical rate limiting steps in the carcinogenic pathway of both inherited and sporadic disease.
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PMID:Molecular genetics of prostate cancer. 871 27

Current androgen ablation therapies for advanced prostate cancer are not curative. Several recently identified critical biochemical pathways, including the E-cadherin/catenin complex, programmed cell death, telomerase activity, and receptor kinases, may represent targets for new therapeutic approaches. Different forms of gene therapy are also being investigated. Drug development is at the pre-clinical stage, but phase I and II clinical trials are planned, and may lead to a wider choice of therapeutic options for prostate cancer in the not too distant future.
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PMID:New perspectives in the treatment of prostate cancer. 907 7

Cadherins are a family of calcium-dependent cell-cell adhesion molecules involved in cell-cell aggregation and morphoregulatory cell function. Dysfunction of the cadherin pathway is involved in tumour invasiveness and disease progression for a variety of carcinomas. E-cadherin is a prognostic marker in prostatic cancer, based on the correlation of the grade of E-cadherin expression and tumour grade, stage, metastasis and survival, as well as recurrence after radical prostatectomy. P-cadherin was shown to be lost in all prostatic cancers, although this most likely reflects loss of the basal cell population rather than a transcriptional down-regulation, suggesting that loss of P-cadherin expression is an early event in the tumorigenesis of prostatic carcinomas. Catenins, particularly alpha-catenin, also play an important role in the dysfunction of the cell adhesion complex. Mechanisms of inactivation of the cadherin-catenin pathway include LOH, gene deletions and gene promoter hypermethylation. Therapeutic strategies have been investigated in tumour models, i.e. the use of demethylating agents for the hypermethylated promoter region of E-cadherin or gene transfer in PC-3 cells with homozygous deletion of the alpha-catenin gene. The complexity of neoplastic changes cannot be explained by alterations of cell adhesion molecules alone; but as demonstrated, cadherins and catenins play an important role in this process.
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PMID:The cadherin cell-cell adhesion pathway in prostate cancer progression. 908 71

Alterations in the E-cadherin-mediated cell-cell adhesion pathway are commonly observed in urologic malignancies. This issue has been addressed most thoroughly in prostate cancer. Whereas both cadherin and catenin dysfunction have been seen in human prostate cancers, only down-regulation of E-cadherin has been shown for bladder cancer and renal-cell carcinoma. Although studies in bladder cancer and renal-cell carcinoma are less mature than studies in prostate cancer, they support the hypothesis that immunostaining for E-cadherin may be of significance for both diagnostic and prognostic purposes. Finally, the E-cadherin-mediated cell-cell adhesion pathway may represent a novel chemotherapeutic target for bladder cancer, prostate cancer, and renal-cell carcinoma. Obviously, more work lies ahead to translate these important observations from the bench to the bedside.
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PMID:The E-cadherin cell-cell adhesion pathway in urologic malignancies. 911 56

The E-cadherin-catenin complex plays an important role in establishing and maintaining intercellular connections and morphogenesis and reduced expression of its constituent molecules is associated with invasion and metastasis. In the present study, we examined E-cadherin and alpha-, beta- and gamma-catenin levels in tumour tissues obtained by radical prostatectomy in order to investigate the relationship with histopathological tumour invasion. Immunohistochemical findings for 45 prostate cancer specimens demonstrated aberrant expression of each molecule to be associated with dedifferentiation and, in addition, alteration of staining patterns for the three types of catenin was significantly correlated with capsular but not lymphatic or vascular invasion. The data thus suggest that three types of catenin may be useful predictive markers for biological aggressiveness of prostate cancer.
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PMID:E-cadherin and alpha-, beta- and gamma-catenin expression in prostate cancers: correlation with tumour invasion. 1020 8

Normally functioning cell-cell adhesion plays an important role in the maintenance of tissue architecture and cell cohesion. E-cadherin is an important adhesion molecule of epithelial cells. In many types of cancer the expression of E-cadherin is reduced leading to increased risk of disease progression. alpha-Catenin is one of the intracellular elements of the E-cadherin-catenin complex. The abnormalities in the expression of alpha-catenin seem to associate with malignant cellular features and disease progression in prostate cancer. To further analyse the significance of alpha-catenin expression, we studied 215 cases of prostate cancer by immunohistochemistry and the results were related to other known prognostic factors and patient survival during a mean follow-up period of 13 years. alpha-Catenin expression was down-regulated in 19% of the cases and 3% of the tumours were totally alpha-catenin-negative. The abnormal alpha-catenin expression and cytoplasmic signal were significantly linked with high T-category, metastatic disease, high Gleason score, perineural growth, high mitotic rate, high S phase fraction and DNA aneuploidy (P < 0.05 for all). In the survival analysis, reduced alpha-catenin expression (P = 0.06) and cytoplasmic signal (P = 0.04) were related to unfavourable patient outcome. In the multivariate analysis, including TM-classification and Gleason score, alpha-catenin expression had independent prognostic value in T1-2 M0 tumors. In the M0 tumours, abnormal alpha-catenin signal was independently associated with recurrence-free survival as well. The results indicate that down-regulation of alpha-catenin is related to several malignant cellular features, and it seems to have prognostic significance in the early phases of cancer progression. We suggest that alpha-catenin expression can provide prognostic information in early prostate cancer.
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PMID:Alpha-catenin expression has prognostic value in local and locally advanced prostate cancer. 1040 56

The progression of carcinomas is associated with the loss of epithelial morphology and a concomitant acquisition of a more mesenchymal phenotype, which in turn is thought to contribute to the invasive and/or metastatic behavior of the malignant process. Changes in the expression of cadherins, "cadherin switching," plays a critical role during embryogenesis, particularly in morphogenetic processes. Loss of E-cadherin is reported to be associated with a poor prognosis; however, thus far, evidence (R. Umbas, et al., Cancer Res. 54: 3929-3933, 1994) for up-regulation of other cadherins has only been reported in vitro, ie., we have found evidence (M. J. G. Bussemakers et al., Int. J. Cancer, 85: 446-450, 2000) for cadherin switching in prostate cancer cell lines (up-regulation of N-cadherin and cadherin-11, two mesenchymal cadherins, in cell lines that lack a functional E-cadherin-catenin adhesion complex). Here, we report on the immunohistochemical analysis of the expression of N-cadherin and cadherin-11 in human prostate cancer specimens. N-cadherin was not expressed in normal prostate tissue; however, in prostatic cancer, N-cadherin was found to be expressed in the poorly differentiated areas, which showed mainly aberrant or negative E-cadherin staining. Cadherin-11 is expressed in the stroma of all prostatic tumors, in the area where stromal and epithelial cells are found. In addition, cadherin-11 is also expressed in a dotted pattern or at the membrane of the epithelial cells of high-grade cancers. In a number of metastatic lesions, N-cadherin and cadherin-11 are expressed homogeneously. These data raise the possibility that cadherin switching plays an important role in prostate cancer metastasis.
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PMID:Cadherin switching in human prostate cancer progression. 1091 81


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