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)

CD44 is a glycosylated adhesion molecule which may undergo alternative splicing of 10 possible exons to generate variant isoforms. A number of CD44 variant isoforms expressed by tumor cells have been correlated with metastatic and proliferative behavior. In this study, we have characterized CD44 isoform expression on three prostate cancer cell lines: ALVA-31, PPC-1, and LNCaP. Using reverse transcriptase-polymerase chain reaction, we have found that ALVA-31 and PPC-1 cells express multiple CD44 isoforms, including CD44s (standard form), CD44E (epithelial form), and an exon 14-containing form. In addition, two smaller forms have been detected: one using an alternative donor splice site within exon 5, and a novel form omitting exon 5 entirely. The CD44 isoforms expressed by ALVA-31 and PPC-1 cells appear to be preferentially located on the cell surface. By contrast, LNCaP cells do not express any of the CD44 forms at the RNA or protein level. Both PPC-1 and ALVA-31 cells display tumorigenesis and invasiveness in nude mice, whereas LNCap cells exhibit a less malignant phenotype, suggesting a correlation between CD44 variant (CD44v) expression and aggressive prostate tumor behavior. Functional characterization reveals that CD44 mediates prostate cell adhesion to extracellular hyaluronic acid (HA). In addition, the CD44 cytoplasmic domain binds specifically to ankyrin, a membrane cytoskeletal protein. Double immunofluorescence labeling and confocal microscopic analyses indicate that HA binding induces the HA receptor (i.e., CD44) to form capped structures. Importantly, intracellular ankyrin is preferentially accumulated underneath HA receptor-capped structures. These results suggest that cytoskeletal proteins such as ankyrin are closely associated with CD44-mediated signaling events induced by HA. Finally, HA-mediated transmembrane interactions between CD44 isoforms and cytoskeletal proteins (i.e. ankyrin) may play a pivotal role in regulating tumor cell behavior during human prostate cancer development.
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PMID:Interaction of CD44 variant isoforms with hyaluronic acid and the cytoskeleton in human prostate cancer cells. 754 57

We have examined the expression of the transmembrane glycoproteins CD44 in four human prostate tumor cell lines. Expression was examined at the protein level by flow cytometric analysis and Western blot, and at the mRNA level by reverse transcription-polymerase chain reaction (RT-PCR). All four cell lines (DU145, LNCaP, PC3, and ND1) expressed the standard CD44 isoform (CD44s) at the mRNA level and all cell lines except LNCaP expressed CD44s at the protein level. All four cell lines contained one or more isoforms containing the v6 region (exon 10) at the mRNA level, which has been associated with metastatic potential. However, a subpopulation of LNCaP and ND1 cells showed protein expression of v6. In addition, soluble CD44 isoforms were identified in cultured supernatants from all cell lines except LNCaP. These results show that CD44 isoforms are expressed on human prostate tumor cell lines, including the expression of variant isoforms containing the v6 region, and provide a rationale for the further study of this cellular adhesion molecule in prostate cancer. In addition, preliminary results indicate altered expression of CD44 in human prostatic adenocarcinomas examined immunohistochemically.
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PMID:Expression of CD44 isoforms in human prostate tumor cell lines. 889 7

There is a great need for markers that distinguish slowly progressive from rapidly progressive prostate cancers in paraffin-embedded tissues. CD44, an adhesion molecule that has been useful for the prediction of prognosis in some other cancers, has not been described in prostate cancer. The expression of CD44 was investigated with the monoclonal antibody GKW.A3 in prostate cancer in formalin-fixed, paraffin-embedded tissue sections of (1) whole prostates from 50 patients with 74 prostate cancers; and (2) lymph node metastases from 14 patients. Sixty percent of primary prostate cancers expressed CD44 moderately to strongly. No metastases expressed CD44 moderately to strongly; only 14% of metastases expressed even low levels of immunohistochemically detectable CD44. There is a difference between primary and metastatic prostate cancer (P <.0006) in the expression of CD44 and an inverse correlation (P <.05) between histological differentiation (Gleason grade) and the expression of CD44. The magnitude of the differential expression of CD44 in primary and metastatic prostate cancers suggests it should be investigated as an indicator of prognosis in a large prospective study.
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PMID:Altered expression of CD44 in human prostate cancer during progression. 892 76

Adhesion molecules play an important role in organogenesis, would healing, inflammation, and progression of malignant tumors. Three major classes of adhesion molecules may be discriminated by function: (a) calcium-dependent homotypic adhesion molecules (e.g. cadherins), (b) substrate adhesion molecules (e.g. integrins) and (c) heterotypic adhesion molecules (e.g. ICAM-1). Molecules of each of the three classes have been identified in urologic tumors. Results of research on substrate adhesion molecules and heterotypic adhesion molecules have not yet led to new clinical concepts. In contrast, loss of E-cadherin in tumors of the bladder and prostate has been clearly associated with de-differentiation of tumors and diminished survival of patients. Loss of another adhesion molecule, C-CAM, has been observed in prostate cancer. This has led to new therapeutic approaches, which are in an experimental stage at present. It may be expected that, in the future, new therapeutic concepts will be based on research on adhesion molecules in urologic tumors.
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PMID:[Adhesion molecules in urologic tumors]. 899 27

C-CAM1 is an epithelial adhesion molecule of immunoglobulin supergene family and has been implicated in the growth suppression of prostate cancer cells. Here we show that C-CAM1 can also suppress the tumorigenicity of breast cancer cells. These observations suggest that C-CAM1 may be a general growth suppressor in epithelial cells. In addition, we have identified the cytoplasmic domain, but not the extracellular adhesion domain, of C-CAM1 as critical for the growth suppression. Thus, the adhesion and the growth suppression functions of C-CAMI are independent of each other. Furthermore, mutation at the tyrosine phosphorylation site in the cytoplasmic domain of C-CAM1 did not obliterate C-CAM1's growth suppression function, suggesting that tyrosine phosphorylation is not involved in the signal transduction pathway leading to cell growth suppression. These studies provide the structural basis for future development of therapeutics that may selectively activate C-CAM1's growth suppression function.
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PMID:Suppression of tumorigenicity of breast cancer cells by an epithelial cell adhesion molecule (C-CAM1): the adhesion and growth suppression are mediated by different domains. 913 71

Down-regulation of the cell-surface adhesion molecule CD44 has been suggested to play an important role in tumor progression and metastasis of prostate cancer. CD44 is encoded by a gene that contains a CpG-rich region (CpG island) in its 5' regulatory sequence. We tried to assess whether hypermethylation of this region is the mechanism responsible for CD44 transcriptional inactivation. A panel of prostatic-carcinoma cell lines, Du145, LNCaP, PC3, PC346C and TSU, was analyzed for CD44 mRNA and protein expression. Du145, PC3 and TSU were positive for CD44, whereas in LNCaP and PC346C both CD44 mRNA and protein expression was suppressed. Methylation-sensitive restriction-enzyme analysis of genomic DNA showed that, in contrast to the CD44-positive cell lines, the CD44-negative lines were hypermethylated in the CD44 promoter CpG island. Furthermore, treatment of a PC346C culture with the demethylating agent 5-azacytidine resulted in re-expression of CD44 mRNA. It is concluded that hypermethylation of the CD44 5' promoter region is one of the mechanisms by which CD44 expression is down-regulated in prostatic-carcinoma cell lines.
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PMID:Down-regulation of CD44 expression in human prostatic carcinoma cell lines is correlated with DNA hypermethylation. 993 87

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

Human neoplasms are often caused by cumulative alterations in oncogenes and tumor-suppressor genes. By identifying the early genetic changes involved in tumorigenesis, one can develop strategies to prevent and detect cancers at early stages, when treatment is most effective. C-CAM1, a cell-adhesion molecule (CAM) isoform (I), was recently shown to play a critical role in prostate cancer initiation and progression. Loss of C-CAM1 expression occurs early in the development of prostate cancer, suggesting that C-CAM1 may help maintain the differentiated state of the prostate epithelium. Reintroduction of C-CAM1 into cancer cells can reverse their cancerous growth. Thus, the C-CAM1 molecule itself or drugs that increase C-CAM1 expression are promising agents for prostate cancer treatment. The mechanisms by which C-CAM1 suppresses tumorigenesis are different from those of p53 and Rb. Therefore, C-CAM1 therapy is a new form of prostate cancer treatment. To exploit C-CAM1's therapeutic potential, a human C-CAM1 adenovirus expression vector (Ad-hu-C-CAM1) has been used to treat prostate tumor xenografts in nude mice. The preliminary results have shown great promise. In addition, while C-CAM gene therapy may have immediate application in prostate cancer treatment, the knowledge to be learned from mechanistic studies of C-CAM1-mediated tumor suppression may also help us design better strategies for prevention and treatment for prostate cancer.
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PMID:Function and therapeutic implication of C-CAM cell-adhesion molecule in prostate cancer. 1059 33

To elucidate the sequence of molecular events intricate with angiogenesis and the initiation and progression prostate cancer, the temporal and spatial expression patterns of platelet endothelial cell adhesion molecule-1 (PECAM1/CD31), hypoxia-induced factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), and the cognate receptors VEGFR1 and VEGFR2 were characterized. Immunohistochemical and in situ analyses of prostate tissue specimens derived from the spontaneous autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) model identified a distinct early angiogenic switch consistent with the expression of PECAM-1, HIF-1alpha, and VEGFR1 and the recruitment of new vasculature to lesions representative of high-grade prostatic epithelial neoplasia (PIN). During progression of prostate cancer, the intraductal microvessel density (IMVD) was also observed to increase as a function of tumor grade. Immunoblot and in situ analyses further demonstrated a distinct late angiogenic switch consistent with decreased expression of VEGFR1, increased expression of VEGFR2, and the transition from a differentiated adenocarcinoma to a more poorly differentiated state. Analysis of clinical prostate cancer specimens validated the predictions of the TRAMP model. This resolution of prostate cancer-associated angiogenesis into distinct early and late molecular events establishes the basis for a "progression-switch" model to explain how the targets of antiangiogenic therapy might change as a function of tumor progression.
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PMID:Angiogenesis and prostate cancer: identification of a molecular progression switch. 1128 56

E-cadherin is a calcium 2+-dependent cell-adhesion molecule that determines epithelial development in the embryo and maintains adult differentiated epithelium and homeostasis. Aberrant or decreased expression has been reported to be associated with prostate carcinoma progression. The degree of E-cadherin expression in prostate cancer remains controversial. Some studies have reported decreased expression of E-cadherin as tumors advance and metastasize. Other studies have not demonstrated this relationship. To address these variations, we undertook a study to systematically evaluate E-cadherin expression in a broad range of prostate tissue. Benign prostate, clinically localized prostate cancer, and hormone-refractory metastatic prostate cancer were analyzed under uniform conditions using high-density tissue microarrays (TMA). Formalin-fixed, paraffin-embedded prostate carcinoma from men with clinically localized prostate carcinoma and autopsy material from men who died of widely metastatic, hormone-refractory prostate carcinoma were arrayed into 6 high-density TMA blocks. Benign and atrophic prostate tissue and high-grade prostatic intraepithelial neoplasia (PIN) were also included from the clinically localized cases. Immunohistochemistry was performed using the immunoglobulin G1 mouse monoclonal antibody (HECD-1; Zymed, San Francisco, CA). Membranous staining was recorded as low (aberrant) or high (normal). E-cadherin expression was considered aberrant if less than 70% of the cells had strong membranous staining. A total of 1,220 prostate TMA samples were analyzed. High (normal) E-cadherin expression was seen in 87% of 757 benign, 80% of 41 high-grade PIN, 82% of 325 prostate carcinoma and 90% of 97 hormone-refractory prostate carcinoma TMA samples. Mean E-cadherin expression was determined for each of the 128 clinically localized prostate cancer cases. Aberrant E-cadherin expression showed a statistical trend toward an association with positive surgical margins (P =.012), higher Gleason score (P =.18), and prostate-specific antigen (PSA) failure (Kaplan-Meier analysis, log-rank P =.09). There was a statistically significant association between aberrant E-cadherin expression and larger tumor size (P =.01). No significant associations were seen with extraprostatic extension and seminal vesicle invasion. The current study shows a broad-spectrum approach to evaluating E-cadherin protein expression in prostate carcinoma. Clinically localized prostate tumors, treated with surgery alone, show a high level of E-cadherin expression. Aberrant expression was identified in tumors with positive surgical margins, higher Gleason score, and a higher rate of PSA failure. However, these trends were not statistically significant. A statically significant association between aberrant E-cadherin expression and larger tumor size was identified. In the metastatic hormone-refractory prostate tumors, E-cadherin expression was vastly expressed, and only rare cases had aberrant expression. Therefore, the findings of this study are most consistent with a transient down-regulation of E-cadherin in localized prostate cancer. Metastatic prostate cancer shows strong E-cadherin expression as determined by anti-E-cadherin antibody HECD-1.
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PMID:E-cadherin expression in prostate cancer: a broad survey using high-density tissue microarray technology. 1148 67


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