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)

Current hormone withdrawal therapies used for treatment of advanced prostate cancer lead to androgen-independent tumor growth. Increased prostatic neuroendocrine (NE) cell density has been implicated in promoting progression of prostate cancer, but the process by which this occurs remains unclear. The aim of this study was to determine whether there is an association of increased NE differentiation with neoadjuvant hormone therapy and Gleason grade. Using adjacently sectioned tissue microarrays, the expression profile of novel and known NE markers were monitored. L-Dopa decarboxylase (DDC), a catecholamine synthesis enzyme and androgen receptor (AR) coregulator protein, was identified as an additional NE marker of prostate cancer. Immunohistochemical analysis of DDC with the established NE markers, chromogranin A and bombesin, revealed a significant increase in NE differentiation after 6 months of hormone therapy and after progression to androgen independence but no apparent correlation with Gleason grade. In addition, dual immunofluorescence analysis revealed that approximately 55% of the mixed population of DDC- and chromogranin A-expressing NE cells continue to express AR. Taken together, these results suggest that the increase of NE differentiation in prostate cancers depends specifically on duration of hormone therapy. This increase may be due to the transdifferentiation of AR-expressing epithelial-derived adenocarcinoma cells into an NE cell phenotype.
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PMID:Comprehensive expression analysis of L-dopa decarboxylase and established neuroendocrine markers in neoadjuvant hormone-treated versus varying Gleason grade prostate tumors. 1699 53

The clinical significance of neuroendocrine differentiation in patients who have undergone surgery for localized prostate cancer is still unclear. The aims of this study were to assess the relationship between serum neuroendocrine markers and well-known prognostic factors in prostate cancer (pathological staging, definitive Gleason score and serum PSA) and to search for correlations between serum chromogranin A (CgA) levels and pathological findings. Forty-one consecutive patients who had undergone radical retropubic prostatectomy for clinically localized prostate cancer were evaluated. Serum PSA, CgA and neuron-specific enolase were measured immediately before surgery. Twenty-six surgical specimens were phenotypically and immunohistochemically evaluated using an antibody against CgA. Significant correlations were found between serum CgA, pathological staging and Gleason score (p=0.049 and p=0.038, respectively). Serum CgA did not correlate with PSA, patient age, or immunohistochemical findings. There was a significant correlation between positive immunohistochemical CgA staining and Gleason score (p=0.014). An increase in serum CgA levels, independent of PSA values, might be the expression of pathologically more advanced tumor stage and higher Gleason score; this could help to identify a high-risk patient group eligible for adjuvant therapy.
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PMID:The possible role of chromogranin A as a prognostic factor in organ-confined prostate cancer. 1717 61

A 62-year-old man had been treated with combined androgen blockade due to cT2bN1M0 prostate cancer, and his serum prostate-specific antigen (PSA) levels decreased and remained under the level of 0.5 ng/mL during therapy. Approximately 40 months after the initial therapy, difficulty on urination and constipation developed gradually, and serum carcinoembryonic antigen (CEA) and pro-gastrin-releasing peptide (ProGRP) levels were high at this point. He underwent transrectal and transurethral biopsy of the prostate, which revealed adenocarcinoma positive for CEA and chromogranin A. He received palliative pelvic irradiation, and oral estramustine phosphate and etoposide combined therapy. Tumor markers decreased and clinical symptoms improved for several months. The patient died of encephalopathy of unknown etiology approximately 11 months after the relapse.
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PMID:Relapsed prostate cancer with neuroendocrine differentiation and high serum levels of carcinoembryonic antigen without elevation of prostrate-specific antigen: a case report. 1730 72

Multiple studies indicate that neuroendocrine (NE) differentiation in prostate cancer (PC) contributes to androgen-independent progression. Levels of chromogranin A (CgA), which is produced by NE cells, are increased in advanced PC. However, the mechanism by which high levels of circulating CgA contribute to PC progression is unknown. To examine the effects of CgA on PC cells, we first performed proliferation assays in the presence of recombinant CgA (rCgA) in LNCaP and C4-2 PC cells, and found that rCgA increased cell proliferation in a dose and time-dependent manner. NE differentiated PC cells, also overexpress the antiapoptosis protein survivin. Therefore, we examined survivin expression in the presence of CgA in PC cells. Western blot analysis showed that survivin was significantly increased by rCgA and inhibited by an anti-CgA antibody in both LNCaP and C4-2 cells. Survivin expression is believed to be regulated by PI3K/Akt pathway. We next assessed the phosphorylation status of Akt and found that Akt phosphorylation was increased by treatment with rCgA. To determine whether Akt phosphorylation is necessary for rCgA-induced survivin expression, we examined the effects of Akt, MAPK kinase, and protein kinase C inhibitors on CgA-induced survivin expression, and found that survivin expression was reduced in the presence of Akt inhibitors, but not MAPK kinase or protein kinase C inhibitors. Furthermore, in the presence of an Akt inhibitor or small interfering RNA of survivin, CgA-enhanced proliferation of C4-2 and LNCaP cells significantly decreased. Together, our results demonstrate that CgA can increase PC cell survival through Akt-mediated survivin up-regulation.
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PMID:Attenuation of apoptosis by chromogranin A-induced Akt and survivin pathways in prostate cancer cells. 1758 63

Neuroendocrine (NE) differentiation in prostate cancer (CaP) has been reported to be an early marker associated with the development of androgen independence. The mechanisms by which CaP acquires NE properties are poorly understood. In this study, a putative role of adrenomedullin (AM) in the NE differentiation was investigated. The expression of AM and AM receptors (calcitonin receptor-like receptor (CRLR)/receptor activity modifying protein-2 and -3 (RAMP2 and RAMP3) was evaluated after experimental manipulation of androgen status. Levels of AM mRNA and immunoreactive AM (ir-AM) increased four- to sevenfold in androgen-sensitive LNCaP cells after androgen withdrawal in vitro and in LNCaP xenografts in animals after castration. Treatment of LNCaP cells with androgen analogue (dihydrotestosterone; 10(-9) M) prevented the increase in AM mRNA and ir-AM levels. Interestingly, the expression of CRLR, RAMP2 and RAMP3 is not regulated by androgen status. We demonstrate that in the presence of serum, AM is able to induce an NE phenotype in LNCaP cells via CRLR/RAMP2 and RAMP3, which includes extension of neuritic processes and expression of the neuron-specific enolase (NSE), producing cGMP in a dose-dependent manner, which is mediated by a pertussis toxin-sensitive GTP-binding protein. 8-Bromo-cGMP mimicked the effects of AM on cell differentiation. We demonstrate that AM induces a G-kinase Ialpha translocation to the nucleus. The protein kinase G inhibitor KT-5823 inhibited the neurite outgrowth induced by both AM and 8-bromo-cGMP. In noncastrated animals, administration of AM enhanced expression of NSE and chromogranin A in LNCaP xenografts with a significant increase of NSE levels in serum and no changes in tumor growth. In castrated animals, intraperitoneal injection of AM resulted in a 240+/-18% (P<0.001) increase in tumor volume 36 days after treatment, indicating that the nature of effect of AM in CaP depends on the presence or absence of endogenous androgen. Together, these results demonstrate that AM may function as a mediator of NE-like differentiation in culture as well as in vivo and indicate that its production may be important for tumor resurgence following androgen ablation.
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PMID:Adrenomedullin, an autocrine/paracrine factor induced by androgen withdrawal, stimulates 'neuroendocrine phenotype' in LNCaP prostate tumor cells. 1763 48

We provide evidence that recombinant human interferon-beta (rHuIFN-beta) is able to increase androgen receptor (AR) expression, interfere with the acquisition of a neuroendocrine (NE) phenotype, and improve adhesion potential of androgen-insensitive prostate cancer cells (PC-3). The effect of rHuIFN-beta (10-1000 IU/mL) on AR, chromogranin A (CgA), E-cadherin (E-cad), N-cadherin (N-cad), and c-met levels was investigated by Western blotting after 48, 96, and 144 h. In agreement with our previous results, rHuIFN-beta (10-1000 IU/mL) induced a dramatic increase in AR (up to 5.3-fold, p < 0.001) that was already evident with the lowest cytokine concentration (10 IU/mL). A reduction in CgA levels (up to 45%, p < 0.002) was produced by 100 and 1000 IU/mL after 48-144 h. E-cad upregulation (up to 90%, p < 0.05) was observed starting from 96 h of treatment with 100 and 1000 IU/mL rHuIFN-beta and persisted until 144 h. An rHuIFN-beta-dependent reduction occurred in N-cad and c-met signal after a 48-96 h of treatment. This effect was particularly strong after 144 h of exposure to 1000 IU/mL rHuIFN-beta (81.5%, N-cad; 58%, c-met) (p < 0.002). Reverse transcription-PCR (RT-PCR) analysis of c-met expression demonstrated that the IFN-induced c-met downregulation mostly occurs at the transcriptional level (reduction up to nearly 50%, p < 0.000). Together, these results indicate that rHuIFN-beta may reduce the motility and invasiveness of poorly differentiated prostate cancer cells and interfere with the acquisition of an NE phenotype, often characterized by a low AR level.
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PMID:Recombinant human IFN-beta affects androgen receptor level, neuroendocrine differentiation, cell adhesion, and motility in prostate cancer cells. 1778 16

Understanding prostate stem cells may provide insight into the origin of prostate cancer. Primary cells have been cultured from human prostate tissue but they usually survive only 15-20 population doublings before undergoing senescence. We report here that RC-170N/h/clone 7 cells, a clonal cell line from hTERT-immortalized primary non-malignant tissue-derived human prostate epithelial cell line (RC170N/h), retain multipotent stem cell properties. The RC-170N/h/clone 7 cells expressed a human embryonic stem cell marker, Oct-4, and potential prostate epithelial stem cell markers, CD133, integrin alpha2beta1(hi) and CD44. The RC-170N/h/clone 7 cells proliferated in KGM and Dulbecco's Modified Eagle Medium with 10% fetal bovine serum and 5 microg/ml insulin (DMEM+10% FBS+Ins.) medium, and differentiated into epithelial stem cells that expressed epithelial cell markers, including CK5/14, CD44, p63 and cytokeratin 18 (CK18); as well as the mesenchymal cell markers, vimentin, desmin; the neuron and neuroendocrine cell marker, chromogranin A. Furthermore the RC170 N/h/clone 7 cells differentiated into multi tissues when transplanted into the sub-renal capsule and subcutaneously of NOD-SCID mice. The results indicate that RC170N/h/clone 7 cells retain the properties of multipotent stem cells and will be useful as a novel cell model for studying the mechanisms of human prostate stem cell differentiation and transformation.
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PMID:Telomerase-immortalized non-malignant human prostate epithelial cells retain the properties of multipotent stem cells. 1790 May 65

The introduction of prostate-specific antigen (PSA) has revolutionized the detection and management of patients with prostate cancer. Despite this there has always been a concern among clinicians about the usefulness of total PSA levels as a marker for prostate cancer. We discuss the use of calculated variables and molecular forms of PSA. The precursor forms of PSA have been associated with the presence and biological behaviour of prostate cancer. With recent advances in biotechnology, e.g. high-throughput molecular analyses, many potential blood biomarkers have been identified and are currently under investigation. Given the plethora of candidate biomarkers we discuss a selected group of novel blood-based biomarkers, e.g. human glandular kallikrein, early prostate cancer antigen, insulin-like growth factors, urokinase plasminogen activators, transforming growth factor-beta, interleukin-6, chromogranin A, and prostate secretory protein. While these and other markers have shown promise in early-phase studies, no single biomarker is likely to have the appropriate degree of certainty to dictate treatment decisions. Consequently, the future of cancer prognosis might rely on small panels of markers that can accurately predict cancer presence, stage and metastasis, and serve as prognosticators, targets, and/or surrogate endpoints of disease progression and response to therapy.
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PMID:New blood-based biomarkers for the diagnosis, staging and prognosis of prostate cancer. 1794 30

The introduction of prostate-specific antigen (PSA) revolutionized prostate cancer (PCa) screening and ushered the PSA era. However, its use as a screening tool remains controversial and changes in the epidemiology of PCa have strongly limited its prognostic role. Therefore, we need novel approaches to improve our ability to detect PCa and foretell the course of the disease. To improve the specificity of total PSA, several approaches based on PSA derivatives have been investigated such as age-specific values, PSA density (PSAD), PSAD of the transition zone, PSA velocity and assessment of various isoforms of PSA. With recent advances in biotechnology such as high-throughput molecular analyses, many potential blood biomarkers have been identified and are currently under investigation. Given the plethora of candidate PCa biomarkers, we have chosen to discuss a select group of candidate blood-based biomarkers including human glandular kallikrein, early prostate cancer antigens, insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBP-2 and IGFBP-3), urokinase plasminogen activation system, transforming growth factor-beta1, interleukin-6, chromogranin A, prostate secretory protein, prostate-specific membrane antigen, PCa-specific autoantibodies and alpha-methylacyl-CoA racemase. While these and other markers have shown promise in early phase studies, no single biomarker is likely to have the appropriate degree of certainty to dictate treatment decisions. Consequently, the future of cancer prognosis may rely on small panels of markers that can accurately predict PCa presence, stage, metastasis, and serve as prognosticators, targets and/or surrogate end points of disease progression and response to therapy.
Prostate Cancer Prostatic Dis 2008
PMID:New circulating biomarkers for prostate cancer. 1799 18

Neuroendocrine differentiation in prostate cancer correlates with overall prognosis and disease progression after androgen-deprivation therapy, although its specific mechanisms are currently poorly understood. A role of Notch pathway has been reported in determining neuroendocrine phenotype of normal and neoplastic tissues. The aim of this study was to analyze whether this pathway might affect neuroendocrine differentiation in prostate cancer. Human achaete-scute homolog 1 (hASH1), a pivotal member of the Notch pathway, was investigated in 80 prostate cancers selected and grouped according to chromogranin A immunohistochemistry, as follows: prostate cancers without neuroendocrine differentiation, untreated (25 cases); prostate cancers with neuroendocrine differentiation, untreated (40 cases); prostate cancers with previous androgen-deprivation therapy, all having neuroendocrine differentiation (15 cases). Human ASH1 protein was analyzed by immunohistochemistry, whereas the presence of hASH1 mRNA transcripts was investigated on paraffin material by real-time PCR. By immunohistochemistry, hASH1 was colocalized with chromogranin A in neuroendocrine cells of normal prostatic gland. It was absent in all but one prostate cancers without neuroendocrine differentiation, whereas it was positive in 25% of prostate cancers with neuroendocrine differentiation/untreated, with a significant correlation with the extent of neuroendocrine features (P=0.02). Moreover, comparing untreated and treated prostate cancers with neuroendocrine differentiation, a positive association with androgen-deprivation therapy was observed (P=0.01). In prostate cancers with neuroendocrine differentiation, RNA analysis confirmed the association of higher transcript levels in androgen deprivation-treated compared with untreated patients (P=0.01). In addition, hASH1 mRNA analysis in microdissected chromogranin A-positive and chromogranin A-negative areas within the same tumor demonstrated a two- to sevenfold increase of hASH1 mRNA expression in chromogranin A-positive tumor cell populations.
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PMID:Human ASH1 expression in prostate cancer with neuroendocrine differentiation. 1831 Nov 12


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