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)

Neuroendocrine (NE) cells are androgen-independent cells and secrete growth-modulating neuropeptides via a regulated secretory pathway (RSP). We studied NE differentiation after androgen withdrawal in the androgen-dependent prostate cancer xenograft PC-310. Expression patterns of chromogranin A, secretogranin III, and prohormone convertase-1 were analyzed at both protein and mRNA level to mark the kinetics of NE differentiation both in vivo and in vitro. PC-310 tumor-bearing nude mice were killed at 0, 2, 5, 7, 14, and 21 days postcastration. PC-310C cultures initiated from collagenase-treated tumor tissue could be maintained up to four passages, and androgen-deprivation experiments were performed similarly. PC-310 tumor volumes decreased by 50% in 10 days postcastration. Proliferative activity and prostate-specific antigen (PSA) serum levels decreased to zero postcastration, whereas PSA levels in PC-310C culture media first decreased and subsequently increased after 5 days. In vivo, androgen receptor (AR) expression decreased initially but returned to control level from 5 days postcastration on. CgA, secretogranin III, and secretogranin V expression increased in vivo from 5 days postcastration on. Subsequently, prohormone convertase-1 and peptidyl alpha-amidating monooxygenase as well as the vascular endothelial growth factor were expressed from 7 days postcastration on, and, finally, growth factors such as gastrin-releasing peptide and serotonin were expressed in a small part of the NE cells 21 days postcastration. The PC-310 tumors did not show colocalization of the AR on the NE cells in the tumor residues after 21 days. As in the PC-310 xenograft, NE differentiation was induced and AR expression relapsed after prolonged androgen suppression in PC-310C. For PC-310C cells, this relapse was associated with the secretion of PSA. PC-310C is the first culture of human prostatic cancer cells having the NE phenotype. The PC-310 model system is a potential androgen-dependent model for studying the role of NE cells in the progression of clinical prostate cancer. Androgen deprivation of NE-differentiated prostate cancer may induce the formation of both NE- and AR-positive dormant tumor residues, capable of actively producing NE growth factors via a RSP, possibly leading to hormone refractory disease.
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PMID:Androgen deprivation of the PC-310 [correction of prohormone convertase-310] human prostate cancer model system induces neuroendocrine differentiation. 1067 62

The prognostic significance of neuroendocrine differentiation in prostatic malignancy is controversial, but the results of recent studies with markers such as chromogranin A and neurone-specific enolase suggest that neuroendocrine differentiation, as reflected by increased tissue expression or blood concentrations of these neuroendocrine secretory products, is associated with a poor prognosis, tumour progression, and androgen independence. As all malignant neuroendocrine cells are devoid of androgen receptors and the expression of neuroendocrine cells is not suppressed by androgen ablation, clonal propagation of androgen receptor-negative neuroendocrine cells may have an important role in the development of androgen-independent prostatic carcinoma. This has significant implications for the treatment of prostate cancer, because several of the hormones that are secreted by neuroendocrine differentiated, malignant prostatic cells are potential candidates for use in drug treatment. A limited number of hormones have been tested in this context, in particular somatostatin, bombesin, and serotonin. As there is currently no successful treatment for differentiated prostate cancer, new therapeutic procedures and trials need to be developed to test drugs based on neuroendocrine hormones or their antagonists.
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PMID:Neuroendocrine cells in tumour growth of the prostate. 1073 Sep 4

In this exploratory study, our objectives were to correlate the serum and bone marrow concentrations of putative markers of prostate cancer progression in patients with advanced androgen-independent prostate cancer (AIPC), to assess the frequency and quantity of relative expression of these markers, and to correlate the expression of the markers with extent of disease (EOD) and overall survival. In a cohort of 50 patients with AIPC with bone metastases, we obtained serum and bone marrow samples and measured prostate specific antigen (PSA), serum interleukin-6 (sIL-6), bone marrow interleukin-6, serum chromogranin A (sCgA), bone marrow chromogranin A, and prostate specific membrane antigen (PSMA) by immunoassays. EOD was determined by quantifying identifiable bone lesions on radionuclide bone scans. Each variable was categorized into two groups (low and high) based on the median found in this cohort or on the cutoff based on normal limits when available. Analyses were performed in two subsets of patients with EOD either <20 or >/=20. Results showed that: (1) PSA is associated with EOD but not with outcome; (2) sIL-6 and sCgA may be intermediate markers of early progression in AIPC, because they are predictive of outcome only in patients with EOD <20; (3) elevated PSMA is associated with elevated sIL-6 but not with PSA, suggesting that PSMA may be a useful marker in AIPC; and (4) the ratio of PSA to putative markers of progression may reflect the complex clonal progression of prostate cancer. We conclude that patients with advanced AIPC exhibit one of two patterns of serologic marker expression: in some patients the disease status is reflected by PSA, and in others it is reflected by other markers. If these data are prospectively confirmed, this would help group patients with advanced AIPC into clinically relevant categories.
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PMID:The pattern of serum markers in patients with androgen-independent adenocarcinoma of the prostate. 1076 15

The prostate specific antigen (PSA) content, the neuroendocrine differentiation and the Lewis(y) and the expression of related carbohydrate antigens in pathological prostatic tissues were determined. These included 13 cancers and 11 benign hyperplasias. PSA is expressed strongly in hyperplastic and poorly in neoplastic tissues. The neuroendocrine differentiation detected by a monoclonal antibody directed against chromogranin A (CgA) is a frequent event in carcinomas and rare in hyperplastic prostate. The Lewis(y) and related carbohydrate antigens, evaluated by the reactivity of the tissues to two monoclonal antibodies MAbB3 and MAbB1, are expressed in a considerable percentage in malignant tissues of prostate and only occasionally in benign lesions. Our results suggest that immunoblotting with antibodies against CgA, B3 and B1 on the tissues, obtained after surgery, may be useful to obtain more information on the neoplastic transformation of human prostate. Furthermore, the expression of Lewis(y) and related carbohydrate antigens on the surface of prostate cancer suggest that, following a clinical trial, an immunotoxin combination of MAbB3 or MAbB1 and Pseudomonas exotoxin, may be used in the treatment of prostate cancer.
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PMID:Expression of Lewis carbohydrate antigens and chromogranin A in human prostatic cancer. 1085 35

Increased shedding of beta-2 microglobulin (B2m, 11.8 kDa), a component of the major histocompatibility complex class I (MHC I), by tumor cells has significance with regard to escape from immune-surveillance, cellular proliferation, and tumor development and progression. Aberrant expression of MHC I is known to occur in prostate cancer (PCa) but not in benign prostatic hyperplasia. We have determined B2m released by PCa cells in culture and in the urine of 101 patients with advanced PCa by Western blotting and radioimmunoassay. B2m levels in the conditioned medium of human PCa cell lines and primary cultures derived from distant metastasis as well as in the urine of patients with bone and visceral metastasis were higher than normal and also higher than those from patients with local/regional extensions of the disease. In the group of patients with bone metastasis (66 patients), high urine B2m was associated with significantly shortened survival. In addition to the 11.8 kDa B2m, a high molecular weight B2m immunoreactivity of approximately 38 kDa was found in highly tumorigenic PC-3 cell line, but not in the relatively indolent DU-145 and LNCaP human PCa cell lines. The approximately 38 kDa B2m was found in the urine of several PCa patients but not of healthy controls examined by Western analysis. The conditioned medium of a prostatic small cell carcinoma cell line, NCI-H660, had high levels of chromogranin A and B2m, but prostate specific antigen was absent. In conclusion, increased B2m shedding was associated with distant metastasis of PCa and an abnormal B2m immunoreactivity was found in PCa.
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PMID:Changes in beta-2 microglobulin expression in prostate cancer. 1086 61

Androgen, acting via the androgen receptor (AR), is associated with the development and progression of prostate cancer. Anti-androgen therapy is widely used to manage prostate cancer. However, the conversion of the tumor from a hormone-sensitive to a hormone-insensitive status causes such therapy to fail. Several mechanisms have now been put forward for this conversion, including neuroendocrine (NE) differentiation of the tumor cells. In this study, we evaluated the prognostic significance of tumor-cell proliferation activity, NE differentiation and AR expression. Formalin-fixed, paraffin-embedded sections were prepared from 42 patients with adenocarcinoma of the prostate. Using antibodies to AR, the Ki-67 antigen (MIB-1), chromogranin A and synaptophysin, immunohistochemical expression of AR, tumor proliferation activity and NE differentiation were analyzed. Our study revealed that AR expression was significantly lower in adenocarcinoma (52.2 +/- 27.1%) than in non-tumorous prostate tissue (68.3 +/- 18.3%; P < 0.001). NE differentiation was found in 50% of the tumors, which was correlated with the Gleason score (P < 0.05). An univariate analysis revealed a significant correlation between progression-free survival with both AR expression (P < 0.01) and proliferation activity (P < 0.001). NE differentiation was not a prognostic factor in this study.
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PMID:Prognostic significance of neuroendocrine differentiation, proliferation activity and androgen receptor expression in prostate cancer. 1142 7

Serum chromogranin A (CgA) is a useful marker for neuroendocrine tumors and is detectable in carcinomas at advanced stages. Elevated serum CgA is also an indicator of poor prognosis in prostate cancer and is useful for predicting the failure of hormonal therapy for prostate cancer patients. We found that CgA molecules with three different sizes could be detected in normal human serum. However, only the largest CgA molecule appears in patients with liver disease. Serum taken from cancer patients is composed predominantly of the middle-sized molecule, whereas the smallest CgA molecule was elevated in serum drawn from renal patients. Moreover, only the smallest CgA molecule was found in urine. We believe that the largest CgA molecule is metabolized by the liver, whereas the smallest CgA molecule is removed from the blood circulation via the kidney. Because the medium-sized CgA is the dominant molecule in both the cell medium of the tumor cell line SK-N-AS and sera from patients with malignant diseases, CgA from the cell medium was selected as the calibrator for the CgA ELISA assay. Our findings also suggest that it would not be possible to measure the urinary CgA to reflect the serum CgA concentration in order to detect pheochromocytoma among patients with hypertension.
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PMID:Characterization of serum and urinary chromogranin A by size exclusion chromatography: impact on calibrator selection and urinary assay. 1143 2

Neuroendocrine cells have been implicated in many cancers, including small cell lung, cervical, breast, and prostate carcinomas. The increase in neuroendocrine cell number in prostate cancer has been reported to correlate with poor prognosis, progressive tumors, and androgen insensitivity. The mechanisms involved in this differentiation remain unknown. IGF-binding protein-related protein 1 is a member of the IGF-binding protein superfamily and has recently been shown to exhibit differentiation and tumor suppression activity in prostate cancer cell lines stably overexpressing IGF-binding protein-related protein 1. From a yeast two-hybrid screen, a novel IGF-binding protein-related protein 1-interacting protein was identified. Immunocytochemical techniques indicate that this protein, 25.1, and intracellular IGF-binding protein-related protein 1 colocalize in the nucleus. When 25.1 is transiently expressed in a stable prostate cancer cell line overexpressing IGF-binding protein-related protein 1, cells assume a neuritic-like morphology with long dendritic-like processes and express the neuroendocrine markers chromogranin A and neuron-specific enolase. We propose that 25.1 (neuroendocrine differentiation factor) together with IGF-binding protein-related protein 1 can induce neuroendocrine cell differentiation in prostate cancer cells.
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PMID:Interaction of IGF-binding protein-related protein 1 with a novel protein, neuroendocrine differentiation factor, results in neuroendocrine differentiation of prostate cancer cells. 1154

Within normal human prostate epithelium, basal and luminal cells can be discriminated by their expression of keratins (K). While basal cells express K5/14, luminal cells show expression of K8/18 and an intermediate cell population can be identified by co-expression of K5/18. Prostate cancer is predominantly composed of luminal and neuroendocrine cells, while a minority of cells have a basal phenotype. In order to distinguish between basal and intermediate cells, and to assess the effects of androgen deprivation on prostate cancer, 56 human prostate cancer metastases and three cancer cell lines were characterized using antibodies to K5, K14, K18, and the neuroendocrine marker chromogranin A (ChA). The staining was performed on paraffin tissue and visualized by the avidin-biotin-peroxidase complex method. Protein expression was quantified as the number of positive cells in 20 high power fields (HPF; 400x). Keratin expression in the prostate cancer cell lines LNCaP, DU145, and PC3 was analysed by immunofluorescence with triple staining and confocal laser scanning microscopy. Prostate cancer metastases were consistently positive for K18 and negative for K14, irrespective of hormonal therapy. K5 expression was displayed in 28.9% of the tumours without treatment, in 75% after androgen deprivation, and in 57.1% of hormone-escaped prostate carcinomas. After androgen deprivation, the number of K5-expressing cells increased significantly. While androgen-dependent prostate cancer showed a median of 0 cells/20 HPF (range 0-50), regressed tumours displayed 22.5 (range 0-65) and hormone-escaped tumours 7.5 (range 0-361) positive cells/20 HPF. Expression of ChA was observed in 47.4% of the androgen-dependent tumours. The number of neuroendocrine cells was not significantly affected in regressed or hormone-escaped disease. The androgen-dependent cell line LNCaP stained for K18, while the androgen-independent lines DU145 and PC3 both expressed K5 and 18. Expression of K5 in the absence of K14 identifies the existence of an intermediate cell population in prostate carcinoma. Accumulation of intermediate cells in regressed and hormone-escaped prostate cancer indicates that for their survival, these cells are androgen-independent.
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PMID:Expression of basal cell keratins in human prostate cancer metastases and cell lines. 1174 92

In cloning tyrosine kinase genes in dog prostate cells, a fragment of the vascular endothelial growth factor (VEGF) receptor 1 or Flt-1 was sequenced. To test for a functional protein, Flt-1 antibodies were used to probe immunoprecipitated tyrosine phosphorylated proteins. Western blotting revealed a major 170-180 kDa band and a few bands below 116 kDa in dog prostate and human prostatic carcinoma PC-3 cells, with higher levels in PC-3. Similar results were obtained with human placental membranes used as a source of Flt-1. That the major Flt-1 tyrosine phosphorylated protein was likely VEGF-R1 and part of VEGF signaling pathways was shown by enhanced level of only this protein when PC-3 cells were exposed to VEGF. Accordingly specific cell surface receptor complexes, displaced by VEGF but not EGF and compatible with Flt-1 in size, were revealed by chemical cross-linking after 125I-VEGF binding. Similarly to the prostatic neuroproduct, gastrin-releasing peptide/bombesin, VEGF directly triggered the tyrosine phosphorylation of focal adhesion kinase and stimulated PC-3 cell motility. The titration of prostate tissue sections with VEGF-A antibodies revealed a confined staining in chromogranin A and/or serotonin positive neuroendocrine (NE) cells, including in primary tumors and lymph node metastases. Given that NE differentiation is associated with advanced disease, that NE cells are a significant source of VEGF in prostatic tumors, and that VEGF directly act on prostate cancer cells in vitro, VEGF-A may be more than angiogenic in prostate cancer and hence favor progression by affecting tumor cells.
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PMID:Vascular endothelial growth factor and signaling in the prostate: more than angiogenesis. 1203 75


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