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

The literature contains many accounts of studies in which tumour growth has been accelerated by administration of a particular mitogen and the response then inhibited by co-administration of the corresponding antagonist. Much effort has been focused on the development of cytokine or growth factor antagonists. Like most other cancer therapies, biological therapies will undoubtedly have undesirable toxicities because the proteins they target may not be unique to malignant cells. We reviewed the clinical and therapeutic potential of growth factor agonists and antagonists in some non urologic and urologic diseases. In a recent report we demonstrated that both androgen and antiandrogen treatments enhance the proliferation rate of the hormone-dependent prostate cancer cell line LNCaP, expressing a mutated androgen receptor. Simultaneous treatment with 1 nM R1881 and 100 nM OH-Flutamide, completely counteracted the androgen-induced increase of Epidermal Growth Factor (EGF) levels. Moreover we found that Testosterone, DHT and EGF are mainly concentrated in the periurethral zone in human BPH and long term treatment with Finasteride and with Flutamide modify the distribution and concentration of these factors. Some authors analyzed whether and addition of aurin tricarboxylic acid (ATA) can reduce the growth rate of basic FGF-dependent cells in a manner similar to suramin.
 ...
PMID:Peptide growth factors: clinical and therapeutic strategies. 922 27

Fibroblast growth factor 2 (FGF2), also known as basic fibroblast growth factor (bFGF), belongs to the FGF family, which consists of at least 9 closely related members. FGF2 is a potent mitogen for fibroblasts derived from normal prostate and, to a lesser extent, for prostatic epithelial cells. Its role in the physiology of the normal prostate seems to be limited to stromal cells, whereas in prostate cancer FGF2 may also have an autocrine/paracrine effect on epithelial cells. In order to better understand the effects of FGF2 on the prostatic epithelium, especially its role in the progression of prostate cancer by establishing an autocrine-stimulation loop, we transfected FGF2 cDNA into a human prostatic epithelial cell line, PNT1A, immortalized with SV40 large-T antigen. This cell line is non-tumorigenic and expresses a high-affinity FGF2 receptor, FGFR1/flg. We characterized 3 independent FGF2-transfected clones and found that the establishment of an FGF2 autocrine loop on these cells led to (i) serum-independent growth, (ii) increased proliferation and (iii) anchorage-independent growth. Such results argue in favor of the possible action of FGF2 on progression of prostate cancer via an FGF2 autocrine loop on epithelial cells.
 ...
PMID:Constitutive expression of FGF2/bFGF in non-tumorigenic human prostatic epithelial cells results in the acquisition of a partial neoplastic phenotype. 924 2

Progression of prostate cancer from an androgen sensitive to androgen insensitive tumor has previously been shown to be accompanied by a change in alternative splicing of fibroblast growth factor receptor 2 (FGF-R2) in a rat model of prostate cancer. This change results in loss of the FGF-R2(IIIb) isoform and predominant expression of the FGF-R2(IIIc) isoform. We sought to determine whether this change in FGF-R2 splicing is also associated with androgen insensitivity in human prostate tumors. We analysed three well characterized human prostate cancer cell lines and three metastatic prostate tumors which have been maintained as xenografts in nude mice. One of the cell lines, LNCaP, and two of the xenografts, DUKAP-1 and DUKAP-2, have been characterized as androgen sensitive, whereas two of the cell lines, DU-145 and PC-3, and one of the xenografts, DU9479, display androgen independent growth. Using an RT-PCR based assay, we demonstrated that progressive loss of the FGF-R2(111b) isoform correlated with androgen insensitivity in these human prostate cancer models. These findings lend support to the hypothesis that that loss of FGF-R2(IIIb) may be one step in a series of events which lead to progression of human prostate cancer.
 ...
PMID:Alternative splicing of fibroblast growth factor receptor 2 (FGF-R2) in human prostate cancer. 944 54

Alternative splicing of fibroblast growth factor receptor 2 (FGF-R2) is an example of highly regulated alternative splicing in which exons IIIb and IIIc are utilized in a mutually exclusive manner in different cell types. The importance of this splicing choice is highlighted by studies which indicate that deregulation of the FGF-R2 splicing is associated with progression of prostate cancer. Loss of expression of a IIIb exon-containing isoform of FGF-R2 [FGF-R2 (IIIb)] accompanies the transition of a well-differentiated, androgen-dependent rat prostate cancer cell line, DT3, to the more aggressive, androgen-independent AT3 cell line. We have used transfection of rat FGF-R2 minigenes into DT3 and AT3 cancer cell lines to study the mechanisms that control alternative splicing of rat FGF-R2. Our results support a model in which an important cis-acting element located in the intron between these alternative exons mediates activation of splicing using the upstream IIIb exon and repression of the downstream IIIc exon in DT3 cells. This element consists of 57 nucleotides (nt) beginning 917 nt downstream of the IIIb exon. Analysis of mutants further demonstrates that an 18-nt "core sequence" within this element is most crucial for its function. Based on our observations, we have termed this sequence element ISAR (for intronic splicing activator and repressor), and we suggest that factors which bind this sequence are required for maintenance of expression of the FGF-R2 (IIIb) isoform.
 ...
PMID:An intronic sequence element mediates both activation and repression of rat fibroblast growth factor receptor 2 pre-mRNA splicing. 952 92

FGF-1 mRNA is expressed in the prostate cancer cell lines LNCaP and PC-3 and in the breast carcinoma cell line MDA-MB-231. Levels of FGF-1 mRNA have been shown to be up-regulated by serum, phorbol esters, and combinations of growth factors. It was shown that the major FGF-1 mRNA species expressed following serum stimulation in MDA-MB-231 cells is FGF-1.C. To better understand the potential role of FGF-1 in human prostate and breast cancer, we began an analysis of the cis- and trans-acting elements of one of its promoters required for the serum, PMA, and androgen regulation in breast and prostate cancer cell lines. We show that FGF-1.C steady-state mRNA levels are increased following serum or PMA stimulation of PC-3 cells. Further, we determine the FGF-1.C transcription start site in PC-3 cells. By sequence analysis, we show that consensus AP1, AP2, and Sp1 sites and ARE- and CRE-near consensus elements are present in the immediate 5' region of the FGF-1.C transcription start site. Gel-shift assays show that oligonucleotides containing FGF-1.C AP1, AP2, or Spl sequences form specific DNA-protein complexes with nuclear extracts from PC-3 cells. To determine if these or other cis-acting sequences are responsible for the serum, androgen, or growth factor regulation of FGF-1 expression, fragments of the FGF-1.C promoter region were cloned upstream of the luciferase reporter gene. We show that FGF-1 synergizes with androgen to enhance FGF-1.C transcription in LNCaP cells. We further show that the DNA fragment containing sequence up to 1614 nucleotides upstream of the FGF-1.C transcription start site is sufficient for stimulating promoter activity following serum treatment of MDA-MB-231 cells. Thus, FGF-1.C promoter contains sequences that are important for androgen or serum stimulation in prostate and breast cancer cells.
 ...
PMID:Regulation of a promoter of the fibroblast growth factor 1 gene in prostate and breast cancer cells. 971 43

Using quantitative RT-PCR, we found that T1 rat prostate cancer cell relative FGF-1 transcript content was about 180-fold greater than that of FGF-2. This difference in transcript content was not representative of T1 cell relative FGF-1 and FGF-2 protein content which showed, at most, only a 4- to 5-fold greater FGF-1 content. Testosterone caused time-dependent down-regulation of prostate cancer cell FGF-2 transcript content without influencing either FGF-1 or FGF-8 transcript content or T1 cell proliferation. Moreover, testosterone-mediated down-regulation of prostate cancer cell FGF-2 transcripts did not result in a statistically significant change in 21.5 or 17.0 kD FGF-2 isoform content. By contrast, an approximately 20% statistically significant decrement in 19.5 kD FGF-2 isoform content was demonstrable following 24 h testosterone treatment. However, following 72 h testosterone treatment, T1 cell 19.5 kD FGF-2 isoform content was not statistically significantly different from that of control. It is probable that the modest and variable decrement in 19.5 kD isoform content is not physiologically significant and is attributable to artifact resulting from difficulty quantifying this minor component of the FGF-2 isoforms. Transient transfection analysis showed that androgen caused concentration-dependent increases in MMTV-LTR regulated expression of chloramphenicol acetyl transferase activity. Consequently, the failure of androgen to affect either T1 cell FGF-1 and FGF-8 transcript content or T1 cell proliferation could not be attributed to defective androgen receptor function. Moreover, the absence of a close relationship between T1 cell FGF-2 transcript and FGF-2 protein content implies that FGF-2 transcript content is not the dominant determinant of prostate cancer cell FGF-2 protein content. Testosterone-mediated down-regulation of prostate-cancer-cell gene expression may have significance for clinical management of human disease that is treated by androgen ablation. The possibility that such ablation may enhance aggressiveness of "androgen-independent" cells by selective upregulation of gene expression merits further consideration.
 ...
PMID:Androgen regulation of prostate cancer cell FGF-1, FGF-2, and FGF-8: preferential down-regulation of FGF-2 transcripts. 977 71

Sixty nine patients with urogenital cancers (renal, bladder and prostate cancer) were studied to determine whether the serum concentrations of Vascular Endothelial Growth Factor (VEGF) and basic Fibroblast Growth Factor (b-FGF) reflected the status of the patients and/or the prognosis of the disease. Of the patients included in this study, renal cell carcinoma patients expressed the highest levels of VEGF indicating that these tumours are more VEGF dependent. The values of b-FGF could be considered normal in all three malignancies. No correlation was observed between the expression of VEGF and b-FGF, nor between VEGF and b-FGF and patients survival.
 ...
PMID:Serum concentrations of VEGF and b-FGF in renal cell, prostate and urinary bladder carcinomas. 1021 8

Epigenetic mechanisms may be the main driving force for critical changes in gene expression that are responsible for progression of prostate cancers. The three most extensively characterized mechanisms for epigenetic gene-regulation are (i) changing patterns of DNA methylation, (ii) histone acetylations/deacetylations, and (iii) alterations in regulatory feedback loops for growth factors. Several studies have indicated that DNA hypermethylation is an important mechanism in prostate cancer for inactivation of key regulatory genes such as E-cadherin, pi-class glutathione S-transferase, the tumor suppressors CDKN2 and PTEN, and IGF-II. Similarly, histone acetylations and deacetylations are frequently associated respectively with transcriptional activation (e.g. IGFBP-2 and p21) and repression (e.g. Mad:Max dimers) of genes linked to prostate cancer progression. Recently, histone acetyltransferase and deacetylase activities have been shown to be intrinsic with transcriptional coregulator proteins that bind to steroid receptors (e.g. SRC-1 and PCAF). Changes in regulatory feedback loops for growth factors with prostate cancer progression tend toward shifts from paracrine to autocrine control where the receptor and ligand are produced by the same cell. While there are several examples of this progression pattern in prostate tumors such as with IGF, FGF, TGF-alpha and their respective receptors, the precise mechanism (i.e. epigenetic or mutational) is less certain. In the context of treatment options, the contribution of mutational versus epigenetic events to prostate cancer progression is an important consideration. Irreversible genetic changes are likely to be less amenable to therapeutic control than are epigenetic ones.
 ...
PMID:Epigenetic mechanisms for progression of prostate cancer. 1045 84

Interactions between polypeptide growth factors and the androgen receptor (AR) are important for regulation of cellular events in carcinoma of the prostate. Basic fibroblast growth factor (bFGF), the prototype of heparin-binding growth factors, and the AR are commonly expressed in prostate cancer. bFGF diminished prostate-specific antigen protein in the supernatants of androgen-stimulated human prostate cancer cells LNCaP by 80%. In the present study, we asked whether the bFGF effect on prostate-specific antigen is preceded by action on AR expression. LNCaP cells were treated with bFGF and AR protein expression was determined by immunoblotting and ligand binding assay. bFGF down-regulated AR protein in a dose-dependent manner showing a maximal effect at 50 ng ml(-1) both in the presence or absence of dihydrotestosterone. Down-regulation of AR protein expression occurred already after 8 h of bFGF treatment and a maximal inhibition was observed 24 h after addition of bFGF to culture media. As AR expression can be reduced by an increase in intracellular calcium levels, we investigated whether the bFGF effect on AR protein is mediated by this mechanism. Calcium release from intracellular stores and store-operated calcium influx after treatment with either bFGF or calcium ionophore A 23187 were measured by single cell fluorescence technique. The ionophore A 23187 was able to induce calcium influx and an increase in cytoplasmic calcium concentration in LNCaP cells. In contrast, bFGF was incapable of eliciting a similar effect. In contrast to AR protein, AR mRNA levels were not affected by bFGF as shown by semiquantitative reverse transcription polymerase chain reaction. In summary, these studies show that bFGF is a potent negative regulator of AR protein expression in the human prostate cancer cell line LNCaP.
 ...
PMID:Androgen receptor protein is down-regulated by basic fibroblast growth factor in prostate cancer cells. 1063 64

Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins, and there is evidence that they play a role in tumor cell growth, invasion and metastasis. Matrilysin (MMP-7) is over-expressed in prostate cancer cells and increases prostate cancer cell invasion. Prostate stromal fibroblasts secrete a factor(s), including fibroblast growth factor-1 (FGF-1), which induces promatrilysin expression in the prostate carcinoma cell line LNCaP but not in normal prostate epithelial cells (PrECs). Since FGF-1 is present in the prostate, an altered sensitivity to FGF-1 might explain the up-regulation of matrilysin expression in prostate cancer cells compared to normal prostate epithelium. FGF receptor-1 (FGFR-1) is not normally expressed by normal prostate epithelial cells; however, aberrant expression of this receptor has been reported in prostate cancer cells, including the LNCaP cell line. We hypothesized that aberrant expression of FGFR-1 in PrECs would render them sensitive to induction of promatrilysin expression by recombinant FGF-1. To test this hypothesis, we transiently transfected PrECs with an FGFR-1 expression vector, which resulted in over-expression of FGFR-1 protein in approximately 40% of cells. FGF-1 increased promatrilysin expression in FGFR-1-transfected PrECs 4-fold over mock-transfected cells, and this induction was inhibited by a specific FGFR-1 inhibitor, SU5402, and by co-expression of a dominant negative FGFR-1 protein. Our results demonstrate that aberrant FGFR-1 expression, an epigenetic phenomenon that has been associated with prostate cancer progression, allows induction of promatrilysin expression by FGF-1 in PrECs.
 ...
PMID:Aberrant expression of fibroblast growth factor receptor-1 in prostate epithelial cells allows induction of promatrilysin expression by fibroblast growth factors. 1114 43


<< Previous 1 2 3 4 5 6 7 Next >>