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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A human prostate cancer model was established by inoculating a prostate specific antigen (PSA)-producing LNCaP cell line with either prostate or bone fibroblasts. Alternatively, this human prostate cancer model can also be established by inoculating LNCaP cells with growth factor(s) (GFs) and extracellular matrix (ECM) immobilized on Gelfoam. The resulting LNCaP tumors were used to evaluate PSA production and excretion in athymic hosts. This model was also employed to examine the biochemical nature of mesenchymal cell-derived growth-promoting protein(s) and to assess the efficacy of potential chemotherapeutic agents. Because of the propensity of human prostate cancer to metastasize to the bone, this study defined a 1.0 M NaCl-eluted fraction, MS1, from the conditioned medium of a bone stromal cell line (MS) by heparin-affinity column chromatography. The growth-promoting activity was assayed both in vivo (e.g., tumor formation) and in vitro (e.g., soft agar colony formation). We found that the growth-promoting activity was trypsin- and heat-sensitive, and partially degraded by acid and dithiothreitol. Immunochemical studies indicated that the polyclonal antibody raised against MS1 blocked the growth-promoting effect elicited by the bone-conditioned media. This growth-promoting factor was found to be immunochemically dissimilar to KGF, HGF, and bFGF. However, addition of bFGF, HGF and NGF, but not aFGF, TGF beta, IGF1, IGF2, PDGF, EGF, TGF alpha and KGF, stimulated anchorage-independent growth of prostate cells, a condition closely parallel to tumor formation in vivo. We found that the MS1 fraction also contained fibronectin and tenascin but not laminin or collagen IV.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human prostate cancer model: roles of growth factors and extracellular matrices. 128 80

The effect of an EGF-R selective tyrosine kinase inhibitor ZM252868 was evaluated on the proliferation of PC-3 and DU-145 prostate cancer cell lines, which are purported to utilize an EGF-R-mediated autocrine pathway for regulation of cell growth. Basal growth of DU-145 cells was inhibited in a dose-dependent manner by the inhibitor, showing a 70% reduction at 1 microM, whilst the growth of PC-3 cells was not affected at this concentration. In the presence of 0.1 microM inhibitor, EGF and TGF alpha-stimulated DU-145 cell growth was decreased to below basal levels, while only TGF alpha-stimulated PC-3 cell growth was inhibited at a 1-microM concentration. Any growth responses to aFGF, bFGF, KGF, IGF1 and PDGF by DU-145 and PC-3 cells were unaffected by the inhibitor at concentrations of 1 microM or less. Additionally, the distribution of immunoreactive EGF-R varied between DU-145 and PC-3 cells, with EGF-R being predominately located on the cell membrane and in the cytoplasm, respectively.
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PMID:New EGF-R selective tyrosine kinase inhibitor reveals variable growth responses in prostate carcinoma cell lines PC-3 and DU-145. 918 5

Degenerate polymerase chain reaction against conserved kinase catalytic subdomains identified 15 tyrosine and serine-threonine kinases expressed in surgically removed prostatic carcinoma tissues, including six receptor kinases (PDGFBR, IGF1-R, VEGFR2, MET, RYK, and EPH-A1), six non-receptor kinases (ABL, JAK1, JAK2, TYK2, PLK-1, and EMK), and three novel kinases. Several of these kinases are oncogenic, and may function in the development of prostate cancer. One of the novel kinases is a new member of the sterile 20 (STE20) family of serine-threonine kinases which we have called prostate-derived STE20-like kinase (PSK) and characterized functionally. PSK encodes an open reading frame of 3705 nucleotides and contains an N-terminal kinase domain. Immunoprecipitated PSK phosphorylates myelin basic protein and transfected PSK stimulates MKK4 and MKK7 and activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway. Microinjection of PSK into cells results in localization of PSK to a vesicular compartment and causes a marked reduction in actin stress fibers. In contrast, C-terminally truncated PSK (1-349) did not localize to this compartment or induce a decrease in stress fibers demonstrating a requirement for the C terminus. Kinase-defective PSK (K57A) was unable to reduce stress fibers. PSK is the first member of the STE20 family lacking a Cdc42/Rac binding domain that has been shown to regulate both the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and the actin cytoskeleton.
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PMID:PSK, a novel STE20-like kinase derived from prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and regulates actin cytoskeletal organization. 1066 Jun

The incidence of prostate cancer is related to aging. Its increase in the last 10 years, varies from country to country and according to ethnic group, with its greatest incidence among African-American males and the least among Asian males. Only two risk factors have thus far been clearly established for prostate cancer: familial aggregation and ethnic origin. No dietary or environmental cause has yet been identified for prostate cancer. However, some variations in endogenous factors, such as sex steroids or IGF1 circulating levels, may partly explain differences in risk observed between different populations. Genetic polymorphisms of genes encoding for 5alpha-reductase, androgen receptor, or vitamin D receptor have been associated with different degrees of risk for prostate cancer and may explain variations in risk among ethnic groups or within geographic areas. Different studies support the theory that familial prostate cancer may be hereditary and not due to a similar lifestyle. Thus, familial inheritance is a parameter that must be considered when advising screening in high-risk families. Indeed, the relative risk for first-degree relatives of prostate cancer patients can reach 2, 5 and 11 when, respectively, 1, 2 and 3 first-degree relatives are affected. Some familial forms appear to be associated with transmission of a rare, putative, autosomal dominant gene (0.003-0.06 allele frequency) with a high penetrance (88% at age 85). Using this transmission model and linkage analysis, three predisposing loci on chromosome 1: HPC-1 (hereditary prostate cancer 1: 1q24-25), PCaP (predisposing for prostate cancer: 1q42-43) and CAPB (predisposing for prostate and brain tumor: 1p36) and one locus on chromosome 20 (HPC20: 20q13) have been described. Moreover, X-linked transmission has been suggested and related to another predisposing gene locus: HPCX (Xq27-28). It is possible that a large proportion of familial prostate cancer is due not to segregation of a few major gene mutations transmitted according to a monogenic inheritance, but rather to familial sharing of alleles at many loci, each contributing to a small increase in cancer risk.
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PMID:Heterogeneity in genetic susceptibility to prostate cancer. 1117 5

Peptide growth factors play an important role in several intracellular processes, such as cellular growth and differentiation, angiogenesis and apoptosis, as well as in carcinogenesis, since they contribute significantly to the malignant transformation. The prostate gland is abundant in growth factors. The two most known prostatic diseases, prostate cancer (PCa) and benign prostatic hyperplasia (BPH), are among the most common diseases that affect elderly men. This study was conducted using a quantitative real-time RT-PCR method in order to determine mRNA expression levels of peptide growth factors VEGF, FGF2, TGFB1, EGF, and IGF1 in tissue specimens from 42 patients with PCa, 42 with BPH, and 10 normal prostate samples obtained post-mortem from young individuals, in order to examine their association with prostatic hyperplasia and neoplasia. Our results show that in PCa, growth factors VEGF, EGF and FGF2 are overexpressed, while TGFB1 and IGF1 have reduced mRNA levels. In BPH, transcript levels of FGF2 and EGF are normal, while VEGF, TGFB1 and IGF1 exhibit downregulation. Further statistical analysis revealed that PCa patients with high levels of PSA blood levels have decreased FGF2 expression (p=0.016). Additionally, cancer patients with low Gleason score (<7) have increased EGF (p=0.035) and IGF1 (p=0.031) mRNA levels. IGF1 levels are also elevated in tumors with TNM stages T1-T2 (p=0.030). In BPH, older patients have reduced EGF expression (p=0.018), while IGF1 is overexpressed in younger patients (p=0.041). Additionally, the co-expression pattern of the five studied growth factors differs significantly among normal, benign and malignant prostate. These results implicate VEGF, FGF2, TGFB1, EGF and IGF1 in the development of both PCa and BPH, rendering them potential targets for disease detection, monitoring and therapy.
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PMID:Expression analysis of peptide growth factors VEGF, FGF2, TGFB1, EGF and IGF1 in prostate cancer and benign prostatic hyperplasia. 1682 Aug 71

Insulin-like growth factor-I (IGF1) stimulates cell proliferation, decreases apoptosis, and has been implicated in cancer development. Epidemiological studies have shown elevated levels of circulating IGF1 to be associated with increased risk of prostate cancer. To what extent genetic variation in the IGF1 gene is related to prostate cancer risk is largely unknown. We performed a comprehensive haplotype tagging (HT) assessment of single nucleotide polymorphisms (SNPs) representing the common haplotype variation in the IGF1 gene. We genotyped 10 SNPs (9 haplotype tagging SNPs (htSNPs)) within Cancer Prostate in Sweden (CAPS), a case-control study of 2,863 cases and 1,737 controls, in order to investigate if genetic variation in the IGF1 gene is associated with prostate cancer risk. Three haplotype blocks were identified across the IGF1 gene and 9 SNPs were selected as haplotype tagging SNPs. Common haplotypes in the block covering the 3' region of the IGF1 gene showed significant global association with prostate cancer risk (p = 0.004), with one particular haplotype giving an odds ratio of 1.46 (95% CI = 1.15-1.84, p = 0.002). This haplotype had a prevalence of 5% in the study population. Our results indicate that common variation in the IGF1 gene, particularly in the 3' region, may affect prostate cancer risk. Further studies on genetic variations in the IGF1 gene in relation to prostate cancer risk as well as to circulating levels of IGF1 are needed to confirm this novel finding.
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PMID:Comprehensive evaluation of genetic variation in the IGF1 gene and risk of prostate cancer. 1709 24

The EGF/IGF growth factors are potent mitogens that regulate cell proliferation and cell survival and are involved in prostate cancer development. Using laser microdissection technology and real-time PCR, together with immunohistochemistry, we have explored the growth factor and integrin dependent PI3-kinase/PTEN/Akt signalling pathway in prostate cell lines and tumour samples by analysing EGF-R, IGF1-R, ILK, beta3 integrin, PTEN and p-Akt protein expression. We provide evidence that loss of PTEN expression rather than upregulated EGF/IGF1 receptor expression was responsible for increased p-Akt in neoplastic prostate cells. We therefore compared PTEN expression in patient biopsies at first time diagnosis recruited prospectively (Study I, 112 patients) and patients with confirmed metastasis recruited retrospectively from the Luxembourg cancer registry (Study II, 42 patients). In Study I, loss of PTEN expression at first time diagnosis was found in 26 of 112 patients (23%). In Study II, 25 of the 42 patients (59%) with lymph node metastasis had complete loss of PTEN expression in both the neoplastic glands of the prostate and the invasive prostate cancer cells in the lymph node, and of these 13 (52%) exhibited already loss of PTEN expression at first diagnosis. These findings demonstrate that loss of PTEN expression is an important factor in progression towards metastatic disease and could potentially serve as an early prognostic marker for prostate cancer metastasis.
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PMID:Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis. 1716 22

IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses) comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.
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PMID:IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3). 1859 9

Androgens promote the growth and differentiation of prostate cells through ligand activation of the androgen receptor (AR). Sensitization of the androgenic response by multifunctional growth factor signaling pathways is one of the mechanisms via which AR contributes to the emergence of androgen-independent prostate tumors. The ability of AR to cross-talk with key growth factor signaling events toward the regulation of cell cycle, apoptosis, and differentiation outcomes in prostate cancer cells is established. In this paper, we review the functional interaction between AR and an array of growth factor signal transduction events (including epidermal growth factor; fibroblast growth factor; IGF1; vascular endothelial growth factor; transforming growth factor-beta) in prostate tumors. The significance of this derailed cross-talk between androgens and key signaling networks in prostate cancer progression and its value as a therapeutic forum targeting androgen-independent metastatic prostate cancer is discussed.
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PMID:Androgen receptor and growth factor signaling cross-talk in prostate cancer cells. 1866 87

Avoiding age-related disease until late in life is key to 'successful' ageing. Over 300 genome-wide association study papers have been published. Over 50 variants have already been identified as associated with four key age-related diseases, namely cardiovascular disease, type 2 diabetes, osteoporosis and prostate cancer. We review these findings with reference to pathways linked to ageing, including cell cycle control or cell senescence, oxidative stress, insulin, IGF1 and other endocrine signalling, and inflammation. Many variants are disease specific or of unknown function. Of the remainder, those with functions likely to be relevant to ageing are predominantly in cell cycle control and therefore tissue repair. Three loci associated with two or more age-related diseases have been identified, two apparently related to cell cycle control. The third shared locus (near TERT), may be involved in telomerase activity and is associated with several environmentally caused age-related cancers. These findings challenge current ideas, suggesting large numbers of cell type specific effects, often driven by regulatory rather than coding changes. They also confirm the central role of cell cycle and re-growth as a key pathway underlying the human variation in successful ageing.
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PMID:Human genetic variations: Beacons on the pathways to successful ageing. 1958 Aug 24


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