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)

The purpose of the present study was to perform a BPH risk factor analysis in men, relating the prostate gland volume to components of the metabolic syndrome and to identify clues to the etiology of BPH. Our material comprised a consecutive series of 158 patients with lower urinary tract symptoms with or without manifestations of the metabolic syndrome. In this group, the measured volume of the prostate was related consecutively to potential risk factors. The diagnoses atherosclerosis, non-insulin-dependent diabetes mellitus (NIDDM) and treated hypertension were obtained from the patient's medical history. Data on blood pressure, waist and hip measure, body height and weight were collected and body mass index (BMI) and waist/hip ratio (WHR) were calculated. Blood samples were drawn from fasting patients to determine insulin, cholesterol, triglycerides, HDL and LDL-cholesterol, uric acid and ALAT. The prostate gland volume was determined using ultrasound. Our results show that there was a larger prostate gland in men with NIDDM (P=0.0058), treated hypertension (P=0.0317), obesity (P<0.0001), low HDL-cholesterol levels (P=0.0132) and high insulin levels (P<0.0001) than in men without these conditions. The prostate gland volume correlated positively with the systolic blood pressure (r(s)=0.17; P=0.03), obesity (r(s)=0.34; P<0.0001) and fasting insulin (r(s)=0.38; P<0.0001) and negatively with HDL-cholesterol (r(s)=-0.22; P=0.009). On the basis of our findings, we concluded that NIDDM, treated hypertension, obesity, low HDL-cholesterol levels and high insulin levels constitute risk factors for the development of BPH. The results suggest that BPH is a facet of the metabolic syndrome and that BPH patients may share the same metabolic abnormality of a defective insulin-mediated glucose uptake and secondary hyperinsulinemia as patients with the metabolic syndrome. The findings generate a hypothesis of a causal relationship between high insulin levels and the development of BPH. In a clinical setting, the findings of the present report suggest that, in any patient presenting with BPH, the possible presence of NIDDM, hypertension, obesity, high insulin and low HDL-cholesterol levels should be considered. Conversely, in patients suffering from these conditions, the possibility of a clinically important BPH should be kept in mind.
Prostate Cancer Prostatic Dis 1998 Mar
PMID:Components of the metabolic syndrome-risk factors for the development of benign prostatic hyperplasia. 1249 10

We present a review of the epidemiological evidence for relations of prostate cancer risk to circulating total and bioavailable androgens, to alterations in the metabolism of insulin-like growth factor-1 (IGF-1), and to anthropometric indices of longitudinal growth (body stature) and overweight. In addition, we review the physiological inter-relationships between insulin, growth hormone/IGF-1 axis, and sex steroid metabolism, as well as the associations of bioavailable sex steroid levels with overweight and obesity. A first conclusion of this review is that, taken together, epidemiological studies have provided little support for the hypothesis that prostate cancer risk is increased in men with elevated total or biovailable testosterone (T). Although one prospective study showed an increased risk in men with low plasma sex hormone-binding globulin (SHBG) and with elevated plasma T for given levels of SHBG, this was not confirmed by results from other cohort studies. A second conclusion is that overweight, which is generally associated with moderate reductions in both total and bioavailable plasma T, appears to be unrelated to any significant increase or decrease in prostate cancer risk. However, significant increases in risk have been observed for men with a taller body stature, or with elevated plasma IGF-1. IGF-1 may directly enhance prostate tumorigenesis by inhibiting apoptosis and by stimulating cell proliferation. In addition, IGF-1 downregulates the synthesis of SHBG, and enhances sex steroid synthesis. Therefore, we do not entirely rule out that due to an elevation of plasma IGF-1 levels, men at increased risk of prostate cancer also have mildly elevated plasma bioavailable T, which epidemiological studies may have failed to demonstrate because of methodological problems. Prostate Cancer and Prostatic Diseases (2000) 3, 157-172
Prostate Cancer Prostatic Dis 2000 Nov
PMID:Plasma androgens, IGF-1, body size, and prostate cancer risk: a synthetic review. 1249 92

We previously provided evidence that glucagon-like peptide 1 (GLP-1) induces pancreatic beta-cell growth nonadditively with glucose in a phosphatidylinositol (PI) 3-kinase- and protein kinase C zeta-dependent manner. However, the exact mechanism by which the GLP-1 receptor (GLP-1R), a member of the G protein-coupled receptor (GPCR) superfamily, activates the PI 3-kinase signaling pathway to promote beta-cell growth remains unknown. We hypothesized that the GLP-1R could activate PI 3-kinase and promote beta-cell proliferation through transactivation of the epidermal growth factor (EGF) receptor (EGFR), an event possibly linked to GPCRs via activation of c-Src and the production of putative endogenous EGF-like ligands. Both the c-Src inhibitor PP1 and the EGFR-specific inhibitor AG1478 blocked GLP-1-induced [(3)H]thymidine incorporation in INS(832/13) cells as well as in isolated rat islets, while only AG1478 inhibited the proliferative action of betacellulin (BTC), an EGFR agonist. Both compounds also suppressed GLP-1-induced PI 3-kinase activation. A time-dependent increase in tyrosine phosphorylation of the EGFR in response to GLP-1 was observed in INS(832/13) cells. This transactivation of the EGFR was sensitive to both the pharmacological agents PP1 and AG1478. The action of GLP-1 and BTC on INS cell proliferation was found to be not additive. Overexpression of a dominant-negative EGFR in INS cells with a retroviral expression vector curtailed GLP-1-induced beta-cell proliferation. GLP-1 treatment of INS cells caused a decrease in cell surface-associated BTC, as shown by FACS analysis. Also, the metalloproteinase inhibitor GM6001 and an anti-BTC neutralizing antibody suppressed the GLP-1 proliferative effect. Finally, coculturing the prostatic cancer cell line LNCaP that lacks GLP-1 responsiveness with INS cells increased LNCaP cell proliferation in the presence of GLP-1, thus revealing that INS cells secrete a growth factor in response to GLP-1. GM6001 and an anti-BTC neutralizing antibody suppressed increased LNCaP cell proliferation in the presence of GLP-1 in the coculture experiments. The results are consistent with a model in which GLP-1 increases PI 3-kinase activity and enhances beta-cell proliferation via transactivation of the EGFR that would require the proteolytic processing of membrane-anchored BTC or other EGF-like ligands.
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PMID:Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. 1250 2

Because high waist-to-hip ratio (WHR) and high serum insulin levels have been reported to be associated with an increased risk of prostate cancer, we assessed the relationship between insulin resistance and prostate cancer risk in Chinese men. We measured fasting serum glucose and insulin levels in 128 case and 306 control subjects and used the homeostasis model assessment to derive indices of insulin sensitivity and resistance. Relative to men in the lowest tertiles, men in the highest tertile of insulin sensitivity had a reduced risk of prostate cancer (odds ratio [OR] = 0.35, 95% confidence interval [CI] = 0.21 to 0.60), but men in the highest tertile of insulin resistance had an increased risk of prostate cancer (OR = 2.78, 95% CI = 1.63 to 4.72). Considering insulin resistance and WHR together, the effect of insulin resistance was apparent in all tertiles of WHR, with men in the highest tertile of insulin resistance and WHR having the highest risk (OR = 8.21, 95% CI = 2.84 to 23.70). The associations between prostate cancer risk and insulin sensitivity or resistance were independent of total caloric intake and serum levels of insulin-like growth factors, sex hormones, and sex hormone-binding globulin. Because of the retrospective design of this study, the role of insulin resistance in prostate cancer needs to be confirmed in prospective studies.
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PMID:Insulin resistance and prostate cancer risk. 1286 55

Insulin-like growth factor receptor 1 (IGFR1) plays a crucial role in oncogenic transformation [C. Sell et al., Mol. Cell. Biol., 14: 3604-3612,1994]. Compared with the normal human mammary epithelial cell line MCF12A, MCF7 human mammary carcinoma cells overexpress IGFR1 on the cell surface. To measure the effects of IGFR1 inhibition on tumor cells, we tested two mouse neutralizing antibodies against human IGFR1 in cell-based assays. Both MAB391 and anti-IR3 antibodies inhibit IGFR1 autophosphorylation upon IGF-I ligand stimulation with IC50s of 0.58 and 0.80 nM, respectively. When cells were treated with neutralizing anti-IGFR1 antibodies for > or = 4 h, the total receptor level was dramatically decreased. IGF-I-stimulated activation of AKT was also inhibited by anti-IGFR1 antibodies. Furthermore, MAB391 and anti-IR3 inhibited the growth of MCF7 cells in soft agar. In addition to MCF7 cells, MAB391 also inhibited IGFR1 autophosphorylation and induced IGFR1 down-modulation in HT29 colorectal and Du145 prostate cancer cells. Therefore, neutralizing antibodies against IGFR1 represent a valid approach to inhibit growth of tumor cells.
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PMID:Neutralizing anti-insulin-like growth factor receptor 1 antibodies inhibit receptor function and induce receptor degradation in tumor cells. 1251 69

The role of androgens in cardiovascular disease is uncertain. We aimed to determine the vascular effects of androgen suppression in men with prostate cancer. Arterial stiffness (or 'compliance') was measured in 16 men (71+/-9 years, mean+/-S.D.) prior to, and 3 months after, complete androgen suppression with gonadotrophin-releasing hormone analogues as treatment for prostate cancer. Fifteen control men (70+/-7 years) also had arterial stiffness studies at baseline and 3 months later. Two measures of arterial stiffness were employed: systemic arterial compliance (SAC) was measured by simultaneous recording of aortic flow and carotid artery pressure ('area method'), and pulse wave velocities (PWVs) were recorded with the 'Complior' system. The 16 cases underwent glucose-tolerance and fasting-lipids tests on both visits. After 3 months of testosterone suppression, there was a significant fall in SAC, which was not seen in the controls [mean change+/-S.E.M., -0.26+/-0.09 a.c.u. (arbitrary compliance unit) in the cases versus +0.06+/-0.11 in the controls; P =0.03). Central, but not peripheral, PWVs tended to increase in the cases (mean change+/-S.E.M. for aorto-femoral PWV, +0.5+/-0.4 m/s for cases versus -0.3+/-0.3 m/s for controls; P =0.08). After testosterone suppression, fasting insulin levels increased from 6.89+/-4.84 m-units/l to 11.34+/-8.16 m-units/l (mean+/-S.D.), total cholesterol increased from 5.32+/-0.77 mmol/l to 5.71+/-0.82 mmol/l and high-density lipoprotein cholesterol increased from 1.05+/-0.24 mmol/l to 1.26+/-0.36 mmol/l; P <0.005 for all. No significant change occurred in body-mass index, serum glucose, low-density lipoprotein cholesterol or triacylglycerol (triglyceride) levels. Our results indicate that loss of androgens in men leads to an increase in aortic stiffness and serum insulin levels, and may therefore adversely affect cardiovascular risk.
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PMID:Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia. 1254 42

High insulin levels are linked with increased cancer risk, including prostate cancer. We examined the associations between prostate cancer with polymorphisms of the insulin gene (INS) and its neighbouring genes, tyrosine-hydroxylase and IGF-II (TH and IGF2). In this study, 126 case-control pairs matched on age, race, and countries of origin were genotyped for +1127 INS-PstI in INS, -4217 TH-PstI in TH, and +3580 IGF2-MspI in IGF2. The homozygous CC genotype of +1127 INS-PstI occurred in over 60% of the population. It was associated with an increased risk of prostate cancer in nondiabetic Blacks and Caucasians (OR=3.14, P=0.008). The CC genotype was also associated with a low Gleason score <7 (OR=2.60, P=0.022) and a late age of diagnosis (OR=2.10, P=0.046). Markers in the neighbouring genes of INS showed only null to modest associations with prostate cancer. The polymorphism of INS may play a role in the aetiology of prostate cancer. Given the high prevalence of the CC genotype and its association with late age of onset of low-grade tumours, this polymorphism may contribute to the unique characteristics of prostate cancer, namely a high prevalence of indolent cancers and the dramatic increase in incidence with age.
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PMID:Polymorphism of the insulin gene is associated with increased prostate cancer risk. 1261 May 12

Insulin-like growth factor binding protein 2 (IGFBP2) has been shown to be overexpressed in prostatic intraepithelial neoplasia (PIN) and invasive cancer and the serum level to parallel that of prostate-specific antigen (PSA) in prostate cancer. A combination of cDNA and tissue microarray results recently demonstrated overexpression of IGFBP2 in hormone refractory prostate cancer, indicating that the IGF system may be part of a key growth regulatory pathway in prostate cancer. The present study reexamines the immunohistochemical expression of IGFBP2 and its relationship to grade in tissue from 193 radical prostatectomy specimens from patients with localized prostate adenocarcinoma. We found a significant overexpression of IGFBP2 in all instances of PIN and in more than 90% of cancers regardless of the grade. An intense overexpression was noted in the neuroendocrine cells in normal glands as well as in cancer. The IGFBP2 expression was also analyzed in 18 cases of biopsy diagnosed prostate cancer. In all these cases, the glands interpreted as invasive cancer in hematoxylin-eosin stained sections overexpressed IGFBP2, without a significant correlation to grade. We conclude that overexpression of IGFBP2 is a powerful marker for malignant transformation in the prostate epithelium and suggest that optimized immunohistochemical detection of IGFBP2 expression may be an adjunct tool in the diagnosis of prostate cancer.
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PMID:Overexpression of IGBFB2 is a marker for malignant transformation in prostate epithelium. 1268 67

We conducted a review of previous cohort studies on the association between a history of diabetes mellitus (DM) and the occurrence of cancer. We limited the papers to those concerning cohort studies on 9 cancer sites, i.e. the kidney, liver, biliary tract, pancreas, colon or rectum, prostate, breast, endometrium, and ovary, in addition to all cancers. With regard to kidney, liver, biliary tract, pancreatic, colorectal, breast, and endometrial cancers, the risk of cancer development has been consistently reported to be positively associated with DM by two or more cohort studies. In contrast, DM was shown to relate negatively to the risk of prostate cancer by two cohort studies. However, there were no cohort studies which showed an either significantly positive or negative association of DM with ovarian cancer. Elevated levels of insulin or IGFs among DM patients have been proposed as a causal mechanism of increased risk for most of the reviewed cancers. In addition, increased estrogen levels in DM patients have been suggested to explain the casual mechanism of increased risk for kidney, breast and endometrial cancers, and decreased risk for prostate cancer. On the other hand, the possibility of detection bias has been suggested in the association of DM with the risk of most of these cancers. Obesity and heavy consumption of alcohol have been indicated as confounding factors in the relationship of DM to the risk for some of them. Thus, further studies are necessary for firm conclusions regarding the association of DM with cancer risk.
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PMID:A Review of Cohort Studies on the Association Between History of Diabetes Mellitus and Occurrence of Cancer. 1271 99

Activation of alternative growth factor pathways after androgen withdrawal is one mechanism mediating androgen-independent (AI) progression in advanced prostate cancer. Insulin-like growth factor (IGF) I activation is modulated by a family of IGF binding proteins (IGFBPs). Although IGFBP-2 is one of the most commonly overexpressed genes in hormone refractory prostate cancer, the functional significance of changes in IGF-I signaling during AI progression remains poorly defined. In this article, we characterize changes in IGFBP-2 in the LNCaP tumor model after androgen withdrawal and evaluate its functional significance in AI progression using gain-of-function and loss-of-function analyses. IGFBP-2 mRNA and protein levels increase 2-3-fold after androgen withdrawal in LNCaP cells in vitro in LNCaP tumors during AI progression in vivo. Increased IGFBP-2 levels after castration were also identified using a human prostate tissue microarray of untreated and posthormone therapy-treated prostatectomy specimens. LNCaP cell transfectants that stably overexpressed IGFBP-2 progressed more rapidly after castration than control tumors. Antisense oligonucleotides (ASOs) targeting the translation initiation site of IGFBP-2 reduced IGFBP-2 mRNA and protein expression by >70% in a dose-dependent and sequence-specific manner. ASO-induced decreases in IGFBP-2-reduced LNCaP cell growth rates and increased apoptosis 3-fold. LNCaP tumor growth and serum prostate-specific antigen levels in mice treated with castration plus adjuvant IGFBP-2 ASOs were significantly reduced compared with mismatch control oligonucleotides. Increased IGFBP-2 levels after androgen ablation may represent an adaptive response that helps potentiate IGF-I-mediated survival and mitogenesis and promote androgen-independent tumor growth. Inhibiting IGFBP-2 expression using ASO technology may offer a treatment strategy to delay AI progression.
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PMID:Castration-induced increases in insulin-like growth factor-binding protein 2 promotes proliferation of androgen-independent human prostate LNCaP tumors. 1283 44


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