UMLS:C0376358 - FACTA Search

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

Vitamin D analogues have an antiproliferative effect on prostate cancer cells in vitro and thus have been proposed as candidates for chemoprevention of prostate cancer. Insulin-like growth factor (IGF)-I has been shown to protect cells from apoptosis and plays an essential role in normal prostate physiology. We have studied the effects of the 1,25-dihydroxyvitamin D3 analogue EB1089 on the IGF system in the prostate in vivo. Treatment of rats with EB1089 for 14 days caused a 25% decrease in ventral prostate weight. Apoptosis was detected in prostate sections of EB1089-treated rats by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(TUNEL) assay and histologic examination of hematoxylin/eosin stained tissue sections indicated that secretory epithelial cells were flattened, a characteristic of cells undergoing pressure-induced atrophy. Ventral prostate regression was associated with 15- to 25-fold increases in gene expression of IGF-binding proteins (IGFBPs)-2,-3,-4 and -5. We also observed a 40-fold increase in prostatic IGF-I mRNA levels in response to EB1089. Although we have previously shown that castration of rats leads to upregulation of IGFBPs in the ventral prostate, EB1089 treatment had no effect on serum levels of dihydrotestosterone or free testosterone. These results suggest that prostate regression induced by EB1089 may be related to alterations in availability of IGF-I as a result of increased production of IGFBPs.
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PMID:Vitamin D analogue EB1089-induced prostate regression is associated with increased gene expression of insulin-like growth factor binding proteins. 992 91

The protein product of the novH oncogene, a member of the CCN family, is structurally related to the insulin-like growth factor (IGF) binding proteins (IGFBPs). We have characterized aspects of structure, function, and distribution of this protein, which, as IGFBP-related protein 3 (IGFBP-rP3), is a proposed member of the IGFBP Superfamily. Affinity cross-linking experiments performed with baculovirus synthesized recombinant human IGFBP-rP3 established that rhIGFBP-rP3 binds IGF-I, IGF-II, and insulin with low affinity. Specificity of binding was shown by competitive cross-linking experiments; binding to IGF-I and -II was also demonstrated by nondenaturing Western ligand blots. Northern blot analysis indicated the presence of IGFBP-rP3 messenger RNA (mRNA) in a broad range of human tissues. Western immunoblotting studies, using a polyclonal rabbit anti-rhIGFBP-rP3 antibody, demonstrated that IGFBP-rP3 protein is synthesized in vitro by several breast and prostate cancer cell lines: Hs578T, PC3, P69, and LNCaP cells. Western immunoblotting studies of human biological fluids identified that IGFBP-rP3 was present in normal serum, pregnancy serum, serum from patients with growth hormone receptor deficiency, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and follicular fluid, while IGFBP-rP3 fragments were identified in cerebrospinal fluid, amniotic fluid, and prepubertal and pubertal urine samples. Our studies demonstrate that IGFBP-rP3 exhibits IGF binding, albeit at low affinity, and IGFBP-rP3 thus merits inclusion in the IGFBP Superfamily. The low affinity IGF binding suggests that IGFBP-rP3 may act primarily independently of the IGFs. The synthesis of IGFBP-rP3 by several malignant cell lines and its presence in human biological fluids suggest that this protein possesses other interesting roles, potentially in cell growth regulation.
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PMID:Binding properties and distribution of insulin-like growth factor binding protein-related protein 3 (IGFBP-rP3/NovH), an additional member of the IGFBP Superfamily. 1008 1

We have characterized the temporal expression of the insulin-like growth factor (IGF) axis in the transgenic adenocarcinoma of mouse prostate (TRAMP) model as prostate cancer progression in this model closely mimics that observed in the human disease, and the model provides samples representing the earliest stages of prostate cancer that are clinically the most difficult to obtain. We report that prostate-specific IGF-I mRNA expression increased during prostate cancer progression in TRAMP mice and was elevated in the accompanying metastatic lesions, whereas prostatic IGF-I mRNA remained at nontransgenic levels in androgen-independent disease. Expression of IGF-II mRNA, however, was reduced in primary prostate cancer, metastatic lesions, and androgen-independent disease. Expression of type-1 IGF receptor (IGF1R) mRNA, encoding the cognate receptor for both IGF-I and IGF-II, as well as type-2 IGF receptor (IGF2R) mRNA was not found to be altered during primary prostate cancer progression in intact TRAMP mice but was dramatically reduced in metastatic lesions and in androgen-independent disease. Similar to reports from clinical disease, serum IGF-I levels were observed to increase precociously in TRAMP mice early in disease progression but remained at nontransgenic levels after castration. Elevated serum levels of IGF-binding protein 2 were observed to correlate with advanced prostate cancer in the TRAMP model. Together these observations implicate IGF-I as an important factor during the initiation and progression of primary prostate cancer and provide evidence that there is a strong selection against expression of IGF1R and IGF2R in metastatic and androgen-independent disease.
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PMID:The insulin-like growth factor axis and prostate cancer: lessons from the transgenic adenocarcinoma of mouse prostate (TRAMP) model. 1023 9

Chemoprevention is the administration of agents to prevent induction and inhibit or delay progression of cancers. For prostate, as for other cancer targets, successful chemopreventive strategies require well-characterized agents, suitable cohorts, and reliable intermediate biomarkers of cancer for evaluating chemopreventive efficacy. Agent requirements are experimental or epidemiological data showing chemopreventive efficacy, safety on chronic administration, and a mechanistic rationale for the observed chemopreventive activity. On this basis, promising chemopreventive drugs in prostate include retinoids, antiandrogens, antiestrogens, steroid aromatase inhibitors, 5alpha-reductase inhibitors, vitamins D and E, selenium, lycopene, and 2-difluoromethylornithine. Phase II trials are critical for evaluating chemopreventive efficacy. Cohorts in these trials should be suitable for measuring the chemopreventive activity of the agent and the intermediate biomarkers chosen as endpoints. Many cohorts proposed for phase II trials are patients with previous cancers or premalignant lesions. For such patients, trials should be conducted within the context of standard treatment. Two cohorts currently used in phase II prostate cancer chemoprevention trials are patients with PIN and patients scheduled for prostate cancer surgery. Biomarkers should fit expected biological mechanisms, be assayed reliably and quantitatively, measured easily, and correlate to decreased cancer incidence. Protocols for adequately sampling tissue are essential. Changes in PIN provide prostate biomarkers with the ability to be quantified and a high correlation to cancer. PIN measurements include nuclear polymorphism, nucleolar size and number of nucleoli/nuclei, and DNA ploidy. Other potentially useful biomarkers are associated with cellular proliferation kinetics (e.g. PCNA and apoptosis), differentiation (e.g. blood group antigens, vimentin), genetic damage (e.g. LOH on chromosome 8), signal transduction (e.g. TGFalpha, TGFbeta, IGF-I, c-erbB-2 expression), angiogenesis, and biochemical changes (e.g. PSA levels).
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PMID:Chemoprevention of prostate cancer: concepts and strategies. 1032 87

The majority of elderly men is affected by benign and malignant diseases of the prostate. Both proliferative disorders, i.e., benign hyperplasia of the prostate (BPH) and prostate cancer (PCa)-which has recently emerged as the most common male malignancy in industrialized countries-seem to be governed by endocrine factors such as sex steroid hormones, but auto/paracrine factors are involved as well. Age-related changes in levels and ratios of endocrine factors as androgens, estrogens, gonadotropins, and prolactin (PRL) and changes in the balance between auto/paracrine growth-stimulatory and growth-inhibitory factors such as insulin-like growth factors (IGFs), epidermal growth factor (EGF), nerve growth factor (NGF), IGF-binding proteins (IGFBPs), and transforming growth factor beta (TGFbeta) are meant to be responsible for abnormal prostatic growth. We investigated the existence of putative local regulatory circuits involving the protein hormones, human growth hormone (hGH), human placental lactogen (hPL), and hPRL, and their corresponding receptors in prostatic tissue specimens (transurethral resections of the prostate, TURP; n = 11), in the prostatic cancer cell lines PC3, Du145, LnCap, a virus-transformed BPH cell line (BPH-1), and in a normal healthy prostate by RT-PCRs and highly specific and sensitive immunofluorometric assays (IFMA). Neither hPRL nor hGH was detected at the mRNA or protein levels in prostatic tissue and cell lines, with the exception of 2 of 11 prostatic TURP-samples, which showed weak expression of the PL-A/B genes. PRL- and GH-receptors were expressed in all normal and pathological prostatic specimens. Surprisingly, PRL-receptor expression was not detectable in prostatic cancer cell lines. The trophic effects of exogenous hGH, hPL, and hPRL were investigated by cell proliferation assays (WST-I) in prostatic primary cell cultures and PCa cell lines. hGH significantly (p < 0.005) increased cell proliferation up to 138+/-3.2% (1 nM hGH), while hPL and hPRL revealed only moderate effects. Our data suggest that local auto/paracrine networks of protein hormone actions are not involved in the pathology of BPH or prostatic cancer. On the other hand, systemic pituitary-derived hGH can increase the proliferative response of BPH and PCa, acting directly on the target organ prostate, via the hGH-R. In this case, envisaged GH substitution in elderly people must be viewed at with caution because age-related declines in GH/IGF-I could act as a protective mechanism against abnormal cell growth.
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PMID:Proliferative disorders of the aging human prostate: involvement of protein hormones and their receptors. 1036 93

Insulin-like growth factor (IGF)-I has well-characterized mitogenic and antiapoptotic effects that are essential for maintenance of the normal prostate and may be important during regression of the normal prostate and/or prostate tumors induced by androgen-targeting therapies for prostate cancer. IGF-I activity is modulated by IGF-binding proteins (IGFBPs). Here we examine IGFBP expression during regression of androgen-dependent Shionogi carcinoma tumors after castration. In this model, we observe a 90% reduction in Shionogi tumors by 10 days postcastration. Northern blotting of RNA from tumors collected at various times after castration indicates a rapid induction of IGFBP-5 concomitant with apoptotic regression of tumors, as detected by Apoptag staining of tumor sections after castration. IGFBP-5 mRNA was not detectable in tumors from control animals, but levels increased 120-fold in tumors 3 days after castration. The mRNAs for IGFBP-3 and 4 were abundant in Shionogi tumors from intact mice and decreased to -33% and -20% of control, respectively. Castration had no significant effect on IGFBP-2 expression. Treatment with calcium channel blockers inhibited castration-induced apoptosis and tumor regression and also significantly inhibited up-regulation of IGFBP-5 after castration. These data provide strong evidence for a functional role of IGFBP-5 expression in mediating the apoptosis induced by androgen deprivation in androgen-dependent neoplasia.
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PMID:Castration-induced apoptosis of androgen-dependent shionogi carcinoma is associated with increased expression of genes encoding insulin-like growth factor-binding proteins. 1041

Recent case-control studies have found a 7-8% increase in the serum levels of insulin-like growth factor (IGF)-I in patients with prostate cancer (CaP), the most frequently diagnosed cancer in men. We hereby review what is currently known about growth hormone (GH) and the IGF axis in CaP, take a closer inspection of the studies published to date reporting IGF-I levels in CaP patients, and derive implications for the future medical management of patients receiving trophic hormone therapies as well as those at risk for developing CaP. The role of GH in controlling prostate growth and carcinogenesis is still unclear from animal studies and human disease patterns. However, multilayered perturbations of the IGF axis, including the autocrine production of IGFs, IGF binding proteins (IGFBPs) and IGFBP proteases, such as prostate-specific antigen, have been identified in CaP cells and tissues. Interestingly, IGFBP-3 is a potent inhibitor of prostatic IGF action and also mediates prostate apoptosis via an IGF-independent mechanism. Serum IGFBP-3 levels have been identified to be negatively correlated to the risk of CaP. Notably, GH therapy raises both IGF-I and IGFBP-3 levels in serum. Conclusions based on the studies of IGF-I levels in CaP patients are affected by both the populations studied and the types of IGF-I assay employed. While the studies do indicate an association between serum IGF-I levels and CaP risk, causality has not been established. Thus, serum IGF-I level may actually be a confounding variable, serving as a marker for local prostatic IGF-I production. Increased GH levels as seen in acromegaly have been associated with benign prostatic hyperplasia but not with CaP. Thus, serum IGF-I may lead to an ascertainment bias among younger men with benign prostatic hyperplasia who are more likely to present with prostatic symptoms and have subclinical CaP diagnosed. Should serum IGF-I levels be proven to play a causal role in the pathogenesis of CaP, interpreting the risk associated with therapies such as GH must take into account both the duration of exposure and the risk magnitude associated with the degree of serum IGF-I elevation. Since GH-deficient patients often have a subnormal IGF-I serum level, which normalizes on therapy, their CaP risk on GH therapy probably does not increase substantially above that of the normal population. Until further research in the area dictates otherwise, ongoing surveillance and routine monitoring of IGF-I and IGFBP-3 levels in GH recipients must become standard of care.
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PMID:Growth hormone and prostate cancer: guilty by association? 1044 74

Growth hormone (GH) secretion in the elderly is generally diminished although there are marked individual differences ranging from normal GH secretion and normal levels of insulin-like growth factor (IGF)-I through low GH and subnormal IGF-I. It is assumed that the reduced central cholinergic activity leading to unrestrained somatostatin release leads to impaired GH secretion. The somatopause, if it occurs at all, is, in contrast to the menopause, a subtly developing physiological event. The menopause often causes severe symptoms that justify hormone replacement therapy, but the somatopause is a physiological event at the end of the lifespan with no acute symptoms that can be attributed to GH deficiency with certainty. Whether the non-specific symptoms of old age, i.e. truncal obesity, muscle atrophy, decreasing energy, and mental disorders, can be--even partially--blamed on decreased GH secretion is unclear. Thus, GH therapy in elderly patients, in the absence of pituitary disease cannot be recommended. In addition, the following has to be considered: 1) GH has to be given by subcutaneous injection, which may be technically difficult in elderly patients. 2) It is difficult to find the right individual dosage of GH since elderly patients may show increased sensitivity to GH therapy (compared with children) or may be GH-resistant. 3) Manifestation of diabetes mellitus may be enhanced in elderly patients. 4) The elevation of IGF-I levels may enhance the progression of malignant disease; it has been shown that the concentration of IGF-I in the circulation correlates to the frequency of prostatic cancer. Furthermore, acromegalic patients have a higher frequency of colonic polyps and gastrointestinal malignancies. 5) Even if problems such as dosage, mode of application and the questions of safety are resolved, the present costs of GH therapy will not allow to advocate GH treatment of all elderly patients with low levels of IGF-I. However, since some patients seem to benefit from GH therapy in senescence, further studies are needed. There may be a subset of elderly patients in whom GH treatment is useful. However, unless these patients are included in a study protocol, GH treatment should not be given to elderly patients in the absence of pituitary disease.
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PMID:The somatopause is no indication for growth hormone therapy. 1044 83

Converging data from epidemiological and biological research implicate insulin-like growth factor (IGF) physiology in the regulation of prostate epithelial cell proliferation and in the pathophysiology of prostate cancer. This review (1) outlines elements of IGF physiology, (2) reviews recent evidence that circulating IGF-I level is related to risk of prostate cancer, (3) provides a hypothesis concerning the biological basis for the relationship between IGF-I level and risk of prostate cancer, (4) discusses IGF-I physiology in the context of neoplastic progression of prostate cancer, and (5) discusses clinical implications of these lines of research with respect to prevention and treatment.
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PMID:Insulin-like growth factors and prostate cancer. 1045 82

Insulin-like growth factor (IGF)-I is an important mitogen required by some cell types to progress from the G1 phase to the S phase of the cell cycle. IGF binding proteins (IGFBPs) can have opposing actions, in part by binding IGF-I, but also by direct inhibitory effects on target cells. As mitogens and anti-apoptotic agents, IGFs may be important in carcinogenesis, possibly by increasing the risk of cellular transformation by enhancing cell turnover. Indeed, many types of neoplastic cells express or overexpress IGF-I receptors, which stimulate mitogenesis when activated by IGF-I in vitro. In vivo, tissue IGF bioactivity is determined not only by circulating IGF-I and IGFBP levels, but also by local production of IGFs, IGFBPs, and possibly IGFBP proteases that enhance IGF-I availability by cleaving IGFBPs. Because determinants of tissue IGF bioactivity appear to be regulated in parallel with circulating IGF-I level, it is reasonable to hypothesize that the substantial intraindividual variability in circulating levels of IGF-I and IGFBP-3 may be important in determining risk of some cancers. In recent epidemiologic studies, relatively high plasma IGF-I and low IGFBP-3 levels have been independently associated with greater risk of prostate cancer in men, breast cancer among premenopausal women, and colorectal adenoma and cancer in men and women and possibly lung cancer. These include prospective data from the Physicians' Health Study and the Nurses' Health Study. In general, two- to fourfold elevated risks have been observed for prostate cancer in men in the top quartile of IGF-I relative to those in the bottom quartile, and low levels of IGFBP-3 were associated with an approximate doubling of risk. For breast cancer, an association with IGF-I for postmenopausal women was not apparent, but strong associations were observed for premenopausal cases in the Nurses' Health Study. Further study is needed to confirm this subgroup finding in women. Recent data also indicate that high IGF-I and low IGFBP-3 increase risk of colorectal cancer and large or villous adenomas. Of note, for colorectal neoplasia, fourfold elevated risks were observed in men and women with low IGFBP-3, whereas high IGF-I was associated with a doubling of risk. These emerging epidemiologic data indicate that high levels of IGF-I and low levels of IGFBP-3 are associated with an increased risk of at least several types of carcinoma that are common in economically developed countries. Further study is required to determine the clinical relevance of these findings.
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PMID:Insulin-like growth factor-I and binding protein-3 and risk of cancer. 1059 42

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