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

Prostate cancer is the leading form of newly diagnosed cancer cases in men in the United States. However, the molecular mechanisms contributing to the initiation, progression and ultimate development of metastatic and androgen independent disease are poorly understood. This is due in part to the difficulty in obtaining clinical samples representing early disease and the lack of animal models that recapitulate the full spectrum of the clinical disease. To this end we have developed and characterized the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) animal model that expresses the oncogene SV40 T antigen specifically in the epithelium of the prostate. TRAMP develops spontaneous autochthonous prostate cancer compelte with distant site metastasis and can progress to androgen independent disease. Changes in the fibroblast growth factor (FGF) axis and the insulin-like growth factor (IGF) axis have been examined during prostate cancer progression utilizing the TRAMP model and these data generally support observations reproted in the clinical disease. Moreover, we report novel changes in the FGF axis and IGF axis utilizing TRAMP. Thus, TRAMP can be used as a potent tool in understanding the mechanism of prostate cancer initiation and progression.
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PMID:Peptide growth factors and prostate cancer: new models, new opportunities. 1045 74

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

An important biological feature of prostate cancer (PCa) is its marked preference for bone marrow as a metastatic site. To identify factors that may support the growth of PCa in bone marrow, expression of receptor and nonreceptor tyrosine kinases by androgen-independent PCa bone marrow metastases was assessed. Bone marrow biopsies largely replaced by PCa were analyzed using reverse transcriptase-polymerase chain reaction amplification with degenerate primers that amplified the conserved kinase domain. Sequence analyses of the cloned products demonstrated expression of multiple kinases. Expression of the receptor and nonreceptor tyrosine kinases, alpha platelet-derived growth factor receptor and Jak 1, respectively, was confirmed by immunohistochemistry. In contrast, the type 1 insulin-like growth factor receptor, thought to play a role in PCa development, was lost in metastatic PCa. These results implicate several specific growth factors and signaling pathways in metastatic androgen-independent PCa and indicate that loss of the type 1 insulin-like growth factor receptor contributes to PCa progression.
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PMID:Tyrosine kinases expressed in vivo by human prostate cancer bone marrow metastases and loss of the type 1 insulin-like growth factor receptor. 1051 9

African-American men have the highest and Asian-American men have the lowest prostate cancer incidence rates in the United States; internationally, rates for the Asian continent are among the lowest. Higher insulin-like growth factor (IGF)-1, which participates in the control of cellular growth and differentiation and is modulated by IGF-binding protein-3 (IGFBP-3), was associated with an increased prostate cancer risk in three recent studies. We, therefore, investigated whether plasma levels of IGF-1 and IGFBP-3 vary by race in United States men selected from among members of the Health Professionals Follow-up Study who were 47-78 years old in 1993-1995 when they provided blood (n = 18,000). All of the men who described their major ancestry as African American (n = 63) and a random sample of 75 Asians and 75 Caucasians were invited to provide a second blood sample in 1997, of whom 42, 52, and 55, respectively, did so. IGF-1 and IGFBP-3 concentrations were determined by ELISA. We used nonparametric methods to assess racial variation in age-adjusted levels. Caucasians had the highest median IGF-1 level (224 ng/ml), followed by Asians (208 ng/ml) and African Americans (205 ng/ml). Median IGFBP-3 concentration was similar between Caucasians and Asians but was more than 13% lower in African Americans. Median molar IGF-1:IGFBP-3 ratio was greatest in Caucasians and lowest in Asians. The lower IGF-1 blood levels relative to IGFBP-3 levels among Asian men are consistent with their lower prostate cancer incidence. Although differences in circulating IGF-1 do not seem to account for the greater prostate cancer risk among African-American men, their absolute lower levels of IGFBP-3 may be contributory.
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PMID:Racial variation in insulin-like growth factor-1 and binding protein-3 concentrations in middle-aged men. 1061 44

Previous studies have reported that adult height is positively associated with the risk of prostate cancer. The authors carried out a population-based case-control study involving 317 prostate cancer cases and 480 controls to further investigate the possibility that height is more strongly associated with advanced, compared with localized forms of this disease. Since the inherited endocrine factors, which in part determine height attained during the growing years, may influence the risk of familial prostate cancer later in life, the relationship with height was also investigated for familial versus sporadic prostate cancers. Adult height was not related to the risk of localized prostate cancer, but there was a moderate positive association between increasing height and the risk of advanced cancer (relative risk (RR) = 1.62; 95% confidence interval (CI) 0.97-2.73, upper versus lowest quartile, P-trend = 0.07). Height was more strongly associated with the risk of prostate cancer in men with a positive family history compared with those reporting a negative family history. The RR of advanced prostate cancer for men in the upper height quartile with a positive family history was 7.41 (95% CI 1.68-32.67, P-trend = 0.02) compared with a reference group comprised of men in the shortest height quartile with a negative family history. Serum insulin-like growth factor-1 levels did not correlate with height amongst men with familial or sporadic prostate cancers. These findings provide evidence for the existence of growth-related risk factors for prostate cancer, particularly for advanced and familial forms of this disease. The possible existence of inherited mechanisms affecting both somatic and tumour growth deserves further investigation.
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PMID:Height-related risk factors for prostate cancer. 1063 96

Interest in the role of the insulin-like growth factor (IGF) axis in growth control and carcinogenesis has recently been increased by the finding of elevated serum insulin-like growth factor I (IGF-I) levels in association with three of the most prevalent cancers in the United States: prostate cancer, colorectal cancer, and lung cancer. IGFs serve as endocrine, autocrine, and paracrine stimulators of mitogenesis, survival, and cellular transformation. These actions are mediated through the type 1 IGF-receptor (IGF-1R), a tyrosine kinase that resembles the insulin receptor. The availability of free IGF for interaction with the IGF-1R is modulated by the insulin-like growth factor-binding proteins (IGFBPs). IGFBPs, especially IGFBP-3, also have IGF-independent effects on cell growth. IGF-independent growth inhibition by IGFBP-3 is believed to occur through IGFBP-3-specific cell surface association proteins or receptors and involves nuclear translocation. IGFBP-3-mediated apoptosis is controlled by numerous cell cycle regulators in both normal and disease processes. IGFBP activity is also regulated by IGFBP proteases, which affect the relative affinities of IGFBPs, IGFs and IGF-1R. Perturbations in each level of the IGF axis have been implicated in cancer formation and progression in various cell types.
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PMID:Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis. 1069 60

Although insulin-like growth factor (IGF) binding protein-5 (IGFBP-5) is highly up-regulated in normal and malignant prostate tissues after androgen withdrawal, its functional role in castration-induced apoptosis and androgen-independent progression remains undefined. To analyze the functional significance of IGFBP-5 overexpression in IGF-I-mediated mitogenesis and progression to androgen-independence, IGFBP-5-overexpressing human androgen-dependent LNCaP prostate cancer cells were generated by stable transfection. The growth rates of IGFBP-5-transfected LNCaP cells were significantly faster, compared with either the parental or vector-only transfected LNCaP cells in both the presence and absence ofdihydrotestosterone. IGFBP-5-induced increases in LNCaP cell proliferation occurs through both IGF-I-dependent and -independent pathways, with corresponding increases in the cyclin D1 messenger RNA expression and the fraction of cells in S + G2/M phases of the cell cycle. Changes in Akt/protein kinase B, a downstream component of phosphatidylinositol 3'-kinase (PI3K) pathway, in the LNCaP sublines also paralleled changes in their growth rates. Although treatment with a PI3K inhibitor induced apoptosis in both control and IGFBP-5-overexpressing LNCaP cells, this PI3K inhibitor-induced apoptosis was prevented by exogenous IGF-I treatment only in IGFBP-5 transfectants, suggesting that IGFBP-5 overexpression can potentiate the antiapoptotic effects of IGF-I. Furthermore, tumor growth and serum prostate-specific antigen levels increased several fold faster in mice bearing IGFBP-5-transfected LNCaP tumors after castration, despite having similar tumor incidence and tumor growth rates with controls when grown in intact mice before castration. Collectively, these data suggest that IGFBP-5 overexpression in prostate cancer cells after castration is an adaptive cell survival mechanism that helps potentiate the antiapoptotic and mitogenic effects of IGF-I, thereby accelerating progression to androgen independence through activation of the PI3K-Akt/ protein kinase B signaling pathway.
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PMID:Overexpression of insulin-like growth factor binding protein-5 helps accelerate progression to androgen-independence in the human prostate LNCaP tumor model through activation of phosphatidylinositol 3'-kinase pathway. 1083 Mar 16

Although insulin-like growth factor binding protein-5 (IGFBP-5) has been shown to be implicated in prostate cancer progression, the functional role of IGFBP-5 in progression to androgen-independence remains largely undefined. Here, we demonstrate substantial up-regulation of IGFBP-5 during castration-induced regression and androgen-independent (AI) progression in the mouse androgen-dependent (AD) Shionogi tumor model. To analyze the functional significance of these changes in IGFBP-5, human AD LNCaP prostate cancer cells were stably transfected with IGFBP-5 gene, and IGFBP-5-overexpressing LNCaP tumors progressed significantly faster to androgen independence after castration compared with controls. Antisense mouse IGFBP-5 oligodeoxynucleotides (ODNs) were then designed that reduced IGFBP-5 expression in Shionogi tumor cells in vitro in a dose-dependent and sequence-specific manner. Growth of Shionogi tumor cells was inhibited by antisense IGFBP-5 ODN treatment in a time- and dose-dependent manner, which could be reversed by exogenous IGF-I. However, antisense IGFBP-5 ODN treatment had no additive inhibitory effect on Shionogi tumor cell growth when IGF-I activity was neutralized by anti-IGF-I antibody. Antisense IGFBP-5 ODN treatment resulted in decreased mitogen-activated protein kinase activity and number of cells in the S + G2-M phases of the cell cycle that directly correlated with reduced proliferation rate of Shionogi tumor cells. Systemic administration of antisense IGFBP-5 ODN in mice bearing Shionogi tumors after castration significantly delayed time to progression to androgen independence and inhibited growth of AI recurrent tumors. These findings suggest that up-regulation of IGFBP-5 after castration serves to enhance IGF bioactivity and raise the possibility that the response of prostate cancer to androgen withdrawal can be enhanced by strategies, such as antisense IGFBP-5 ODN therapy, that target IGF signal transduction.
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PMID:Castration-induced up-regulation of insulin-like growth factor binding protein-5 potentiates insulin-like growth factor-I activity and accelerates progression to androgen independence in prostate cancer models. 1085 Apr 57

LNCaP prostatic cancer cells are characterized by having a PTEN mutation, low levels of type 1 insulin-like growth factor receptor (IGF-IR) and no IRS-1, one of the major substrates of the IGF-IR. The absence of IRS-1, an activator of PI3-kinase, is compensated in these cells by the mutation in PTEN, an inhibitor of PI3-kinase. However, IGF-IR signaling in the absence of IRS-1 can cause cell differentiation and growth arrest. We hypothesized that these three characteristics may not be unrelated, specifically that, together, they may favor the metastatic spread of prostatic cancer cells without decreasing their growth potential. In support of this hypothesis, we report here that: (1) IRS-1 expression increases cell adhesion and decreases cell motility; (2) over-expression of the IGF-IR, in the absence of IRS-1, causes growth arrest and (3) a combination of IGF-IR and IRS-1 restores the transformed phenotype of LNCaP cells. These findings suggest a mechanism by which prostatic cancer cells can achieve metastatic potential without interfering with their growth potential. Oncogene (2000).
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PMID:IGF-I receptor signaling in a prostatic cancer cell line with a PTEN mutation. 1085 Oct 68

The type 1 insulin-like growth factor receptor (IGF-1R), a transmembrane tyrosine kinase, is widely expressed across many cell types in foetal and postnatal tissues. Activation of the receptor following binding of the secreted growth factor ligands IGF-1 and IGF-2 elicits a repertoire of cellular responses including proliferation, and the protection of cells from programmed cell death or apoptosis. As a result, signalling through the IGF-1R is the principal pathway responsible for somatic growth in foetal mammals, whereas somatic growth in postnatal animals is achieved through the synergistic interaction of growth hormone and the IGFs. Forced overexpression of the IGF-1R results in the malignant transformation of cultured cells: conversely, downregulation of IGF-1R levels can reverse the transformed phenotype of tumour cells, and may render them sensitive to apoptosis in vivo. Elevated levels of IGF-IR are observed in a variety of human tumour types, whereas epidemiological studies implicate the IGF-1 axis as a predisposing factor in the pathogenesis of human breast and prostate cancer. The IGF-1R has thus emerged as a therapeutic target for the development of antitumour agents. Recent progress towards the elucidation of the three-dimensional structure of the extracellular domain of the IGF-1R represents an opportunity for the rational assembly of small molecule antagonists of receptor function for clinical use.
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PMID:Structure and function of the type 1 insulin-like growth factor receptor. 1096 44


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