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 intricate balance maintained between cell growth and proliferation factors and apoptosis-inducing factors is fundamental to the regulation of prostate growth. Disruptions in this homeostasis often trigger the loss of apoptosis and the over-expression of factors promoting cell survival and proliferation, inevitably leading to tumorigenesis and cancer. Deregulation of prostate growth during prostate cancer development and progression is characterized by apoptotic evasion, uncontrolled proliferation, and increased invasive potential. Thus, in advanced stages of disease progression, surviving prostate tumour cells acquire the ability to migrate and invade heterotopic tissues, with the bone and lymph nodes being the most common sites for human prostate cancer metastasis. The challenges in the implementation of effective therapeutic strategies for the treatment of advanced metastatic prostate cancer reflect the multidimensional nature and functional significance of antiapoptotic pathways in the emergence of therapeutic resistance of prostate tumours. In this chapter, we discuss the current understanding of the molecular mechanisms governing growth factor signalling pathways with often overlapping functions that contribute to loss of apoptosis control and activation of cell proliferation towards aggressive prostate tumorigenic growth and metastatic behaviour. While a full understanding of the prosurvival characteristics of these growth factor pathways is still evolving, the impact that growth factors such a epidermal growth factor and transforming growth factor-beta can be recognized by the vigorous attempts at therapeutic targeting of their key signalling steps.
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PMID:Growth factor signalling in prostatic growth: significance in tumour development and therapeutic targeting. 1646 79

Calcitriol (1 alpha,25-dihydroxycholecalciferol) inhibits prostate cancer cell growth. It has been shown that inhibition of growth of prostate cancer LNCaP cells by calcitriol is androgen-dependent. Using cDNA microarray we showed that calcitriol induced expression of placental transforming growth factor-beta (PTGF-beta), which is known to suppress cell growth. We studied regulation of PTGF-beta gene expression by calcitriol and 5alpha-dihydrotestosterone and analyzed whether induction of PTGF-beta transcription by calcitriol is androgen-dependent. Using real-time PCR we demonstrate that 5alpha-dihydrotestosterone up-regulates PTGF-beta mRNA. We do not find an effect of 5alpha-dihydrotestosterone or antiandrogen Casodex on calcitriol-induced PTGF-beta mRNA level and conclude that induction of PTGF-beta transcription by calcitriol is androgen-independent.
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PMID:[Transcriptional regulation of placental transforming growth factor-beta by calcitriol in prostate cancer cells is androgen-independent]. 1652 95

The high prevalence of osteoblastic bone metastasis in prostate cancer is thought to be attributable to the production of osteoblast-stimulating factors by prostate cancer cells. Prostate-specific antigen (PSA) expression is arguably the most distinctive features of prostate cancer. PSA is a serine protease and an important serological marker for prostate cancer. Expression, secretion, and activation of transforming growth factor-beta (TGF-beta) is induced by PSA, and PSA-induced osteoblastic changes in bone were caused by an autonomous increase in mature osteoblasts and by depletion of the osteoclast population. Osteoblastic changes result from an imbalance between the rate of bone resorption and formation.
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PMID:[Mechanism of osteoblastic bone metastasis of prostate cancer]. 1658 5

Macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor-beta superfamily, is important in regulating inflammation. Inflammation of the prostate has been suggested to favor tumor development. A recent study (JNCI 2004, 96:1248-1254) found marginal evidence of an association between the presence of the mature MIC-1 protein nonsynonymous polymorphism H6D C-to-G (rs1058587) with reduced prostate cancer risk [odds ratio, 0.83; 95% confidence interval (95% CI), 0.69-0.99]. We tested this in a population-based study of 819 cases and 731 controls from Australia and found a similar, yet not significant, odds ratio of 0.85 (95% CI, 0.7-1.04; P = 0.11). We also tested the potential association between the H6D variant and disease-specific survival in 640 cases followed-up for an average of 8.2 years. We found that cases carrying the H6D G allele had an increased risk of death from prostate cancer than cases carrying two copies of the C allele (hazard ratio, 1.72; 95% CI, 1.06-2.78; P = 0.03). Our data suggest that the H6D variant in MIC-1 might play a role in prostate cancer, but it is difficult to explain how a variant can be associated with lower risk of developing prostate cancer but more aggressive growth if cancer develops.
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PMID:Macrophage inhibitory cytokine-1 H6D polymorphism, prostate cancer risk, and survival. 1677 85

Recent studies have highlighted that Activin A, a member of the transforming growth factor-beta (TGF-beta) superfamily, may be involved in the regulation of osteoblastic activity and in osteoclast differentiation. Therefore, we have investigated the clinical significance of its circulating levels in patients with bone metastasis. Activin A serum concentrations were determined, by a commercially available enzyme-linked immunosorbent assay kit, in 72 patients with breast cancer (BC) or prostatic cancer (PC) with (BM+) or without (BM-) bone metastases, in 15 female patients with age-related osteoporosis (OP), in 20 patients with benign prostatic hypertrophy (BPH) and in 48 registered healthy blood donors (HS) of both sex (25 female and 23 male). Activin A serum concentrations were significantly increased in BC or PC patients as compared to OP (P < 0.0001) or BPH (P = 0.045), respectively, or to sex matched HS (P < 0.0001). Additionally, these levels resulted more elevated in PC patients as compared to BC patients (P = 0.032). Interestingly, Activin A was significantly higher in BM+ patients than in BM- patients (BC, P = 0.047; PC, P = 0.016). In BC patients, a significant correlation was observed only between Activin A and number of bone metastases (P = 0.0065) while, in PC patients, Activin A levels were strongly correlated with the Gleason score (P = 0.011) or PSA levels (P = 0.0001) and, to a lessen extent, with the number of bone metastases (P = 0.056). Receiver operating characteristic curve (ROC) analysis showed a fair diagnostic accuracy of Activin A to discriminate between BM+ and BM- patients (BC: AUC = 0.71 +/- 0.09, P = 0.03; PC: AUC = 0.73 +/- 0.081, P = 0.005). These findings indicate that Activin A may be implicated in the pathogenesis of bone metastasis. Therefore, this cytokine may be considered a novel potential target for a more selective therapeutic approach in the treatment of skeletal metastasis and may be also useful as additional biochemical marker of metastatic bone disease.
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PMID:Activin A circulating levels in patients with bone metastasis from breast or prostate cancer. 1684 Dec 34

The transforming growth factor-beta (TGF-beta) signaling pathway has an important role in regulating normal prostate epithelium, inhibiting proliferation, differentiation, and both androgen deprivation-induced and androgen-independent apoptosis. During prostate cancer formation, most prostate cancer cells become resistant to these homeostatic effects of TGF-beta. Although the loss of expression of either the type I (TbetaRI) or type II (TbetaRII) TGF-beta receptor has been documented in approximately 30% of prostate cancers, most prostate cancers become TGF-beta resistant without mutation or deletion of TbetaRI, TbetaRII, or Smads2, 3, and 4, and thus, the mechanism of resistance remains to be defined. Here, we show that type III TGF-beta receptor (TbetaRIII or betaglycan) expression is decreased or lost in the majority of human prostate cancers as compared with benign prostate tissue at both the mRNA and protein level. Loss of TbetaRIII expression correlates with advancing tumor stage and a higher probability of prostate-specific antigen (PSA) recurrence, suggesting a role in prostate cancer progression. The loss of TbetaRIII expression is mediated by the loss of heterozygosity at the TGFBR3 genomic locus and epigenetic regulation of the TbetaRIII promoter. Functionally, restoring TbetaRIII expression in prostate cancer cells potently decreases cell motility and cell invasion through Matrigel in vitro and prostate tumorigenicity in vivo. Taken together, these studies define the loss of TbetaRIII expression as a common event in human prostate cancer and suggest that this loss is important for prostate cancer progression through effects on cell motility, invasiveness, and tumorigenicity.
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PMID:The type III transforming growth factor-beta receptor as a novel tumor suppressor gene in prostate cancer. 1728 42

Growth differentiation factor (GDF15) is a distant member of the transforming growth factor-beta superfamily, a diverse group of structurally related proteins that exert multiple effects on cell fate such as on cell growth and differentiation but little is known about GDF15 in these processes. Previously we observed the mature GDF15 to be associated with human prostate carcinogenesis hence prompting us to study GDF15 further. Here we report gdf15 expression both at the RNA and protein levels, in normal prostatic tissues of wild type (wt) and prostatic intraepithelial neoplasia (PIN) of transgenic (Tg) 12T-7s model mice during embryonic, postnatal, and adult prostate formation up to 15 weeks after birth. Dynamic changes in expression, at both the mRNA and protein level, correlated with cell proliferation and differentiation during distinct phases of normal mouse prostate development and alterations in the dynamics of gdf15 expression correlated with the changes in development resulting in PIN formation. Most notably mature gdf15 protein was significantly elevated during hyperplasia and PIN development. Changes in the protein levels did not always correlate well with the mRNA levels. This was more prominent during PIN than during normal prostate development suggesting that this may also be an indicator of disturbed regulation of gdf15 in PIN. We propose that gdf15 is a growth factor with dual function either promoting proliferation or growth arrest and differentiation due most likely to differences in cellular differentiation. Because of the differentiation defect in PIN its epithelium no longer responds to gdf15 by cellular growth arrest as does the normal epithelium and gdf may even stimulate proliferation. The data supports our hypothesis that GDF15 plays a role in the early stages of human prostate cancer.
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PMID:Dynamics of expression of growth differentiation factor 15 in normal and PIN development in the mouse. 1728 5

Data regarding the molecular response of prostate cancer to hormone therapy continue to emerge, identifying a complex network of autocrine and paracrine signaling events mediating the tumor response to androgen suppression. Emerging data provide insight into cellular pathways important in the apoptotic response to therapy, including the transforming growth factor-beta, insulin-like growth factor-1, and vascular endothelial growth factor signaling axes. They also reveal mechanisms of direct antitumor cytotoxicity mediated by various hormonal agents and highlight the importance of developing antiandrogens capable of irreversibly inhibiting the androgen receptor. Accumulated data emphasize the presence of residual androgens and persistent activation of androgen receptor signaling in advanced prostate tumors despite castration. These factors suggest that a multitargeted treatment approach designed to ablate all contributions to the androgen receptor signaling axis within the prostate tumor microenvironment will be required in order for hormonal therapy to achieve optimal antitumor efficacy.
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PMID:The basic biochemistry and molecular events of hormone therapy. 1745 72

Metastasis is a final stage of tumor progression. Breast and prostate cancer cells preferentially metastasize to bone, wherein they cause incurable osteolytic and osteoblastic lesions. The bone matrix is rich in factors, such as transforming growth factor-beta and insulin-like growth factors, which are released into the tumor microenvironment by osteolysis. These factors stimulate the growth of tumor cells and alter their phenotype, thus promoting a vicious cycle of metastasis and bone pathology. Physical factors within the bone microenvironment, including low oxygen levels, acidic pH, and high extracellular calcium concentrations, may also enhance tumor growth. These elements of the microenvironment are potential targets for chemotherapeutic intervention to halt tumor growth and suppress bone metastasis.
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PMID:Molecular biology of bone metastasis. 1793 57

The introduction of prostate-specific antigen (PSA) has revolutionized the detection and management of patients with prostate cancer. Despite this there has always been a concern among clinicians about the usefulness of total PSA levels as a marker for prostate cancer. We discuss the use of calculated variables and molecular forms of PSA. The precursor forms of PSA have been associated with the presence and biological behaviour of prostate cancer. With recent advances in biotechnology, e.g. high-throughput molecular analyses, many potential blood biomarkers have been identified and are currently under investigation. Given the plethora of candidate biomarkers we discuss a selected group of novel blood-based biomarkers, e.g. human glandular kallikrein, early prostate cancer antigen, insulin-like growth factors, urokinase plasminogen activators, transforming growth factor-beta, interleukin-6, chromogranin A, and prostate secretory protein. While these and other markers have shown promise in early-phase studies, no single biomarker is likely to have the appropriate degree of certainty to dictate treatment decisions. Consequently, the future of cancer prognosis might rely on small panels of markers that can accurately predict cancer presence, stage and metastasis, and serve as prognosticators, targets, and/or surrogate endpoints of disease progression and response to therapy.
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PMID:New blood-based biomarkers for the diagnosis, staging and prognosis of prostate cancer. 1794 30


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