Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Androgen withdrawal induces the regression of human prostate cancers, but such cancers eventually become androgen-independent and metastasize. Thus, deciphering the mechanism of androgen withdrawal-induced apoptosis is critical to designing new therapies for prostate cancer. Previously, we showed that in the rat, castration-induced apoptosis is accompanied by a reduction in the expression of the apical caspase inhibitor FLICE-like inhibitory protein (FLIP). To test the functional role of FLIP in inhibiting prostate epithelial cell apoptosis, we employed the rat prostate epithelial cell line NRP-152, which differentiates to a secretory phenotype in a low-mitogen medium and then undergoes apoptosis following the addition of transforming growth factor beta1 (TGFbeta1), mimicking androgen withdrawal-induced apoptosis. FLIP levels decline with TGFbeta1 treatment, suggesting that apoptosis is mediated by caspase-8 and indeed the caspase inhibitor crmA blocks TGFbeta1-induced apoptosis. Small interfering RNA-mediated knockdown of FLIP recapitulates and enhances TGFbeta1-induced cell death. NRP-152 cells stably transfected with constitutively expressed FLIP were refractory to TGFbeta1-induced apoptosis. TGFbeta1-induced caspase-3 activity is proportional to the level of cell death and inversely proportional to the level of FLIP expression in various clones. Moreover, neither caspase-3 nor PARP is cleaved in clones expressing high levels of FLIP. Furthermore, insulin, which inhibits differentiation, increases FLIP and inhibits TGFbeta-induced death in a FLIP-dependent manner. Although neither Fas-Fc, sTNFRII-Fc, nor DR5-Fc blocked TGFbeta1-induced cell death, there is a significant increase in tumor necrosis factor mRNA following TGFbeta stimulation, suggesting both an unexpected role for tumor necrosis factor in this model system and the possibility that FLIP blocks another unknown caspase-dependent mediator of apoptosis.
 ...
PMID:FLICE-like inhibitory protein blocks transforming growth factor beta 1-induced caspase activation and apoptosis in prostate epithelial cells. 1831 84

Androgen refractory prostate cancer metastasis is a major clinical challenge. Mechanism-based approaches to treating prostate cancer metastasis require an understanding of the developmental origin of the metastasis-initiating cell. Properties of prostate cancer metastases such as plasticity with respect to differentiated phenotype and androgen independence are consistent with the transformation of a prostate epithelial progenitor or stem cell leading to metastasis. This review focuses upon current evidence and concepts addressing the identification and properties of normal prostate stem or progenitor cells and their transformed counterparts.
 ...
PMID:Prostate cancer and metastasis initiating stem cells. 1841 48

Androgen refractory cancer of the prostate (ARCaP) cells contain androgen receptor (AR) and synthesize and secrete prostate specific antigen (PSA). We isolated epithelia-like ARCaP(E) from parental ARCaP cells and induced them to undergo epithelial-mesenchymal transition (EMT) by exposing these cells to soluble factors including TGFbeta1 plus EGF, IGF-1, beta2-microglobulin (beta2-m), or a bone microenvironment. The molecular and behavioral characteristics of the resultant ARCaP(M) were characterized extensively in comparison to the parental ARCaP(E) cells. In addition to expressing mesenchymal biomarkers, ARCaP(M) gained 100% incidence of bone metastasis. ARCaP(M) cells express receptor activator of NF-kappaB ligand (RANKL), which was shown to increase tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in culture, and when metastatic to bone in vivo. We provide evidence that RANKL expression was promoted by increased cell signaling mediated by the activation of Stat3-Snail-LIV-1. RANKL expressed by ARCaP(M) cells is functional both in vitro and in vivo. The lesson we learned from the ARCaP model of EMT is that activation of a specific cell signaling pathway by soluble factors can lead to increased bone turnover, mediated by enhanced RANKL expression by tumor cells, which is implicated in the high incidence of prostate cancer bone colonization. The ARCaP EMT model is highly attractive for developing new therapeutic agents to treat prostate cancer bone metastasis.
Clin Exp Metastasis 2008
PMID:Epithelial to mesenchymal transition (EMT) in human prostate cancer: lessons learned from ARCaP model. 1853 13

The use of androgen deprivation therapy (ADT) to treat prostate cancer has favorably impacted outcomes for men with prostate cancer. Androgen deprivation therapy is effective in reducing painful bony metastases and soft tissue visceral disease in advanced-stage prostate cancer. The use of ADT has expanded beyond the metastatic setting and can also be used as adjuvant therapy for patients with locally advanced prostate cancer who received surgery or localized radiation therapy. Luteinizing hormone-releasing hormone agonists are the most common medical therapy used to deprive men of androgen production. Despite the beneficial effects that ADT has on prostate cancer, ADT causes side effects that can impair quality of life. This article will review the impact and treatment of hot flashes in men treated for prostate cancer.
 ...
PMID:Management of hot flashes in men with prostate cancer being treated with androgen deprivation therapy. 1863 64

Androgen deprivation therapy (ADT) and bone metastases are the most important risk factors for developing skeletal complications (eg, bone loss, pathologic fractures) in prostate cancer (PC) patients with locally advanced and metastatic disease. Bisphosphonates, which inhibit excessive osteoclast activity caused by ADT and bone metastases, have proven to be safe and effective in preventing skeletal complications and presently are the standard of care in patients with metastatic disease. Bisphosphonates should be considered for use in all PC patients with locally advanced disease initiating ADT for an intended duration of at least 1 year, especially those with a low baseline bone mineral density.
 ...
PMID:Managing bone loss and bone metastases in prostate cancer patients: a focus on bisphosphonate therapy. 1866 Aug 63

The probability of extraprostatic disease may be estimated based on clinical T-stage, pretreatment prostatic-specific antigen, Gleason score, and percent positive core biopsies. Patients with disease confined to the prostate may be treated with either prostatectomy or radiotherapy (RT). Patients with extraprostatic disease without evidence of distant metastases are best managed with RT. RT consisting of either external beam and/or brachytherapy results in a relatively high likelihood of cure, particularly for those with low- and intermediate-risk disease. The impact of elective nodal RT on survival is unclear. Dose escalation results in improved biochemical relapse-free survival compared with standard dose RT. Androgen deprivation therapy likely improves the probability of disease control in patients with high-risk cancers.
 ...
PMID:Definitive radiotherapy for prostate cancer. 1883 89

Androgen deprivation therapy (ADT) has been the cornerstone of treatment for advanced prostate cancer for over 65 years. Although there can be worrisome side effects, data will be presented that for men with metastatic prostate cancer, immediate ADT can reduce the likelihood of developing the rare but catastrophic sequellae of metastatic disease, although it is unlikely to prolong survival compared with waiting for symptoms before initiating ADT. Additionally, for patients with extremely high risk prostate cancer that is not distantly metastatic (e.g. have a life expectancy from prostate cancer less than 10 years with all other available treatments except immediate ADT) and, whose life expectancy from non-prostate cancer diseases is excellent during this period, early ADT both alone and in conjunction with definitive local treatment prolongs survival. Moreover, ADT seems to be most effective when the cancer volume is low. However, eventually most men receiving ADT experience disease progression. The biological mechanisms explaining how prostate cancer escapes from ADT's control include: 1) Alterations in the androgen receptor (AR) and in the AR co-factors (which modify the responsiveness of the AR to androgens) allow molecules and medications which are not normally AR agonists to act as agonists. 2) The human prostate gland, and particularly prostate cancer, may be able to synthesize androgens from both cholesterol and adrenal androgens. This may occur because prostate cancer tissue has higher concentrations of androgens than does the serum in patients receiving ADT. Thus, castrated men may not be starving their prostate cancers of androgens. 3) The AR in prostatic stroma far more strongly stimulates both malignant and benign prostatic epithelial growth than the epithelial AR does. Indeed, the epithelial AR, particularly in advanced prostate cancer, may have anti-proliferative and anti-tumor progression properties. That is, the AR in the prostatic epithelial cells, particularly malignant ones, may act as a tumor suppressor. Thus, by inhibiting the epithelial AR, its protective effects may be abrogated. The controversial nature of these concepts, as well as the clinical and experimental data which support and question them, will be presented. Additionally, strategies for addressing each of these escape mechanisms, which may be able to prolong responsiveness to ADT, will be discussed.
 ...
PMID:Androgen deprivation therapy for advanced prostate cancer: why does it fail and can its effects be prolonged? 1904 91

Prostate cancer (PC) cells express the androgen receptor (AR) and need the presence of androgens to survive. Androgen suppression is the gold standard first-line therapy for metastatic disease. Almost all PC patients initially respond to hormonal therapy, but most of them gradually develop resistance to castration. There is evidence that these tumours that are considered castration-resistant continue to depend on AR signalling. Several mechanisms that enhance AR signalling in an androgen-depleted environment have been elucidated: (1) AR mutations that allow activation by low androgen levels or by other endogenous steroids, (2) AR amplification and/or overexpression, (3) increased local intracrine synthesis of androgens, (4) changes in AR cofactors and (5) cross-talk with cytokines and growth factors. Today, there are a number of novel agents targeting the AR signalling pathway under development, including more effective antiandrogens; inhibitors of CYP17, inhibitors of HSP90, inhibitors of histone deacetylases and inhibitors of tyrosine kinase inhibitors.
 ...
PMID:Molecular biology of androgen-independent prostate cancer: the role of the androgen receptor pathway. 1915 98

Androgen deprivation therapy remains a critical component of treatment for men with advanced prostate cancer, and data support its use in metastatic disease and in conjunction with surgery or radiation in specific settings. Alternatives to standard androgen deprivation therapy, such as intermittent androgen suppression and estrogen therapy, hold the potential to improve toxicity profiles while maintaining clinical benefit. Current androgen deprivation strategies seem to incompletely suppress androgen levels and androgen-receptor-mediated effects at the tissue level. Advances in the understanding of mechanisms that contribute to castration-resistant prostate cancer are leading to rationally designed therapies targeting androgen metabolism and the androgen receptor. The results of large trials investigating the optimization of primary androgen deprivation therapy, including evaluation of intermittent androgen suppression and phase III studies of novel androgen synthesis inhibitors, such as abiraterone acetate, are eagerly awaited.
 ...
PMID:Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. 1919 21

Prostate cancer is a heterogeneous disease with different stages subject to a broad range of appropriate therapies to the patient or to the point in the disease course. Hormonotherapy has been developed for metastatic cancer and palliative therapy but is commonly used to treat all stages of prostate cancer nowadays. However its toxicity is not negligible and the cardiovascular, bone and metabolic side-effects are mainly responsible of a decrease of the benefits and in observance. The observational study CAPITAL has defined the conditions of prescriptions of androgen-deprivation therapy by physicians (n=208) in France (i.e., urologists and oncologists) and the effects of hormonotherapy in a population of more than 1,000 patients. Androgen-deprivation therapy was mainly given in case of biochemical recurrence after first-line treatment (32.2 %) or for metastasis (32.9 %). Overall, 83 % patients were satisfied of LH-RH agonists. Hormone therapy might be debated especially in young men with prostate cancer whose quality of life should be reduced. The prescription has to be associated with a global personal and stringent follow-up to prevent and reduce the toxicity.
 ...
PMID:[Observational study CAPITAL and prescription of hormonotherapy by French urologists in daily practice]. 1946 33


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>