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

Androgen deprivation therapy has become the mainstay of the treatment of advanced prostate cancer, being used in every clinical setting of the disease, from neoadjuvant to metastatic disease. Despite success in controlling the disease in the majority of men, hormonal manipulations will eventually fail. New agents are being developed for patients with hormone refractory disease. Important advances in molecular oncology have improved our understanding regarding the cellular mechanisms that regulate cell death in the prostate. It is hoped that these new insights will lead to development of more efficacious and easy to tolerate therapies for cancer prostate. This review focuses on the current literature on tumor vaccines, angiogenesis inhibitors, antisense oligonucleotides, differentiation agents, cancer-specific genes, endothelial receptor antagonists, anti-apoptotic agents, agents acting on signaling pathways and androgen and estrogen receptors.
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PMID:New therapeutic targets in the treatment of prostate cancer. 1967 66

Androgen deprivation is the mainstay of therapy for progressive prostate cancer. Despite initial and dramatic tumor inhibition, most men eventually fail therapy and die of metastatic castration-resistant (CR) disease. Here, we characterize the profound degree of genomic alteration found in CR tumors using array comparative genomic hybridization (array CGH), gene expression arrays, and fluorescence in situ hybridization (FISH). Bycluster analysis, we show that the similarity of the genomic profiles from primary and metastatic tumors is driven by the patient. Using data adjusted for this similarity, we identify numerous high-frequency alterations in the CR tumors, such as 8p loss and chromosome 7 and 8q gain. By integrating array CGH and expression array data, we reveal genes whose correlated values suggest they are relevant to prostate cancer biology. We find alterations that are significantly associated with the metastases of specific organ sites, and others with CR tumors versus the tumors of patients with localized prostate cancer not treated with androgen deprivation. Within the high-frequency sites of loss in CR metastases, we find an overrepresentation of genes involved in cellular lipid metabolism, including PTEN. Finally, using FISH, we verify the presence of a gene fusion between TMPRSS2 and ERG suggested by chromosome 21 deletions detected by array CGH. We find the fusion in 54% of our CR tumors, and 81% of the fusion-positive tumors contain cells with multiple copies of the fusion. Our investigation lays the foundation for a better understanding of and possible therapeutic targets for CR disease, the poorly responsive and final stage of prostate cancer.
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PMID:Comparative analyses of chromosome alterations in soft-tissue metastases within and across patients with castration-resistant prostate cancer. 1977 49

* Introduction * Serially heterotransplanted human tumours in immunosuppressed mice: similarity to the tumour of origin - Cytological and histological analysis - Karyotype - Marker expression - Other PC markers - Tumour cell proliferation and frequency of mitosis - Vasculature - Stromal compartment - Heterotransplant hormone dependency - Androgen dependent - Partially androgen dependent - Androgen independent - Metastases * Conclusions Preclinical research on prostate cancer (PC) therapies uses several models to represent the human disease accurately. A common model uses patient prostate tumour biopsies to develop a cell line by serially passaging and subsequent implantation, in immunodeficient mice. An alternative model is direct implantation of patient prostate tumour biopsies into immunodeficient mice, followed by serial passage in vivo. The purpose of this review is to compile data from the more than 30 years of human PC serial heterotransplantation research. Serially heterotransplanted tumours are characterized by evaluating the histopathology of the resulting heterotransplants, including cellular differentiation, karyotype, marker expression, hormone sensitivity, cellular proliferation, metastatic potential and stromal and vascular components. These data are compared with the initial patient tumour specimen and, depending on available information, the patient's clinical outcome was compared with the heterotransplanted tumour. The heterotansplant model is a more accurate preclinical model than older generation serially passaged or genetic models to investigate current and newly developed androgen-deprivation agents, antitumour compounds, anti-angiogenic drugs and positron emission tomography radiotracers, as well as new therapeutic regimens for the treatment of PC.
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PMID:Serially heterotransplanted human prostate tumours as an experimental model. 1987 22

Androgen-deprivation therapy for prostate cancer (PC) eventually leads to castration-resistant PC (CRPC). Intratumoral androgen production might contribute to tumor progression despite suppressed serum androgen concentrations. In the present study, we investigated whether PC or CRPC tissue may be capable of intratumoral androgen synthesis. Steroidogenic enzyme mRNAs were quantified in hormonally manipulated human PC cell lines and xenografts as well as in human samples of normal prostate, locally confined and advanced PC, local nonmetastatic CRPC, and lymph node metastases. Overall, the majority of samples showed low or absent mRNA expression of steroidogenic enzymes required for de novo steroid synthesis. Simultaneous but low expression of the enzymes CYP17A1 and HSD3B1, essential for the synthesis of androgens from pregnenolone, could be detected in 19 of 88 patient samples. Of 19 CRPC tissues examined, only 5 samples expressed both enzymes. Enzymes that convert androstenedione to testosterone (AKR1C3) and testosterone to dihydrotestosterone (DHT; SRD5A1) were abundantly expressed. AKR1C3 expression was negatively regulated by androgens in the experimental models and was increased in CRPC samples. Expression of SRD5A1 was upregulated in locally advanced cancer, CRPC, and lymph node metastases. We concluded that intratumoral steroid biosynthesis contributes less than circulating adrenal androgens, implying that blocking androgen production and its intraprostatic conversion into DHT, such as via CYP17A1 inhibition, may represent favorable therapeutic options in patients with CRPC.
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PMID:Evidence of limited contributions for intratumoral steroidogenesis in prostate cancer. 2094 Apr 9

Androgen-deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer. One factor that has been implicated in the metastatic process is the cell adhesion molecule N-cadherin. In this study, we investigated if the expression of N-cadherin was influenced by androgen deprivation and was associated with metastasis in prostate cancer. The effect of androgen deprivation on N-cadherin expression was initially studied in androgen-dependent (AD) LNCaP and androgen-independent (AI) LNCaP-19 and PC-3 prostate cancer cell lines. Expression of N-cadherin increased in the absence of androgens in AI LNCaP-19 primary tumors and metastases and also in vitro, but not in AI PC-3 tumors, indicating a possible involvement of the androgen receptor in the regulation of N-cadherin. N-cadherin was absent in AD LNCaP tumors. No clear associations between N-cadherin and factors related with epithelial-mesenchymal transition or neuroendocrine differentiation could be established. In addition, N-cadherin was evaluated by immunohistochemistry in human prostate tumors. Expression of N-cadherin was more frequently found in tumors from patients treated with ADT than in tumors from patients with no prior hormonal treatment. N-cadherin expression was also associated with metastasis and Gleason score. Furthermore, increased N-cadherin was detected in prostate cancer biopsies already 3 months after initiation of ADT when tumors were in a regressed state. In summary the results indicate that androgen deprivation induces N-cadherin in prostate tumors. Moreover, N-cadherin was increased in castration-resistant tumors in patients with established metastases. This might indicate that castration induces molecular alterations in the tumor cells, resulting in a more invasive and metastatic phenotype.
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PMID:N-cadherin increases after androgen deprivation and is associated with metastasis in prostate cancer. 2023 7

Prostate cancer is currently diagnosed in more than 34,000 men every year and claims more than 10,000 lives per annum in the UK. Recently, prostate specific antigen (PSA) population screening has been evaluated in two major randomised, controlled studies. Even though the more mature European study confirmed that PSA screening is capable of reducing prostate cancer mortality, anxieties still persist, particularly surrounding the issue of overdiagnosis of clinically insignificant cancer. The recent identification of 29 genetic variants that predispose towards prostate cancer offers another, more targeted, opportunity to reduce mortality. It also raises the possibility of the identification of a sub-group of men who are especially susceptible to prostate cancer. In lower-risk patients with localised cancer active surveillance may be sufficient. In fitter men, with more clinically significant disease, eradication of the cancer by surgical removal of the gland is often involved. This is the only treatment which has been proven in a randomised controlled trial to reduce the rate of metastases and mortality compared with watchful waiting. Metastatic prostate cancer is associated with high mortality--approximately 70% within 5 years. Androgen deprivation, which has become the mainstay of treatment, effectively lowers intraprostatic DHT by more than 80%, resulting in reduced androgen receptor stimulation and increased prostate cancer apoptosis.
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PMID:Advances in the diagnosis and treatment of prostate cancer. 2030 26

Androgen deprivation therapy with LHRH agonists is the gold standard in the treatment of metastatic prostate cancer. This treatment leads to decrease the bone mass, thus bone mineral density evaluation is recommended after one year of hormonal treatment to measure bone loss. Bisphosphonate is recommended when metastasis occurred during hormonal resistance phase to reduce bone events. The necessity of preventive treatment and the appropriate schedule is not well established. Long term fracture risk should be ideally evaluated with a CT scan and an MRI. Fragmented and focal radiotherapy is considered as the treatment of choice to decrease localized pain. Metastasis surgery has functional results and should be performed before major neurologic symptoms occur. Metabolic radiotherapy is an option for multifocal bone metastases.
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PMID:[How to manage bone metastasis in prostate cancer. A case report]. 2049 51

Androgen receptors (ARs) are probably of importance during all phases of prostate cancer (PC) growth, but their role in bone metastases is largely unexplored. Bone metastases were therefore collected from hormone-naive (n=11), short-term castrated (n=7) and castration-resistant PC (CRPC, n=44) patients by biopsy (n=4) or at surgery to alleviate symptoms from metastases complications (metastasis surgery, n=58), and immunostained for nuclear ARs, Ki67, active caspase-3, prostate-specific antigen (PSA) and chromogranin A, and results were related to serum PSA, treatments and outcome. Nuclear AR immunostaining was decreased and apoptosis was increased, but cell proliferation remained largely unaffected in metastases within a few days after surgical castration. In CRPC patients, nuclear AR staining of metastases was increased when compared to short-term castrated patients. The nuclear AR staining score was related to tumour cell proliferation, but it was not associated with other downstream effects of AR activation such as apoptosis and PSA staining, and it was only marginally related to the presence of neuroendocrine tumour cells. Serum PSA at metastasis surgery, although related to outcome, was not associated with AR staining, markers of metastasis growth or PSA staining in metastases. High nuclear AR immunostaining was associated with a particularly poor prognosis after metastasis surgery in CRPC patients, suggesting that such men may benefit from the potent AR blockers now tested in clinical trials.
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PMID:Nuclear androgen receptor staining in bone metastases is related to a poor outcome in prostate cancer patients. 2068 81

The diagnosis and treatment of prostate cancer have steadily been improving since the late 1980s. However, clinicians still confront a large group of men developing disease metastatic to bone. Adequate control of bone complications plays a fundamental role in achieving control of symptoms and quality of life in this group. Androgen deprivation therapy, the standard treatment for advanced prostate cancer, increases the risk of various complications, including bone disease. This review addresses the prevention of bone complications related not only to prostate cancer metastases but also to impaired bone integrity caused by androgen deprivation therapy.
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PMID:Preventing bone complications in advanced prostate cancer. 2088 36

Androgen deprivation therapy (ADT) has been used in the management of prostate cancer for more than four decades. Initially, hormone therapy was given largely for palliation of symptomatic metastases. Following several randomized trials of patients with intermediate- to high-risk prostate cancer that demonstrated improvements in biochemical control and survival with the addition of ADT to external beam radiotherapy, there was a dramatic increase in the use of hormone therapy in the definitive setting. More recently, the safety of ADT has been questioned, as some studies have suggested an association of hormone therapy with increased cardiovascular morbidity and mortality. This is particularly worrisome in light of practice patterns that show ADT use extrapolated to situations for which there has been no proven benefit. In the setting of dose escalation with modern radiotherapy, in conjunction with the latest concerns about cardiovascular morbidity with ADT, the magnitude of expected benefit along with potential risks of ADT use must be carefully considered for each patient.
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PMID:Androgen deprivation therapy: a survival benefit or detriment in men with high-risk prostate cancer? 2092 34


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