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)

Conventional prostate adenocarcinomas consist mainly of tumour cells of luminal immunophenotype with scattered neuroendocrine (NE) cells. NE cells are defined by chromogranin A (CGA) immunoreactivity. Unlike luminal cells, NE cells lack androgen receptor (AR) and prostate specific antigen (PSA) immunoreactivity. This report describes the first case of conventional prostate adenocarcinoma expressing CGA, PSA, and AR as determined by immunohistochemistry. A 64 year old man was diagnosed with conventional prostate adenocarcinoma in 1993; he underwent cystoprostatectomy in 1994; he developed an iliac bone metastasis in 1997 and mediastinal lymph node metastases in 1999. All specimens obtained during the progression of the disease consisted primarily of luminal cells with only scattered NE cells. In contrast, in samples of non-osseous and osseous metastases obtained at necropsy in 2001, greater than 80% of tumour cells were shown to express PSA, AR, and CGA. This suggests that during tumour progression, conventional prostate adenocarcinomas may evolve into an NE cell phenotype.
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PMID:Metastatic conventional prostatic adenocarcinoma with diffuse chromogranin A and androgen receptor positivity. 1499 Jun 10

An invasive micropapillary component has been described in tumors of several organs and is nearly always associated with aggressive biologic behavior. We present 14 cases of salivary duct carcinoma (SDC) with an invasive micropapillary component (invasive micropapillary SDC) and compare the clinicopathologic findings of these cases with those of cases of conventional SDC. The mean age of the 14 patients (10 men, 4 women) was 65.8 years (range, 26-80 years). The mean size of the tumors was 2.4 cm (range, 1.3-5 cm). The parotid gland was involved in 12 patients and the submandibular gland in 2. Histologically, all tumors had an invasive micropapillary architecture admixed with features typical for SDC. Invasive micropapillary carcinoma was characterized by morula-like small cell clusters without fibrovascular cores, surrounded by a clear space. Tumor cells exhibited moderate- to high-grade nuclear features, conspicuous nucleoli, and eosinophilic cytoplasm. This component was distributed diffusely in 9 tumors and focally in 5. Angiolymphatic and perineural invasion was seen in all tumors. A residual pleomorphic adenoma was detected in four tumors. Of the 12 tumors examined, all were diffusely positive for cytokeratin 7 and epithelial membrane antigen (with a distinctive "inside-out" pattern) but negative for cytokeratin 20. Tumors were frequently immunoreactive for BRST-2 (gross cystic disease fluid protein-15) and androgen receptor protein. Aberrant expression of HER-2/neu or p53 was detected in seven tumors each. The mean Ki-67 labeling index was 33.1% (range, 6.3%-61.6%). All 14 patients with invasive micropapillary SDC had cervical or periglandular lymph node metastasis, and this value was significantly higher than for conventional SDCs. Local recurrence developed in 4 patients and distant metastatic disease in 9. Clinical follow-up (mean, 25.5 months) was available for 13 patients: 9 died of disease within 24 months after the diagnosis (mean, 17.6 months), 1 was alive with metastatic disease at 19 months, and 3 were free of disease. Overall survival of these patients with invasive micropapillary SDC was significantly shorter than that of patients with conventional SDC (n = 49) in our series (P = 0.031). Our results suggest that invasive micropapillary SDC is a distinct, aggressive variant of SDC, with a propensity for extensive lymph node metastasis and rapid disease progression.
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PMID:Invasive micropapillary salivary duct carcinoma: a distinct histologic variant with biologic significance. 1510 94

The androgen receptor (AR) is implicated in regulation of cellular events in advanced prostate cancer. It is expressed in primary tumours as well as in metastases from patients who failed endocrine therapy. Activation of the AR in metastatic tumours occurs as a result of increased sensitivity of the receptor, point mutations that alter activation spectrum and in response to various nonsteroidal compounds. Peptide growth factors that activate the signalling pathway of mitogen-activated protein kinases (MAPK) stimulate AR activity in ligand-independent or synergistic manner. Outcome of nonsteroidal activation depends on cellular and promoter context. AR activation by Her-2/neu is associated with enhanced tumour growth of the LAPC-4 xenograft. The issue whether MAPK or protein kinase Akt involved in growth factor signalling directly phosphorylate the AR is a matter of debate. AR ligand-independent activation by protein kinase A activators was also demonstrated. Under physiological conditions, potentiation of AR activity by low doses of androgen might be of importance in prostate cancer patients who receive endocrine therapy. Interleukin-6 (IL-6) and related cytokines also activate AR in a ligand-independent and synergistic manner. IL-6 is a pleiotropic regulator of tumour growth, which in some prostate cancers acts as a paracrine growth inhibitor and in other cases as an autocrine growth stimulator. Activation of the AR by IL-6 requires functional pathways of Janus kinases/signal transducers and activators of transcription factors and MAPK. Studies on AR co-activators implicated in ligand-independent activation may further improve understanding of cross-talk between signalling pathways.
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PMID:Androgen receptor cross-talk with cell signalling pathways. 1551 41

By virtue of their potent proliferative and anti-apoptotic effects, the insulin-like growth factors (IGFs) have been the subject of long-term scrutiny for their role in tumorigenesis. With regard to prostate cancer in particular, IGF-1 has been shown to stimulate the proliferation of human prostate epithelial cells in culture and to be necessary for normal growth and development of the rat and mouse prostate. Epidemiological studies have established a link between high circulating serum IGF-1 levels and the risk of later developing advanced prostate cancer, and overexpression of IGF-1 in the prostate basal epithelial layer of transgenic mice results in prostate adenocarcinoma that is similar to human disease. Thus, IGF-1 action appears to be important for prostate cancer initiation. On the other hand, decreased IGF action, subsequent to the down-regulation of IGF-1 receptor expression, is associated with advanced, metastatic disease. This decrease in IGF-1 receptor may confer a survival advantage to prostate cancer cells that have entered the circulation by making them resistant to the differentiative effects of IGF-1 at metastatic sites such as bone. The molecular mechanisms that effect IGF-1 receptor down-regulation appear to involve novel oncogenic functions of the Wilms' tumour suppressor, as well as novel actions of the androgen receptor.
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PMID:IGF-1 and prostate cancer. 1556 30

Prostate cancer is the most frequently diagnosed cancer among men and the second leading cause of male cancer deaths in the United States. When prostate cancer initially presents in the clinic, the tumour is dependent on androgen for growth and, therefore, responsive to the surgical or pharmacological ablation of circulating androgens. However, there is a high rate of treatment failure because the disease often recurs as androgen-independent metastases. Surprisingly, this late-stage androgen-independent prostate cancer almost always retains expression of the AR (androgen receptor), despite the near absence of circulating androgens. Although late-stage prostate cancer is androgen-independent, the AR still seems to play a role in cancer cell growth at this stage of disease. Therefore a key to understanding hormone-independent prostate cancer is to determine the mechanism(s) by which the AR can function even in the absence of physiological levels of circulating androgen. This review will focus on the role of growth factor signalling in prostate cancer progression to androgen independence and thus outline potential molecular areas of intervention to treat prostate cancer progression.
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PMID:Signal transduction in prostate cancer progression. 1560 54

Recent evidence demonstrates that the androgen receptor (AR) continues to influence prostate cancer growth despite medical therapies that reduce circulating androgen ligands to castrate levels and/or block ligand binding. Whereas the mutation, amplification, overexpression of AR, or cross-talk between AR and other growth factor pathways may explain the failure of androgen ablation therapies in some cases, there is little evidence supporting a causal role between AR and prostate cancer. In this study, we functionally and directly address the role whereby AR contributes to spontaneous cancer progression by generating transgenic mice expressing (i) AR-WT to recapitulate increased AR levels and ligand sensitivity, (ii) AR-T857A to represent a promiscuous AR ligand response, and (iii) AR-E231G to model altered AR function. Whereas transgenes encoding either AR-WT or AR-T857A did not cause prostate cancer when expressed at equivalent levels, expression of AR-E231G, which carries a mutation in the most highly conserved signature motif of the NH2-terminal domain that also influences interactions with cellular coregulators, caused rapid development of prostatic intraepithelial neoplasia that progressed to invasive and metastatic disease in 100% of mice examined. Taken together, our data now demonstrate the oncogenic potential of steroid receptors and implicate altered AR function and receptor coregulator interaction as critical determinants of prostate cancer initiation, invasion, and metastasis.
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PMID:Mutation of the androgen receptor causes oncogenic transformation of the prostate. 1565 28

Human androgen receptor (AR) associates with coactivator or corepressor proteins that modulate its activation in the presence of ligand. Early studies on AR coactivators in carcinoma of the prostate were hampered because of lack of respective antibodies. Investigations at mRNA level revealed that most benign and malignant prostate cells express common coactivators. AR coactivators SRC-1 and TIF-2 are up-regulated in tissue specimens obtained from patients who failed prostate cancer endocrine therapy. Increased expression of these coactivators is associated with enhanced activation of the AR by the adrenal androgen dehydroepiandrosterone. Similar association between AR coactivator expression and high prostate cancer grade and stage was reported for RAC-3 (SRC-3). The transcriptional integrator CBP was detected in clinical specimens representing organ-confined prostate cancer, lymph node metastases and tumour cell lines. Agonistic effect of the nonsteroidal antiandrogen hydroxyflutamide was strongly potentiated in prostate cells transfected with CBP cDNA. A functional homologue of CBP, p300, is implicated in ligand-independent AR activation by interleukin-6. The AR coactivator Tip60, which is up-regulated by androgen ablation, is recruited to the promoter of the prostate-specific antigen gene in the absence of androgen in androgen-independent prostate cancer sublines. It was proposed that the cofactor ARA70 is a specific enhancer of AR action. However, research from other laboratories has demonstrated interaction between ARA70 and other steroid receptors. Although in some cases dominant-negative coactivator mutants inhibited proliferation of prostate cancer cells in vitro, confirmation from in vivo tumour models is missing. In summary, several abnormalities in AR coactivator expression and function are associated with prostate cancer progression.
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PMID:Expression and function of androgen receptor coactivators in prostate cancer. 1566 89

Prostate cancer represents one of the most important health problems in industrialized countries. It is the second leading cause of cancer-related death in the United States. Therapeutic options are different according to the stage of the disease at the diagnosis. Patients with localized disease may be treated with surgery or radiation, whereas the treatment for patients with a metastatic disease is purely palliative. Hormonal treatment represents the standard therapy for stage IV prostate cancer, but patients ultimately become unresponsive to androgen ablation and are classified as hormone-refractory prostate cancer patients. The molecular mechanisms involved in progression in hormone resistance are characterized by mutations, down and up-regulation in the androgen receptor gene, mutations in p53 and over-expression of Bcl2 and other alterations in genes and in gene expression. The important thing is that we understand these mechanisms to define potential therapeutic agents for the treatment of hormone-refractory prostate cancer patients. Conventional options for patients with hormone-refractory prostate cancer include secondary hormone therapy, radiotherapy and cytotoxic chemotherapy. The commonest antineoplastic agents are mitoxantrone, estramustine and taxanes. Despite an improvement in the palliative benefit, none of these agents has demonstrated a beneficial impact on the overall survival of patients. Therefore, there is no standard therapy for these patients, thus we need new approaches which should be studied in clinical trials. The evaluation and incorporation of new agents into current treatment regimens could have a role in the treatment of hormone-refractory prostate cancer, but their efficacy has not yet been demonstrated.
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PMID:Treatment options in hormone-refractory metastatic prostate carcinoma. 1576 53

Cancer of the prostate can be associated with coagulopathy characterized as primary fibrinolysis or diffuse intravascular coagulopathy (DIC) with secondary fibrinolysis. These complications are usually associated with surgical manipulation of the prostate or with advanced metastatic disease. This report describes a patient with DIC and fibrinolysis following medical management of advanced prostate cancer with gonadotropin-releasing hormone leuprolide, while receiving the androgen receptor blocking agent flutamide. This report suggests that release of procoagulant material from prostatic carcinoma may be so rapid following hormonal management that consumptive coagulopathy with fibrinolysis can follow. Shortened Abstract: Medical management with gonadotropin releasing hormone allowed the expression of consumptive coagulopathy in patients with metastatic prostate cancer.
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PMID:Coagulopathy, following medical therapy, for carcinoma of the prostate. 1601 49

Metastasis is the major cause of prostate cancer deaths and there is a need for clinically relevant in vivo models allowing elucidation of molecular and cellular mechanisms underlying metastatic behavior. Here we describe the development of a new in vivo model system for metastatic prostate cancer. Pieces of prostate cancer tissue from a patient were grafted in testosterone-supplemented male NOD-SCID mice at the subrenal capsule graft site permitting high tumor take rates. After five serial transplantations, the tumor tissues were grafted into mouse prostates. Resulting tumors and suspected metastatic lesions were subjected to histopathological and immunohistochemical analysis. Samples of metastatic tissue were regrafted in mouse anterior prostates and their growth and spread examined, leading to isolation from lymph nodes of a metastatic subline, PCa1-met. Orthotopic grafting of PCa1-met tissue in 47 hosts led in all cases to metastases to multiple organs (lymph nodes, lung, liver, kidney, spleen and, notably, bone). Histopathological analysis showed strong similarity between orthotopic grafts and their metastases. The latter were of human origin as indicated by immunostaining using antibodies against human mitochondria, androgen receptor, prostate-specific antigen and Ki-67. Spectral karyotyping showed few chromosomal alterations in the PCa1-met subline. This study indicates that transplantable subrenal capsule xenografts of human prostate cancer tissue in NOD-SCID mice can, as distinct from primary cancer tissue, be successfully grown in the orthotopic site. Orthotopic xenografts of the transplantable tumor lines and metastatic sublines can be used for studying various aspects of metastatic prostate cancer, including metastasis to bone.
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PMID:An orthotopic metastatic prostate cancer model in SCID mice via grafting of a transplantable human prostate tumor line. 1615 94


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