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)

The high morbidity and mortality associated with prostate cancer (PCa) result from its tendency to metastasize to bone where it produces predominantly osteoblastic lesions. The Wnt signaling pathway plays an important role in embryogenesis, tumorigenesis, osteoblast development, and bone formation. Androgen signaling via the androgen receptor (AR) is critical in both PCa and bone cell growth. We examined the effects of androgens on cell growth and Wnt signaling in the AR-positive MDA-PCa-2b cell line and MC3T3 preosteoblasts, grown alone and in coculture. We show that the potent androgen dihydrotestosterone increases AR expression and transcriptional activity only in the preosteoblasts. Although dihydrotestosterone induced an 80% increase in PCa cell growth when the cells were grown alone, dihydrotestosterone had a more significant effect on MDA-PCa-2b cell proliferation (3.2-fold increase) when the PCa cells were cocultured with preosteoblasts. Dihydrotestosterone addition to preosteoblasts promoted Wnt-dependent transcriptional reporter activity associated with GSK3beta(S-9) phosphorylation and accumulation of nuclear beta-catenin as well as elevated Runx2 expression. In addition, the increased proliferation of PCa cells in coculture with MC3T3 cells in response to dihydrotestosterone was abrogated by the addition of either exogenous DKK-1 or sFRP-1 protein, two naturally occurring Wnt antagonists. Finally, we show that the paracrine growth-promoting effect of androgens is limited to MDA-PCa-2b cells. These data imply that Wnt signaling is involved in the androgen-regulated crosstalk between preosteoblasts and PCa cells and suggest that androgens may stimulate growth of some prostate tumor cells indirectly, via up-regulation of Wnt signaling in bone cells.
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PMID:Androgen-induced Wnt signaling in preosteoblasts promotes the growth of MDA-PCa-2b human prostate cancer cells. 1757 41

A 69-year-old male with tinnitus, vertigo, and progressive hearing loss of left ear was admitted to our hospital. Head magnetic resonance imaging and computed tomography (CT) revealed swelling of multiple neck lymph nodes (LNs) invading the skull base, which involved left mastoid sinus/the eighth cranial nerve. Biopsy of the cervical LN demonstrated small-cell carcinoma (SCC). Whole body CT showed systemic lymphadenopathies (subclavian, para-aortic, and bilateral iliac LNs) and prostatic swelling with multiple pelvic masses. Needle biopsy of the prostate revealed SCC (Gleason score: 5+ 5). Immunohistochemically, neuron-specific enolase (NSE) and NCAM were detected in <10% and -100% of cancer cells, respectively. Despite SCC histology, prostate-specific antigen (PSA) and androgen receptor (AR) were also expressed in -20% and -70% of tumor cells, respectively. Serum PSA and NSE were 464 ng/ml and 12 ng/ml, respectively. After maximum androgen blockade (MAB) with leuprorelin/bicalutamide, the patient showed recovery of hearing loss, regression of cervical LNs (partial response), and decline of serum markers (PSA 7.38 ng/ml and NSE 3.7 ng/ml, respectively). As re-increase of PSA was observed after ten months, MAB menu was changed to leuprorelin/fultamide. Another four months later, the treatment was changed to docetaxel/ estramustine due to the appearance of systemic bone pain and recurrence of LN metastases. He is alive (39 months after diagnosis) with cancer. Widespread metastases at the time of diagnosis were compatible with SCC. However, this case was AR-positive and responded to androgen ablation, at least temporarily. Even though the initial symptoms are atypical for a prostatic carcinoma, SCC of prostate needs to be included as a rare differential diagnosis.
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PMID:[Prostatic carcinoma that arose with hearing loss: a case report]. 1762 42

Androgens play a central role in prostate development and prostate cancer proliferation. Induction of telomerase is an early event in prostate carcinogenesis and is considered as a marker for both primary tumors and metastases. Interestingly, several reports suggest that telomerase activity is regulated by androgens in vivo. Here, we show that the wild-type (WT) human androgen receptor (AR) inhibits the expression of the human telomerase reverse transcriptase (hTERT) and telomerase activity via inhibition of hTERT promoter activity in the presence of androgen receptor agonists. However, pure androgen antagonists failed to repress hTERT transcription. The androgen-mediated repression of hTERT is abrogated in a human prostate cancer cell line exhibiting hormone-dependent growth, which expresses a mutant AR (T877A) frequently occurring in prostate cancer. We reveal that this single amino acid exchange is sufficient for the lack of transrepression. Interestingly, chromatin immunoprecipitation data suggest that, in contrast to the WT AR, the mutant AR is recruited less efficiently to the hTERT promoter in vivo, indicating that loss of transrepression results from reduced chromatin recruitment. Thus, our findings suggest that the WT AR inhibits expression of hTERT, which is indicative of a protective mechanism, whereas the T877A mutation of AR not only broadens the ligand spectrum of the receptor but abrogates this inhibitory mechanism in prostate cancer cells. This novel role of AR mutations in prostate cancer development suggests the benefit to a search for new AR antagonists that inhibit transactivation but allow transrepression.
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PMID:Wild-type but not mutant androgen receptor inhibits expression of the hTERT telomerase subunit: a novel role of AR mutation for prostate cancer development. 1799 30

This review is triggered by recent developments that offer new explanations for the mechanism of progression of prostate cancer to androgen independence. Established and hypothetical mechanisms, which have been described in the past, are put into perspective with recent progress in the field. A total of seven mechanisms can be identified that relate to progression to androgen independence. Five of those are dependent on the androgen receptor, which is present or over-expressed in androgen-independent prostate cancer tissue. Probably due to selective pressure, AIPC cells have the capability to escape from the effect of castration and antiandrogens; exclusion of the androgen receptor activity by inhibition of dimerisation or inhibition of DNA binding seem to be the logical next steps. Although androgen levels and androgen synthesis are suppressed in prostatic tissues during the phase of response to endocrine treatment, androgen levels and, specifically, 5-alpha-dihydrotestosterone (DHT) were elevated in tissues derived from metastases of AIPC. In addition, all enzymes needed to synthesise androgens from the level of pregnenolone on are present or over-expressed in such tissue. This offers new potential for treatment.
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PMID:Progress in understanding androgen-independent prostate cancer (AIPC): a review of potential endocrine-mediated mechanisms. 1860 49

The presence of invasive micropapillary component has been reported to be associated with salivary duct carcinoma and poor outcomes. Herein is described a rare case of invasive micropapillary salivary duct carcinoma of the parotid gland in a 60-year-old man. The micropapillary component was approximately 70% of the area of the tumor. Squamous differentiation was focally seen adjacent to the micropapillary component. On immunohistochemistry the ordinary salivary duct carcinoma component was positive for gross cystic disease fluid protein-15 (GCDFP-15), androgen receptor (AR), and HER2/neu, whereas both micropapillary and squamous components were negative for GCDFP-15 and AR. Immunohistochemical staining for D2-40 highlighted the lymph vessel invasion of tumor cells. This patient developed metastases in the lymph nodes of the neck, and also in the liver, lung, and brain. The lymph nodes and liver metastases had both ordinary salivary duct carcinoma and micropapillary components. The patient died of tumor 11 months after the initial surgical operation. The results support that the presence of micropapillary component is associated with more aggressive behavior of salivary duct carcinoma. It is also important for pathologists to recognize that GCDFP-15 and AR expression can be reduced in micropapillary carcinoma in the differential diagnosis of metastatic tumor.
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PMID:Aggressive invasive micropapillary salivary duct carcinoma of the parotid gland. 1842 33

S100P protein regulates calcium signal transduction and mediates cytoskeletal interaction, protein phosphorylation and transcriptional control. We have previously shown how elevated S100P levels in prostate cancer strongly correlate with progression to metastatic disease. In our study, we evaluated the functional significance of S100P expression on prostate tumor growth in vitro and in vivo. S100P levels were modulated by overexpressing S100P in PC3 prostate cancer cells and by silencing S100P levels in 22Rv1 prostate cancer cells. Overexpression of S100P in PC3 cells promoted cell growth, increased the percentage of S-phase cells, decreased basal apoptosis rate and promoted anchorage independent growth in soft agar. Furthermore, prostate cancer cells overexpressing S100P were protected against camptothecin-induced apoptosis. Conversely, silencing of S100P in 22Rv1 cells using siRNA resulted in a prominent cytostatic effect. The influence of S100P on tumor growth and metastases were assessed in vivo. S100P-overexpressing PC3 cells had a dramatically increased tumor formation compared to controls. Microarray analysis showed the involvement of growth pathways including increased androgen receptor expression in S100P-overexpressing cells. These results provide the first functional proof that S100P overexpression can upregulate androgen receptor expression and thereby promote prostate cancer progression by increasing cell growth. Moreover, the results confirm the oncogenic nature of S100P in prostate cancer and suggest that the protein may directly confer resistance to chemotherapy. Hence, S100P could be considered a potential drug target or a chemosensitization target, and could also serve as a biomarker for aggressive, hormone-refractory and metastatic prostate cancer.
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PMID:Functional evidence implicating S100P in prostate cancer progression. 1845 69

Residual tissue androgens are consistently detected within the prostate tumors of castrate individuals and are thought to play a critical role in facilitating the androgen receptor-mediated signaling pathways leading to disease progression. The source of residual tumor androgens is attributed in part to the uptake and conversion of circulating adrenal androgens. Whether the de novo biosynthesis of androgens from cholesterol or earlier precursors occurs within prostatic tumors is not known, but it has significant implications for treatment strategies targeting sources of androgens exogenous to the prostate versus 'intracrine' sources within the prostatic tumor. Moreover, increased expression of androgen-metabolizing genes within castration-resistant metastases suggests that up-regulated activity of endogenous steroidogenic pathways may contribute to the outgrowth of 'castration-adapted' tumors. These observations suggest that a multi-targeted treatment approach designed to simultaneously ablate testicular, adrenal and intracrine contributions to the tumor androgen signaling axis will be required to achieve optimal therapeutic efficacy.
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PMID:Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications. 1847 83

Prostate cancer is a major health problem in the United States and worldwide. In 2007, more than 27,000 men were estimated to have died from prostate cancer in the United States alone. Although important advances have been made in the diagnosis and treatment of prostate cancer, therapies focused on the removal or inhibition of androgen action remain the most important components of therapy for individuals with metastatic disease. Despite the application of such modalities, the vast majority of patients with metastatic disease progress with a median survival of less than 2 years. A number of different mechanisms have been identified that may potentially contribute to the progression of prostate cancer. These insights suggest that signaling via the androgen receptor (AR) -- either via alternate signaling pathways impinging on the AR or through the in situ formation of androgens within progressive tumors -- is an important contributor to such progressive disease. It is anticipated that such mechanistic insights will lead to the development of useful new therapies in the future.
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PMID:Mechanisms of prostate cancer progression to androgen independence. 1847 93

Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription-PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59-0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03-0.44; P < 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P < 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment.
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PMID:Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. 1851 8

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


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