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)

Our objective was to elucidate phenotypic differences between prostate cancer (PCa) liver, lymph node, and bone metastases. PCa metastases were obtained through a rapid tissue acquisition necropsy protocol. We grossly dissected metastatic foci from frozen samples and performed expression analyses using cDNA microarrays. Immunohistochemical analyses using a tissue microarray from thirty individuals with PCa metastases to lymph nodes, liver, and bone was used to confirm the gene expression changes associated with each metastatic site. Transcript alterations statistically-associated with bone metastases included increased expression of IBSP (Bone sialoprotein), F13A1 (factor XIII), and decreased expression of EFNA1 (ephrin-A1) and ANGPT2 (angiopoietin-2) when compared to liver and lymph node metastases. The metastasis-associated changes in proteins involved in coagulation and angiogenesis prompted further analysis of additional factors known to participate in the clotting cascade and blood vessel formation (angiopoitein-1, PAI-1, uPA, PAI-RBP-1 and hepsin). We also assessed tumor-associated microvessel density and distribution in liver, lymph node, and bone metastasis. Intense fibrin(ogen) and fibulin-1 staining was localized to epithelial cells at the periphery of metastatic tumors possibly to facilitate angiogenesis. The expression of hepsin, uPA, PAI-RBP1, PAI-1, and factor XIII may influence fibrinolysis and are regulated by the tumor microenvironment. The expression of angiopoietin-2 and apparent silencing of angiopoietin-1 in PCa bone, liver, and lymph node metastases may be critical for angiogenesis in this tumor type. In addition, the resulting tumor-associated microvessel density and distribution was significantly different between liver and bone metastasis possibly in response to the protein expression changes detailed above.
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PMID:Differential expression of angiogenesis associated genes in prostate cancer bone, liver and lymph node metastases. 1797 46

Transmembrane serine protease 2 (TMPRSS2) is an androgen-regulated member of the type two transmembrane protease (TTSP) family. Two other members of the TTSP family, matriptase and hepsin, are over-expressed in prostate adenocarcinoma and mechanistically influence cancer cell invasion and metastasis. This study was performed to determine TMPRSS2 protein expression in primary and metastatic prostate cancers. We developed a monoclonal antibody capable of the sensitive and specific detection of TMPRSS2 protein. TMPRSS2 regulation by androgen and presence in seminal fluid was measured. TMPRSS2 localization and expression was evaluated in 415 cases of primary prostate cancer and 144 prostate cancer metastases by immunohistochemistry. We determined that TMPRSS2 protein expression is regulated by androgens and that TMPRSS2 is a component of the normal seminal fluid proteome. TMPRSS2 protein is abundantly expressed in the prostate, with low levels in the epithelia of the colon, stomach, epididymis and breast. Pancreatic acini, hepatic bile ducts, testicular Leydig cells and the kidney also express TMPRSS2. In the prostate, TMPRSS2 protein is specifically localized to the secretory epithelium, with enhanced expression in the plasma membrane orientated towards the ductal lumen. TMPRSS2 expression was significantly higher in both neoplastic prostate and in the epithelium of prostatic hyperplasia compared to normal epithelium (p < 0.01). TMPRSS2 expression was further elevated in higher Gleason grade cancers (patterns 4 and 5) compared to pattern 3 (p = 0.04). Furthermore, in most high-grade cancers, TMPRSS2 was mislocalized, being expressed in the cytoplasm as well as in the cell membrane. Prostate cancer metastases also generally expressed high levels of TMPRSS2. In summary, the TMPRSS2 protease is expressed highly in primary and metastatic prostate cancers and is associated with tumour cell differentiation. Based on studies with the related proteins matriptase and hepsin, TMPRSS2 should be investigated for causal roles in prostate carcinogenesis.
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PMID:The androgen-regulated type II serine protease TMPRSS2 is differentially expressed and mislocalized in prostate adenocarcinoma. 1833 34

Early detection and diagnosis of prostate cancer is key to designing effective treatment strategies. Microarrays have resulted in the discovery of hepsin (HPN) as a biomarker for detection of prostate cancer. In this study, we explore the development of HPN imaging probes for detection of prostate cancer. We used phage display to isolate HPN binding peptides with 190 + 2.2 nmol/L affinity in monomeric form and high specificity. The identified peptides were able to detect human prostate cancer on tissue microarrays and in cell-based assays. HPN-targeted imaging agents were synthesized by conjugating multiple peptides to fluorescent nanoparticles to further improve avidity through multivalency and to improve pharmacokinetics. When injected into mouse xenograft models, HPN-targeted nanoparticles bound specifically to HPN-expressing LNCaP xenografts compared with non-HPN-expressing PC3 xenografts. HPN imaging may provide a new method for detection of prostate cancer.
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PMID:Detection of early prostate cancer using a hepsin-targeted imaging agent. 1838 35

Selected transcript markers as well as their combinations were analyzed on minimal prostate tissue specimens with regard to their diagnostic potential. Artificial prostate biopsies from RPE explants were used for evaluation and optimization of the techniques used followed by application to diagnostic prostate needle core biopsies. Minimal prostate specimens were cryopreserved and processed with standardized methods. The RNA amount of a half of each biopsy was sufficient for the analysis of 11 marker genes and one reference gene (TBP) using quantitative PCR assays.The relative transcript amounts obtained were included in several analyses including calculations for each single marker gene like median overexpression rate as well as marker combinations. Two optimized mathematical models based on relative expression levels of EZH2, hepsin, PCA3, prostein, and TRPM8 were evaluated with regard to their diagnostic potential. Compared to single marker analyses these models show higher sensitivity and specificity for prostate cancer detection.Thus biomolecular prostate cancer identification may represent a suitable diagnostic tool to supplement conventional techniques on prostate biopsies. Furthermore, an extension of this approach to PCa prognosis and the transfer to urine samples appear very promising.
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PMID:[Molecular genetic markers for prostate cancer. Evidence in fine needle biopsies for improved confirmation of the diagnosis]. 1867 47

Hepsin, a cell surface protease, is widely reported to be overexpressed in more than 90% of human prostate tumors. Hepsin expression correlates with tumor progression, making it a significant marker and target for prostate cancer. Recently, it was reported that in a prostate cancer mouse model, hepsin up-regulation in tumor tissue promotes progression and metastasis. The underlying mechanisms, however, remain largely uncharacterized. Hepsin transgenic mice displayed reduced laminin-332 (Ln-332) expression in prostate tumors. This is an intriguing cue, since proteolytic processing of extracellular matrix macromolecules, such as Ln-332, is believed to be involved in cancer progression, and Ln-332 expression is lost during human prostate cancer progression. In this study, we provide the first direct evidence that hepsin cleaves Ln-332. Cleavage is specific, since it is both inhibited in a dose-dependent manner by a hepsin inhibitor (Kunitz domain-1) and does not occur when catalytically inactive hepsin is used. By Western blotting and mass spectrometry, we determined that hepsin cleaves the beta3 chain of Ln-332. N-terminal sequencing identified the cleavage site at beta3 Arg(245), in a sequence context (SQLR(245) LQGSCFC) conserved among species and in remarkable agreement with reported consensus target sequences for hepsin activity. In vitro cell migration assays showed that hepsin-cleaved Ln-332 enhanced motility of DU145 prostate cancer cells, which was inhibited by Kunitz domain-1. Further, hepsin-overexpressing LNCaP prostate cancer cells also exhibited increased migration on Ln-332. Direct cleavage of Ln-332 may be one mechanism by which hepsin promotes prostate tumor progression and metastasis, possibly by up-regulating prostate cancer cell motility.
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PMID:Laminin-332 is a substrate for hepsin, a protease associated with prostate cancer progression. 1878 72

Hepsin is a type II transmembrane serine protease overexpressed in the majority of human prostate cancers. We recently demonstrated that hepsin promotes prostate cancer progression and metastasis and thus represents a potential therapeutic target. Here we report the identification of novel small-molecule inhibitors of hepsin catalytic activity. We utilized purified human hepsin for high-throughput screening of established drug and chemical diversity libraries and identified sixteen inhibitory compounds with IC(50) values against hepsin ranging from 0.23-2.31 microM and relative selectivity of up to 86-fold or greater. Two compounds are orally administered drugs established for human use. Four compounds attenuated hepsin-dependent pericellular serine protease activity in a dose dependent manner with limited or no cytotoxicity to a range of cell types. These compounds may be used as leads to develop even more potent and specific inhibitors of hepsin to prevent prostate cancer progression and metastasis.
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PMID:Identification and characterization of small-molecule inhibitors of hepsin. 1885 37

The transmembrane serine protease hepsin is one of the most highly upregulated genes in prostate cancer. Here, we investigated its tumor-promoting activity by use of a mouse orthotopic prostate cancer model. First, we compared the tumor growth of low hepsin-expressing LnCaP-17 cells with hepsin-overexpressing LnCaP-34 cells. After implantation of cells into the left anterior prostate lobe, LnCaP-34 tumors not only grew faster based on increased serum prostate-specific antigen levels but also metastasized to local lymph nodes and, most remarkably, invaded the contralateral side of the prostate at a rate of 100% compared with only 18% for LnCaP-17 tumors. The increased tumor growth was not due to nonspecific gene expression changes and was not predicted from the unaltered in vitro growth and invasion of LnCaP-34 cells. A likely explanation is that the in vivo effects of hepsin were mediated by specific hepsin substrates present in the tumor stroma. In a second study, mice bearing LnCaP-34 tumors were treated with a PEGylated form of Kunitz domain-1, a potent hepsin active site inhibitor derived from hepatocyte growth factor activator inhibitor-1 (K(i)(app) 0.30 +/- 0.02 nmol/L). Treatment of established tumors with PEGylated Kunitz domain-1 decreased contralateral prostate invasion (46% weight reduction) and lymph node metastasis (50% inhibition). Moreover, serum prostate-specific antigen level remained reduced during the entire treatment period, reaching a maximal reduction of 76% after 5 weeks of dosing. The findings show that hepsin promotes invasive prostate tumor growth and metastasis and suggest that active site-directed hepsin inhibition could be effective in prostate cancer therapy.
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PMID:Pegylated kunitz domain inhibitor suppresses hepsin-mediated invasive tumor growth and metastasis. 1984 51

The large amounts of microarray data provide us a great opportunity to identify gene expression profiles (GEPs) in different tissues or disease states. Disease-specific biomarker genes likely share GEPs that are distinct in disease samples as compared with normal samples. The similarity of the GEPs may be evaluated by Pearson Correlation Coefficient (PCC) and the distinctness of GEPs may be assessed by Kolmogorov-Smirnov distance (KSD). In this study, we used the PCC and KSD metrics for GEPs to identify disease-specific (cancer-specific) biomarkers. We first analyzed and compared GEPs using microarray datasets for smoking and lung cancer. We found that the number of genes with highly different GEPs between comparing groups in smoking dataset was much larger than that in lung cancer dataset; this observation was further verified when we compared GEPs in smoking dataset with prostate cancer datasets. Moreover, our Gene Ontology analysis revealed that the top ranked biomarker candidate genes for prostate cancer were highly enriched in molecular function categories such as 'cytoskeletal protein binding' and biological process categories such as 'muscle contraction'. Finally, we used two genes, ACTC1 (encoding an actin subunit) and HPN (encoding hepsin), to demonstrate the feasibility of diagnosing and monitoring prostate cancer using the expression intensity histograms of marker genes. In summary, our results suggested that this approach might prove promising and powerful for diagnosing and monitoring the patients who come to the clinic for screening or evaluation of a disease state including cancer.
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PMID:Discovering disease-specific biomarker genes for cancer diagnosis and prognosis. 2044 Dec 32

Molecular imaging has moved to the forefront of drug development and biomedical research. The identification of appropriate imaging targets has become the touchstone for the accurate diagnosis and prognosis of human cancer. Particularly, cell surface- or membrane-bound proteins are attractive imaging targets for their aberrant expression, easily accessible location, and unique biochemical functions in tumor cells. Previously, we published a literature mining of potential targets for our in-house enzyme-mediated cancer imaging and therapy technology. Here we present a simple and integrated bioinformatics analysis approach that assembles a public cancer microarray database with a pathway knowledge base for ascertaining and prioritizing upregulated genes encoding cell surface- or membrane-bound proteins, which could serve imaging targets. As examples, we obtained lists of potential hits for six common and lethal human tumors in the prostate, breast, lung, colon, ovary, and pancreas. As control tests, a number of well-known cancer imaging targets were detected and confirmed by our study. Further, by consulting gene-disease and protein-disease databases, we suggest a number of significantly upregulated genes as promising imaging targets, including cell surface-associated mucin-1, prostate-specific membrane antigen, hepsin, urokinase plasminogen activator receptor, and folate receptors. By integrating pathway analysis, we are able to organize and map "focused" interaction networks derived from significantly dysregulated entity pairs to reflect important cellular functions in disease processes. We provide herein an example of identifying a tumor cell growth and proliferation subnetwork for prostate cancer. This systematic mining approach can be broadly applied to identify imaging or therapeutic targets for other human diseases.
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PMID:General approach to identifying potential targets for cancer imaging by integrated bioinformatics analysis of publicly available genomic profiles. 2143 57

The serine-protease hepsin is one of the most prominently overexpressed genes in human prostate carcinoma. Forced expression of the enzyme in mice prostates is associated with matrix degradation, invasive growth, and prostate cancer progression. Conversely, hepsin overexpression in metastatic prostate cancer cell lines was reported to induce cell cycle arrest and reduction of invasive growth in vitro. We used a system for doxycycline (dox)-inducible target gene expression in metastasis-derived PC3 cells to analyze the effects of hepsin in a quantitative manner. Loss of viability and adhesion correlated with hepsin expression levels during anchorage-dependent but not anchorage-independent growth. Full expression of hepsin led to cell death and detachment and was specifically associated with reduced phosphorylation of AKT at Ser(473), which was restored by growth on matrix derived from RWPE1 normal prostatic epithelial cells. In the chorioallantoic membrane xenograft model, hepsin overexpression in PC3 cells reduced the viability of tumors but did not suppress invasive growth. The data presented here provide evidence that elevated levels of hepsin interfere with cell adhesion and viability in the background of prostate cancer as well as other tissue types, the details of which depend on the microenvironment provided. Our findings suggest that overexpression of the enzyme in prostate carcinogenesis must be spatially and temporally restricted for the efficient development of tumors and metastases.
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PMID:Matrix-dependent regulation of AKT in Hepsin-overexpressing PC3 prostate cancer cells. 2175 Jun 52


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