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 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite the high incidence and mortality of prostate cancer (PCa), molecular and genetic events involved in its progression remain poorly understood due to difficulty in establishing premalignant lesions and primary tumors in vitro. The most used cancer cell lines, which have been established primarily from metastatic lesions, do not accurately recapitulate the biological behaviour of primary tumors as compared to primary cultures generated from clinical PCa specimens. However, prostate primary cultures contain a mixture of different cell types which must be characterized completely to obtain reproducible information for studying the biology of single tumors and for evaluating the effectiveness of therapeutical approaches. In this report we show the differential expression of epithelial and prostatic markers in 30 PCa-, 6 high grade prostate intraepithelial neoplasia (PIN)- and 6 BPH-derived primary cell cultures. After organoids attached, outgrowths appeared with cells maintaining close cell-to-cell associations: cell colonies express either cyto-keratin 14 [K14 (20-60%)], or cytokeratin 18 [K18 (10-70%)] with moderately high levels of androgen receptor (AR), prostate-specific antigen (PSA) and kallikrein (hK2). The differences observed for K14 immunostaining was not statistically different between PIN- and BPH-derived cultures, whereas the difference of expression of the same marker resulted highly significant (p<0.001) in the comparison between PIN- and PCa-derived cultures and between BPH- and PCa-derived cultures. In addition, the percentage of positivity for lumenal K18 was statistically lower for BPH cultures respect to the positivity observed for both PIN and PCa-derived cultures (p<0.05 and p<0.001, respectively). A reduced expression of K18+ cells, without modification in K14 expression, was evident in high grade PCa in which we observed also an increment in K5 expression representing an intermediate basal/differentiating epithelial cell marker. The primary cultures derived from prostatic tissues can be an extremely important method to study genetic and molecular changes involved in PCa progression.
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PMID:Epithelial and prostatic marker expression in short-term primary cultures of human prostate tissue samples. 1580 28

The serine protease inhibitor (serpin) protein C inhibitor (PCI) has been found in the prostate and possibly is a marker to distinguish normal prostate, benign prostatic hyperplasia, and prostate cancer. In this study, we assessed PCI expression in normal, hyperplastic, and malignant prostatic tissues, prostate cancer cell lines, and the CWR22 prostate cancer xenograft model that allowed us to study PCI expression and its regulation in response to androgens. By Northern blot, immunohistochemistry, and in situ hybridization, we found that PCI was expressed in both benign and malignant prostate tissues. Protein C inhibitor was expressed in both androgen-independent (PC-3) and androgen-dependent (LNCaP) prostate cancer cell lines. Furthermore, PCI was detected in all CWR22 tumor samples (androgen dependent, 6 days post-castration, 12 days post-castration followed by 72 h of testosterone treatment, and recurrent CWR22 tumor), although expression of the mature forms of both prostate-specific antigen (PSA) and its homolog, kallikrein 2 (hK2), was clearly androgen-dependent. These results suggest that PCI expression is not regulated by androgens and that PCI is unlikely to be a tumor suppressor gene, but also that PCI may be involved in regulating key serine proteases involved in metastatic prostate disease.
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PMID:Protein C inhibitor (plasminogen activator inhibitor-3) expression in the CWR22 prostate cancer xenograft. 1587 12

Human tissue kallikrein genes, located on the long arm of chromosome 19, are a subgroup of the serine protease family of proteolytic enzymes. Initially thought to consist of three members, the human kallikrein locus has now been extended and includes 15 tandemly located genes. These genes, and their protein products, share a high degree of homology and are expressed in a wide array of tissues, mainly those that are under steroid hormone control. PSA (hK3) is one of the human kallikreins, and is the most useful tumor marker for prostate cancer screening, diagnosis, prognosis and monitoring. hK2, another prostate-specific kallikrein, has also been proposed as a complementary prostate cancer biomarker. In the past 5 years, the newly discovered kallikreins (KLK4-KLK15) have been associated with several types of cancer. For example, hK4, hK5, hK6, hK7, hK8, hK10, hK11, hK13 and hK14 are emerging biomarkers for ovarian, breast, prostate and testicular cancer. New evidence raises the possibility that some kallikreins are directly involved with cancer progression. We here review the evidence linking kallikreins and cancer and their applicability as novel biomarkers for cancer diagnosis and management.
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PMID:Human tissue kallikrein gene family: applications in cancer. 1591 Oct 97

The human kallikrein gene 10 (KLK10) is a member of the kallikrein gene family on chromosome 19q13.4. This gene was identified by its downregulation in breast cancer, and preliminary evidence suggests that it may act as a tumor suppressor. A computer-based analysis was performed on EST and SAGE clones from the Cancer Genome Anatomy Project and other databases. Experimental verification of differential expression of KLK10 in cancer was performed by PCR using gene-specific primers. The mRNA and EST analysis allowed the construction of the longest transcript of the gene and characterization of a 5' extension of the reported mRNA. In addition, seven new splice variants of KLK10 were identified. One of these variants, named KLK10 splice variant 3 (KLK10-SV3) which starts with a novel first exon, was experimentally verified. This variant is predicted to encode for the same protein as the 'classical' KLK10 mRNA, since the first exon is untranslated. One variant mRNA partially matches with the sequence of KLK10, while the rest of the mRNA matches with a portion of the polycystic kidney disease gene, found on chromosome 15. This variant could not be experimentally verified in either normal or cancerous tissues. There are 39 reported single nucleotide polymorphisms (SNPs) for the gene, in which three result in amino acid substitutions. SAGE analysis shows a clear upregulation of KLK10 in ovarian, pancreatic, colon, and gastric cancers. The gene is, however, downregulated in breast and prostate cancers. A three-fold decrease in expression levels was noted in actinic keratosis, compared to normal skin from the same patient. The differential regulation of KLK10 in ovarian and prostate cancers was experimentally verified by RT-PCR analysis. In addition, a significant number of clones were isolated from carcinomas of the head and neck. Fewer clones were found in carcinomas of the skin, brain and prostate. Orthologues were identified in three other species, with the highest degree of homology observed with the mouse and rat orthologues (42% in each). In conclusion new splice variants of the KLK10 gene were identified. These in silico analyses show a differential expression of the gene in various malignancies and provide the basis for directing experimental efforts to investigate the possible role of the gene as a cancer biomarker.
Tumour Biol
PMID:Identification of new splice variants and differential expression of the human kallikrein 10 gene, a candidate cancer biomarker. 1610 44

MTJ1/ERdj1 and its human homologue HTJ1 are membrane proteins that interact with the molecular chaperone BiP through their J-domain. HTJ1 also contains a C-terminal cytosolic region of unknown function that consists of two SANT domains separated by a spacer region. We recently showed that the second SANT domain of HTJ1 (SANT2) binds to alpha1-antichymotrypsin and alters its serpin activity [B. Kroczynska, C.M. Evangelista, S.S. Samant, E.C. Elguindi, S.Y. Blond, The SANT2 domain of the murine tumor cell DnaJ-like protein 1 human homologue interacts with alpha1-antichymotrypsin and kinetically interferes with its serpin inhibitory activity, J. Biol. Chem. 279 (2004) 11432-11443]. Here, we identified a new variant of human inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) that also interacts with the SANT2 domain of HTJ1. Biochemical, mutagenesis, and fluorescence studies demonstrate that SANT2 binds to a carboxyl-terminal fragment that corresponds to the last third of the new ITIH4 isoform sequence (residues 588-930). ITIH4 and MTJ1 co-immunoprecipitate from total liver protein extracts and SANT2 protects the ITIH4(588-930) recombinant fragment from being processed by kallikrein in vitro. This work reveals that the SANT2 domain of HTJ1 is a genuine protein-protein interaction module.
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PMID:BIP co-chaperone MTJ1/ERDJ1 interacts with inter-alpha-trypsin inhibitor heavy chain 4. 1627 2

Angiogenesis provides a mechanism by which delivery of oxygen and nutrients is adapted to compliment changes in tissue mass or metabolic activity. However, maladaptive angiogenesis is integral to the process of several diseases common in Western countries, including tumor growth, vascular insufficiency, diabetic retinopathy and rheumatoid arthritis. Understanding the process of capillary growth, including the identification and functional analyses of key pro- and anti-angiogenic factors, provides knowledge that can be applied to improve/reverse these pathological states. Initially, angiogenesis research focused predominantly on vascular endothelial growth factor (VEGF) as a main player in the angiogenesis cascade. It is apparent now that participation of multiple angiogenic factors and signal pathways is critical to enable effective growth and maturation of nascent capillaries. The purpose of this review is to focus on recent progress in identifying angiogenesis signaling pathways that show promise as targets for successful induction or inhibition of capillary growth. The strategies applied to achieve these contradictory tasks are discussed within the framework of our existing fundamental knowledge of angiogenesis signaling cascades, with an emphasis on comparing the employment of distinctive tactics in modulation of these pathways. Innovative developments that are presented include: (1) inducing a pleiotropic response via activation or inhibition of angiogenic transcription factors; (2) modulation of nitric oxide tissue concentration; (3) manipulating the kallikrein-kinin system; (4) use of endothelial progenitor cells as a means to either directly contribute to capillary growth or to be used as a vehicle to deliver "suicide genes" to tumor tissue.
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PMID:Regulators of angiogenesis and strategies for their therapeutic manipulation. 1630 46

A variety of biomarkers have been developed to monitor growth of ovarian cancer and to detect disease at an early interval. CA125 (MUC16) has provided a useful serum tumor marker for monitoring response to chemotherapy, detecting disease recurrence, distinguishing malignant from benign pelvic masses, and potentially improving clinical trial design. A rapid fall in CA125 during chemotherapy predicts a favorable prognosis and could be used to redistribute patients on multiarmed randomized clinical trials. Several studies now document that CA125 can serve as a surrogate marker for response in phase II trials. Serial measurement of CA125 might also provide a useful marker for monitoring stabilization of disease with cytostatic targeted therapeutic agents. The greatest potential for serum markers may be in detecting ovarian cancer at an early stage. A rising CA125 can be used to trigger transvaginal sonography (TVS) in a small fraction of patients. An algorithm has been developed that calculates risk of ovarian cancer based on serial CA125 values and refers patients at highest risk for TVS. Use of the algorithm is currently being evaluated in a trial with 200,000 women in the UK that will test critically the ability of a two-stage screening strategy to improve survival in ovarian cancer. Whatever the outcome, as 20% of ovarian cancers have little or no expression of CA125, additional serum markers will be required to detect all patients in an initial phase of screening. More than 30 serum markers have been evaluated alone and in combination with CA125 by different investigators. Some of the most promising include: HE4, mesothelin, M-CSF, osteopontin, kallikrein(s), and soluble EGF receptor. Two proteomic approaches have been used: one examines the pattern of peaks on mass spectroscopy and the other uses proteomic analysis to identify a limited number of critical markers that can be assayed by more conventional methods. Both approaches are promising and require further development. Several groups are placing markers on multiplex platforms to permit simultaneous assay of multiple markers with very small volumes of serum. Mathematical techniques are being developed to analyze combinations of marker levels to improve sensitivity and specificity. In the future, serum markers should improve the sensitivity of detecting recurrent disease as well as facilitate earlier detection of ovarian cancer.
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PMID:New tumor markers: CA125 and beyond. 1634 44

Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection has been shown to cause hepatic carcinogenesis. A total 58,251 of cDNA clones of full-length cDNA libraries of HBV and HCV-infected HCC and their surrounding non-tumor tissues, respectively, were sequenced and analyzed by blasting against GENEBANK maintained by NCBI. About 180 and 279 of genes were shown an obviously increased and decreased expression patterns between HCC tissue and its adjacent non-tumor tissue. The candidate genes consisted of the genes encoded liver specific metabolism enzymes, secretory functional proteins, proteases and their inhibitors, protein chaperon, cell cycle components, apoptosis-related proteins, transcriptional factors, and DNA binding proteins. Several genes were further investigated by using real-time PCR to confirm the gene expression levels in at least 24 pairs of HCC tissues and adjacent non-tumor tissues. The results showed that genes encoded reticulon 4, RGS-1, antiplasmin, and kallikrein B were down-regulated with the average of 2.8, 8.5, 3.2, and 10.5-fold, respectively. Our results provide crucial candidate genes to develop clinical diagnosis and gene therapy of HCC.
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PMID:Gene expression analysis of human hepatocellular carcinoma by using full-length cDNA library. 1646 13

The occurrence of various serine proteinases and serine proteinases inhibitors (SERPINs) was investigated by RT-PCR in whole testes of 1-, 3-, and 8-wk-old mice in crude and enriched germ cell fractions, mouse Leydig tumor cells (mLTC-1), and primary cultures of 3- and 8-wk-old enriched fractions of Leydig cells and 3-wk-old Sertoli cells. New members were identified in the testis protease repertoire. Within the Leydig repertoire, a PCR product was found for plasminogen activators urokinase plasminogen activator (uPA) and tissue plasminogen activator (8-wk-old cells), matriptase-2 (mLTC-1), kallikrein-21, SERPINA5, SERPINB2 (primary cultures), and serine peptidase inhibitor Kunitz type 2 (SPINT2). The gonadotropin regulation was explored by semiquantitative RT-PCR, using steroidogenic acute regulatory protein (StAR) as a positive control. Matriptase-2, kallikrein-21, SPINT2, and SERPINA5 were down-regulated, whereas uPA and its receptor were up-regulated by human chorionic gonadotropin (hCG) via cAMP in the mLTC-1 cells. Positive effects were observed transiently after 1-8 h of hCG exposure, and negative effects, first evidenced after 6 h, lasted 48 h. The hCG-induced effects were confirmed in primary cultures. In addition, SERPINB2 was augmented by hCG in primary cultures. Addition of either trypsin or protease inhibitors did not alter the hCG-induced surge of StAR. Because hCG regulated proteases and SERPINs (whereas testosterone did not), it could alter the proteolytic balance of Leydig cells and consequently the metabolism of extracellular matrix components. Therefore, even though a direct interplay between the early hCG-induced surge of uPA and StAR is unlikely, our data together with the literature suggest that extracellular matrix proteins alter Leydig cell steroidogenesis.
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PMID:The mouse testis is the source of various serine proteases and serine proteinase inhibitors (SERPINs): Serine proteases and SERPINs identified in Leydig cells are under gonadotropin regulation. 1674 Sep 73

We have studied the immunohistochemical expression (IE) of eight non-tissue-specific human kallikreins (hKs) (hK5, 6, 7, 10, 11, 12, 13, and 14) in different normal tissues. The IE was always cytoplasmic, showing a characteristic pattern in some tissues. Comparison of the IE of all hKs studied in the different tissues revealed no major differences, suggesting that they share a common mode of regulation. Furthermore, hKs were immunohistochemically revealed in a variety of tissues, indicating that no protein is tissue-specific (except for hK2 and hK3, which have tissue-restricted expression). In general, our results correspond well with data from RT-PCR and ELISA assays. Glandular epithelia constitute the main kallikrein IE sites, and the staining in their secretions confirms that these proteases are secreted. A variety of other tissues express the proteins as well. We have also immunohistochemically evaluated all the above hKs in several malignant tissues. Tumors arising from tissues expressing kallikreins tested positive. Corresponding to the IE in normal glandular tissues, most hKs were expressed in adenocarcinomas. The prognostic value of several hKs was studied in series of prostate, renal cell, colon and urothelial carcinomas.
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PMID:Cellular distribution of human tissue kallikreins: immunohistochemical localization. 1680 Jul 26


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