Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human kallikrein 6 protein is a newly discovered human kallikrein. We determined the amount of human kallikrein 6 in extracts of 182 ovarian tumours and correlated specific activity (ng hK6 mg(-1) total protein) with clinicopathological variables documented at the time of surgical excision and with outcome (progression free survival, overall survival) monitored over a median interval of 62 months. Thirty per cent of the tumours were positive for human kallikrein 6 (>35 ng hK6 mg(-1) total protein). Human kallikrein 6-specific immunohistochemical staining of four ovarian tissues that included benign, borderline and malignant lesions indicated a cytoplasmic location of human kallikrein 6 in tumour cells of epithelial origin, although the intensity of staining was variable. Tumour human kallikrein 6 (ng hK6 mg(-1) total protein) was higher in late stage disease, serous histotype, residual tumour >1 cm and suboptimal debulking (>1 cm) (P<0.05). Univariate analysis revealed that patients with tumour human kallikrein 6 positive specific activity were more likely to suffer progressive disease and to die (hazard ratio 1.71 (P=0.015) and 1.88 (P=0.022), respectively). Survival curves demonstrated the same (P=0.013 and 0.019, respectively). Multivariate analysis revealed that human kallikrein 6 positivity was retained as an independent prognostic variable in several subgroups of patients, namely those with (low) grade I and II tumours (hazard ratio progression free survival 4.3 (P=0.027) and overall survival 4.1 (P=0.023)) and those with optimal debulking (hazard ratio progression free survival 3.8 (P=0.019) and overall survival 5.6 (P=0.011)). We conclude that tumour kallikrein 6 protein levels have utility as an independent adverse prognostic marker in a subgroup of ovarian cancer patients with otherwise apparently good prognosis.
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PMID:Immunofluorometric quantitation and histochemical localisation of kallikrein 6 protein in ovarian cancer tissue: a new independent unfavourable prognostic biomarker. 1223 61

Anti-thrombin, a member of the serpin family and an inhibitor of thrombin and blood coagulation factor Xa, was recently shown to inhibit angiogenesis and tumor growth. In the present study, we examined the expression of anti-thrombin in benign and malignant prostate gland. Using immunohistochemistry, anti-thrombin was found in prostate epithelium and stroma cells. Tissue microarrays of tumors (n = 112) and three different prostate cancer cell lines (PC-3, LNCaP, and DU-145) were all positive for anti-thrombin. Abundant expression in a population of prostatic tumor cells was further evidenced by in situ hybridization experiments. The immunostaining for anti-thrombin was confined to the cytoplasm, was most intense in Gleason grade 3 tumors, and in part overlapped with that of prostate-specific antigen. Western blotting of benign and malignant tissue homogenates revealed a predominant 58-kd anti-thrombin immunoreactive component. In vitro, anti-thrombin formed complexes more readily with human kallikrein 2, particularly in the presence of heparin, and less efficiently with prostate-specific antigen. Both complexes could be recognized by polyclonal and monoclonal IgGs against anti-thrombin. We conclude that anti-thrombin is widely expressed in prostate cancer but is gradually lost in tumors of high Gleason grade. Anti-thrombin may act as a local anti-angiogenic factor, the effect of which is partially lost in poorly differentiated prostatic tumors.
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PMID:Anti-thrombin is expressed in the benign prostatic epithelium and in prostate cancer and is capable of forming complexes with prostate-specific antigen and human glandular kallikrein 2. 1246 22

Kallikreins are proteolytic enzymes that constitute a subfamily of serine proteases. Novel kallikrein genes were cloned recently, and it was shown that the human kallikrein family contains 15 genes tandemly aligned on chromosomal locus 19q13.3-q13.4. Based on their altered expression in tumor cells, kallikreins may be involved in the pathogenesis and/or progression of cancer. Evidence is presented that certain kallikreins may be exploited as diagnostic cancer biomarkers. Although the function(s) of novel kallikreins is currently unknown, increasing evidence suggests that kallikreins may participate in regulatory enzymatic cascade(s). Elucidation of the function of novel kallikreins largely depends on the availability of active recombinant proteins. Here, the zymogen for kallikrein 13 was overexpressed in Pichia pastoris and biochemically characterized. It was shown that the kallikrein 13 zymogen displays intrinsic catalytic activity leading to autoactivation. A clipped form of kallikrein 13 was identified, indicating autocatalytic cleavage at the internal bond R114-S115. Mature kallikrein 13 displays trypsin-like activity with restricted specificity on synthetic and protein substrates. Combinatorial P1-Lys libraries of tetrapeptide fluorogenic substrates were synthesized and used for the profiling of the P2 specificity of selected kallikreins. Interestingly, it was shown that human kallikrein 13, similarly to PSA, could specifically cleave human plasminogen to generate angiostatin-like fragments, suggesting that specific kallikreins may have antiangiogenic actions. An understanding of the physiology of human kallikreins is emerging with potential clinical applications.
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PMID:Emerging interest in the kallikrein gene family for understanding and diagnosing cancer. 1272 28

The identification of new diagnostic markers and potential treatment targets for prostate carcinoma (PCa) necessitates the evaluation of expression patterns in both malignant and non-malignant tissue specimens. In this study, we compared the mRNA expression of recently identified prostate-associated genes, prostate stem cell antigen (PSCA) and transient receptor potential p8 (trp-p8), to the mRNA expression of the most commonly used markers for PCa, prostate-specific antigen (PSA) and human kallikrein 2 (hK2). For these four candidates we performed highly specific quantitative real-time LightCycler RT-PCR assays with cDNA originating from matched tissue specimens of 40 patients with primary PCa. The highest transcript amounts were found for PSA in malignant as well as in non-malignant tissue specimens followed by hK2, trp-p8 and PSCA with an mRNA expression remarkably lower. The relative transcript levels of PSA, hK2 and trp-p8 were elevated in malignant in comparison to non-malignant tissues, but only for trp-p8 this increased expression was statistically significant. Focussing on organ confined tumors, we found a significant difference of the mRNA expression of PSA and trp-p8 between malignant and non-malignant tissue specimens. The marker trp-p8 is also suited to differentiate between the tumor stages when quantifying its transcript levels within tumor tissue specimens. The evaluation of the mRNA expression patterns of these markers by quantitative real-time RT-PCR could provide new tools for differential diagnosis and molecular staging. According to our data, the novel marker trp-p8 seems to represent a highly prostate-specific and PCa-associated gene qualifying it as a potential target for specific therapies.
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PMID:Multiple tumor marker analyses (PSA, hK2, PSCA, trp-p8) in primary prostate cancers using quantitative RT-PCR. 1279 97

Human kallikrein 11 (hK11/trypsin-like serine protease/TLSP, encoded by the KLK11 gene) is a member of the kallikrein family of secreted serine proteases. Recently, we developed a highly sensitive and specific immunoassay for hK11 and found that this protease is expressed in the prostate, stomach and trachea as well as in amniotic fluid and milk of lactating women. Elevated serum hK11 levels were found in 60% of men with prostate cancer and 70% of women with ovarian cancer. Also, hK11 expression was found to be under the regulation of steroid hormones, particularly estrogens, at the level of KLK11 transcription. We hypothesized that hK11 may be implicated in endocrine-related malignancies and serve as a novel prostate and ovarian cancer serological marker. The aim of our study was to examine if hK11 expression in ovarian tumors bears any prognostic significance. The concentration of hK11 (ng per mg of total protein) in 104 ovarian tumor cytosolic extracts was quantified and correlated with clinicopathologic variables and outcome over a median follow-up period of 67 months. Outcome was defined as progression-free survival (PFS) and overall survival (OS). hK11 concentration in ovarian tumor cytosols ranged from 0-21 ng/mg of total protein, with a median of 0.54 ng/mg. An optimal cutoff value of 0.54 ng/mg was selected to categorize tumors as hK11-positive or -negative. hK11-positive tumors were more frequently associated with early stage (Stage I/II) disease, pre-/peri-menopausal status and patients who exhibited complete or partial response to chemotherapy (p < 0.05). Univariate analysis revealed that patients with hK11-positive tumors had a significantly decreased risk of relapse with a hazard ratio (HR) of 0.45 (p = 0.007) and death (HR of 0.34, p = 0.005). Cox multivariate analysis indicated that hK11 was an independent prognostic indicator of OS (HR of 0.41, p = 0.025). Kaplan-Meier survival curves further confirmed that women with hK11-positive tumors have longer PFS and OS (p = 0.005 and p = 0.003, respectively). Similarly, in the subgroup of patients with grade 1-2 tumors, hK11-positivity was associated with higher OS in both univariate and multivariate analysis (HR of 0.23 and 0.17, p < 0.05). Finally, in women with optimal debulking after surgery (<1 cm residual tumor), hK11 positivity was associated with a slower disease progression. These results indicate that hK11 is a novel, independent marker of favorable prognosis in patients with ovarian cancer.
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PMID:Favorable prognostic value of tissue human kallikrein 11 (hK11) in patients with ovarian carcinoma. 1284 60

Human kallikrein 6 (hK6) is a trypsin-like serine protease, member of the human kallikrein gene family. Studies suggested a potential involvement of hK6 in the development and progression of Alzheimer's disease. The serum levels of hK6 might be used as a biomarker for ovarian cancer. To gain insights into the physiological role of this enzyme, we sought to determine its substrate specificity and its interactions with various inhibitors. We produced the proform of hK6 and showed that this enzyme was able to autoactivate, as well as proteolyse itself, leading to inactivation. Kinetic studies indicated that hK6 cleaved with much higher efficiency after Arg than Lys and with a preference for Ser or Pro in the P2 position. The efficient degradation of fibrinogen and collagen types I and IV by hK6 indicated that this kallikrein might play a role in tissue remodeling and/or tumor invasion and metastasis. We also demonstrated proteolysis of amyloid precursor protein by hK6 and determined the cleavage sites at the N-terminal end of the protein. Inhibition of hK6 was achieved via binding to different serpins, among which antithrombin III was the most efficient.
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PMID:Characterization of the enzymatic activity of human kallikrein 6: Autoactivation, substrate specificity, and regulation by inhibitors. 1287 3

Kallikreins are serine proteases with diverse physiologic functions. They are represented by multigene families in many animal species, especially in rat and mouse. Recently, the human kallikrein gene family has been fully characterized and includes 15 members, tandemly localized on chromosome 19q13.4. A new definition has now been proposed for kallikreins, which is not based on function but, rather, on close proximity and structural similarities. In this review, we summarize available information about kallikreins in many animal species with special emphasis on human kallikreins. We discuss the common structural features of kallikreins at the DNA, mRNA and protein levels and overview their evolutionary history. Kallikreins are expressed in a wide range of tissues including the salivary gland, endocrine or endocrine-related tissues such as testis, prostate, breast and endometrium and in the central nervous system. Most, if not all, genes are under steroid hormone regulation. Accumulating evidence indicates that kallikreins are involved in many pathologic conditions. Of special interest is the potential role of kallikreins in the central nervous system. In addition, many kallikreins seem to be candidate tumor markers for many malignancies, especially those of endocrine-related organs.
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PMID:An overview of the kallikrein gene families in humans and other species: emerging candidate tumour markers. 1295 Nov 70

Human kallikreins 6, 10 and 13 (hK6, hK10 and hK13) are expressed by many normal, mainly glandular tissues, including prostatic epithelium. Some kallikreins may function as tumor suppressors or are downregulated during cancer progression. The aim of this study was to evaluate the immunoexpression of these kallikreins in benign and malignant prostatic tissues and correlate their expression with prostate cancer (PC) prognosis. Included in the study were 25 cases of nonmalignant prostate and 179 cases of PC. Among them, 122 PC cases were immunostained for hK6, 94 for hK10 and 113 for hK13, respectively. The follow-up period for a subset of 68 patients who had undergone radical prostatectomy (RP) was 1-58 months (mean=13.4 +/- 1.7 and median=8.0 months). A cutoff value of 0.2 microg/l of serum PSA was established as a biochemical recurrence threshold. Follow-up information was available for 26/55 RP cases stained for hK6, 14/32 cases stained for hK10 and 25/59 cases stained for hK13. Gleason score (GS) 7 carcinomas were stratified as 7a and 7b, according to the primary grade. PC with GS 2-7a were histologically categorized as low malignant (LM) and PC with GS 7b-10 as high malignant (HM). The immunohistochemical method of streptavidin-biotin-peroxidase using monoclonal and polyclonal antibodies was performed. In the benign prostate and in prostatic intraepithelial neoplasia, a cytoplasmic immunostaining of varying intensity was evident. In PC, the immunoexpression of all kallikreins was decreased: 102/122 cases (84%) were positive for hK6, 73/94 (78%) for hK10 and 97/113 (86%) for hK13, respectively. A statistically significant difference in expression was found, in comparison to nonmalignant prostates (P=0.029, 0.009 and 0.045, respectively). Also, a positive correlation was observed between the immunoexpression of these three kallikreins. Concerning the histological grade, HM-PC expressed all three kallikreins with a slightly higher percentage than LM-PC: 79 vs 88% for hK6, 76 vs 79% for hK10 and 76 vs 92% for hK13. These differences were statistically significant only in the case of hK13 (P=0.024). Serum PSA did not correlate with kallikrein immunoexpression in PC. Furthermore, there was no significant correlation between kallikrein expression and pathological stage or recurrence, in the cases of RP. All three kallikreins are expressed in the nonmalignant and malignant prostate, with cancer tissues demonstrating slightly lower expression. Expression levels did not correlate with aggressiveness and they do not seem to have value for prostate cancer prognosis.
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PMID:Immunohistochemical localization of human kallikreins 6, 10 and 13 in benign and malignant prostatic tissues. 1297 Jul 25

Prostate-specific antigen (PSA) is the most useful tumor marker for diagnosis and monitoring of prostate cancer (CaP). Recently, we developed a specific immunoassay for human kallikrein 11 (hK11), one of the kallikrein gene family members, and found that hK11 was highly expressed in prostatic tissue and could be detected in seminal plasma (E. P. Diamandis et al., Cancer Res., 62: 295-300, 2002). The aim of this study was to investigate whether serum hK11 levels could be used to discriminate CaP from benign prostatic hyperplasia (BPH). We analyzed for hK11, total PSA, and percentage of free PSA, 150 serum samples from men with histologically confirmed BPH (n = 64) or CaP (n = 86). Total and free PSA levels were measured by the Immulite PSA assay, and hK11 levels were measured by our previously published immunofluorometric assay. Serum hK11 levels and the hK11:total PSA ratio were both significantly lower in CaP patients than in BPH patients. In the subgroup of patients with percentage of free PSA less than 20, an additional 54% of BPH patients could have avoided biopsies by using the hK11:total PSA ratio. Receiver operating characteristic (ROC) curve analysis demonstrated that the hK11:total PSA ratio [area under the curve (AUC), 0.83] and percentage of free PSA (AUC, 0.83) were much stronger predictors of CaP than total PSA (AUC, 0.69). These preliminary data suggest that the hK11:total PSA ratio could be a useful tumor marker for CaP and could be combined with percentage of PSA to further reduce the number of unnecessary prostatic biopsies.
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PMID:The usefulness of serum human kallikrein 11 for discriminating between prostate cancer and benign prostatic hyperplasia. 1455 49

The human kallikrein (hk) family, located on chromosome 19, encodes prostate-specific antigen (PSA [or hK3]), hK2, hK4, and hK15 (prostin), as well as other serine proteases. Although PSA has been used in the detection of prostate cancer for several years, much remains unknown about its function and forms. The regulatory mechanisms of PSA are vital to its understanding. A particular mechanism by which PSA forms complexes with either alpha1-antichymotrypsin or alpha2-macroglobulin may provide important information for disease detection and progression. Data are emerging that show that active hK2, hK4, and hK15 may be important to convert pro-PSA to the active PSA enzyme. This information, along with insights into the precise mechanisms of PSA expression, may be used to suggest that PSA and, perhaps, other members of the hK family contribute critical control mechanisms to tumor invasion or progression. Although much remains to be revealed on the role of these gene products in the detection and progression of prostate cancer, findings from studies that show sensitive signaling of the disease > or =20 years before the diagnosis of clinically significant prostate cancer may alter screening procedures and improve treatment options.
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PMID:Biology of prostate-specific antigen. 1460 15


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