Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HER2/neu (c-erbB2) protooncogene, which encodes a transmembrane receptor (p185neu), contributes to tumor cell invasion/metastasis through mechanism(s) which are, at present, poorly defined. Since basement membrane degradation is a prerequisite for tumor progression, we undertook a study to determine if the expression of urokinase, a key protease implicated in extracellular matrix proteolysis, was regulated by this oncogene. Stable overexpression of a cDNA encoding HER2/neu in H460 lung cancer cells led to elevated secretion of urokinase which was a consequence of a higher level of protease mRNA. Transfection of the HER2/neu-overexpressing B 104-1 cells with a CAT reporter construct driven by the urokinase promoter, gave rise to increased CAT activity when compared with parental NIH3T3 cells, which have low levels of HER2/neu, suggesting that the protooncogene can enhance urokinase promoter activity. Since the enhanced expression of HER2/neu results in increased tumor invasion/metastasis (1), these data suggest that, at least in vitro, HER2/neu-induced expression of urokinase may contribute to tumor progression in p185neu-positive cancers.
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PMID:Up-regulation of urokinase-type plasminogen activator expression by the HER2/neu proto-oncogene. 765 95

For the integration of new cell biological prognostic factors in daily clinical practice, we need to know not only their prognostic power with respect to prediction of relapse free and overall survival, but also their possible relation to response to endocrine therapy or chemotherapy in order to select adequate treatment for each patient. A large number of cell biological parameters are currently available to predict the prognosis of patients with breast cancer, but it is still difficult to predict the response to treatment accurately. A valuable prognostic factor can be a worthless predictive factor for endocrine therapy or chemotherapy, and vice versa. High tumour levels of ER, PGR, AR and PS2 protein predict a relatively good response to endocrine therapy, whereas EGFR positivity, HER2/neu positivity, aneuploidy, high proliferation indices and possibly high u-PA levels indicate a good chance of a poor response to endocrine therapy in metastatic breast cancer. With respect to chemotherapy, a high proliferation rate and HER2/neu amplification predict a good response to therapy in metastatic disease, whereas MDR gene expression and possibly c-myc amplification are related to a worse response. In conclusion, the newer cell biological parameters can be used to select high and low risk patients and type of systemic treatment and can be used as targets for new treatment modalities.
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PMID:Prognostic factors and response to therapy in breast cancer. 801 96

A large number of cell biological parameters are currently available to predict the prognosis of patients with breast cancer, but it is still difficulty accurately to predict the response to treatment. A valuable prognostic factor can be a poor predictive factor for response, and vice versa. High tumor levels of ER, PgR, AR and pS2 predict a relatively good response to endocrine therapy, while EGF-R positively, HER2/neu positivity, aneuploidy, high proliferation indices and possibly high uPA levels indicate a high chance of poor response to endocrine therapy in metastatic breast cancer. With respect to chemotherapy, a high proliferation rate and HER2/neu amplification predict a good response to therapy in metastatic disease, while MDR gene expression and possibly c-myc amplification are related to a worse response. In conclusion, the newer cell biological parameters can be used to select high and low-risk patients, type of systemic treatment, and as targets for new treatment modalities.
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PMID:Cell biological factors associated with the response of breast cancer to systemic treatment. 848 34

We undertook a study to analyze the expression of urokinase-type plasminogen activator (u-PA) protein in colorectal cancer (CRC) and to compare it with c-erbB-2 (HER2/neu) and nm23 protein expression. Paraffin-embedded specimens from 58 patients with CRC were retrospectively collected. Immunohistochemical staining of u-PA, c-erbB-2, and nm23 was quantitatively evaluated using a color video image analysis (color VIA) technique. No correlation was found between u-PA expression and tumor stage, age, sex, or tumor site. Although there was no evidence from our data that the level of u-PA in the primary tumors could predict risk of liver metastasis or survival duration, CRC showing overexpression of u-PA (above 85 pixels) had a worse prognosis (P = 0.013). There were significant positive correlations among all three u-PA, c-erbB-2, and nm23 proteins (u-PA vs. c-erbB-2, P = 0.003; u-PA vs. nm23, P < 0.001; c-erbB-2 vs. nm23, P = 0.001), suggesting that, in vivo, all proteins interact or are similarly regulated.
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PMID:Correlates of urokinase-type plasminogen activator in colorectal cancer: positive relationship with nm23 and c-erbB-2 protein expression. 961 57

Cell lines are valuable resources for the study of the malignancy and potential therapy of human breast cancer. A major problem with adapting fresh breast tumor specimens to grow in vitro is contamination by fibroblasts. Previously, we have reported a technique to overcome this problem (Nayak, S. K; Dillman, R. O. Clin. Biotechnol. 3:237-242; 1991). We have recently established two new breast cancer cell lines, HH315 and HH375, that were derived from abdominal and supraclavicular lymph node metastases from two patients. They were characterized by (1) growth kinetics; (2) staining with monoclonal antibodies (MoAbs) to cytokeratin-19, epithelial membrane antigen (EMA), anticarcinoembryonic antigen (CEA), breast cancer antigen 1 (BRST-1), breast cancer antigen 2 (BRST-2), Her2/neu, and p53; (3) expression of domains of urinary plasminogen activator (uPA), neural cell adhesion molecule (NCAM), and haptoglobin (Hp) (Harvey et al., 1997); and (4) karyotypic analysis. Growth kinetic studies showed that doubling times for both lines ranged from 48 to 96 h. These two cell lines were found to have characteristics of the metastatic breast cancer cells. Both lines stained positive with MoAbs to cytokeratin-19 and EMA, thus confirming their epithelial origin. They also strongly reacted with the pan-breast carcinoma MoAbs BRST-1 and BRST-2, and carcinoembryonic CEA MoAb. Both cell lines overexpressed the oncogene proteins Her2/neu and p53. The tumor cells were negative for estrogen and progesterone receptors. HH315 cells were poorly differentiated, whereas the HH375 cells exhibited adenocarcinoma morphology. Both cell lines showed intense cell surface and some cytoplasmic staining for uPA, NCAM, and Hp domains, which is a characteristic of malignant neoplasms (Harvey et al., 1997). The HH375 cell line showed two cell types, of which 60% were hyperdiploids with 60-70 chromosomes and 5-10 marker chromosomes. The remaining cells were polyploid with more than 200 chromosomes. Cell line HH315 consisted of only a polyploid population. These cell lines may be useful in breast cancer research.
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PMID:Characterization of cancer cell lines established from two human metastatic breast cancers. 1077 59

We compared the prognostic value of routine pathology, cytokeratin-positive (CK+) cells in the bone marrow (BM) and serum tumour markers (TM) in patients with non-small cell lung cancer (NSCLC) at the time of diagnosis with regard to overall survival (OS) and time to progression (TTP). Eighty patients with NSCLC, staged as T2-4, N0-3, M0 (n=52), M1 (n=27), (Mx = 1) were evaluated. Treatment included chemo-radiotherapy with cisplatin/etoposide and subsequent radical surgical resection. There were 23 complete responders, 50 non-responders and 7 patients who died of non-lung cancer causes. The median follow-up was 12 months (range 1-44 months). Besides routine pathology for tissue and BM, CK+ BM cells were detected by immunocytochemistry (IC) and 4 different tumour markers as well as the shedded domain of the oncoprotein Her-2/neu and urokinase plasminogen activator uPA were determined by radio- or enzyme-immunoassay. Patients classified as stage IV and patients with metastases had a significantly lower TTP and OS. No significant correlation was demonstrated for grading, tumour size or number of involved lymph nodes. The tumour marker tissue polypeptide antigen (TPA) and Cyfra 21-1 were the only marker which significantly correlated with OS. Interestingly, routine pathology could not detect minimal residual BM involvement as IC was able to (p=0.0004) and the presence of even a few CK+ cells significantly correlated with reduced OS. Thus, we conclude that the detection of CK+ cells should be added to routine pathology and for tumour marker determination, studies should focus on Cyfra 21-1 and TPA.
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PMID:Evaluation of different markers in non-small cell lung cancer: prognostic value of clinical staging, tumour cell detection and tumour marker analysis for tumour progression and overall survival. 1257 92

To enable individualized risk-oriented adjuvant treatment of breast cancer, validated parameters are needed to help evaluate the individual relapse risk. The clinical significance of these factors is assessed by published evidence (level of evidence) and its utility in the clinical setting (utility score). The traditional prognostic factors (age, TNM stage, grading, and steroid hormone receptor status are of established clinical relevance, and their determination should be obligatory. Of the "new" tumor-biologic parameters, only the measurement of the urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) in the primary tumor of node-negative patients has been adequately validated and can therefore be recommended for clinical application. Promising recent prognostic markers are the expression of Her2/neu, detection of disseminated tumor cells in bone marrow aspirates, various different surrogates for proliferative activity, and tumor-specific gene expression profiles. Currently, however, the data available are insufficient to allow recommendation of the parameters for routine clinical use at this time.
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PMID:[Prognostic factors in carcinoma of the breast. Thereupon depends success of the treatment]. 1286 97

Breast cancer represents a major health problem, with more than 1,000,000 new cases and 370,000 deaths yearly worldwide. In the last decade, in spite of an increasing incidence, breast cancer mortality has been declining in the majority of developed countries. This is the combined result of better education, widespread screening programmes and more efficacious adjuvant treatments. Better knowledge of breast cancer biology now allows the cosmetic, physical and psychological consequences of radical mastectomy to be spared in the majority of breast cancer patients. Use of the sentinel node technique is rapidly expanding and this will further reduce the extent and the consequences of surgery. Several clinico-pathological factors are used to discriminate between patients at low (<10%), average (10-40%) and high risk of relapse. Nodal status, tumour size, tumour grade and age are accepted universally as important factors to define risk categories. Newer factors such as uPA/PAI-1, HERer2-neu, proliferative indices and gene expression profile are promising and will allow better discrimination between patients at different risk. Endocrine manipulation with tamoxifen, ovarian ablation or both is the preferred option in the case of endocrine-responsive tumours. Tamoxifen administered for 5 years is the standard treatment for postmenopausal patients; tamoxifen plus ovarian ablation is more effective than tamoxifen alone for premenopausal women. Recent data demonstrate that, for postmenopausal patients, the aromatase inhibitors are superior to tamoxifen, with a different safety profile. At present, anastrozole can be used in the adjuvant setting in cases of tamoxifen intolerance or toxicity. Chemotherapy is the treatment of choice for steroid receptor-negative tumours. Polychemotherapy is superior to single agents and anthracycline-containing regimens are superior to CMF. Six courses of FEC or FAC or the sequential administration of four doses of anthracycline followed by four of CMF are the recommended regimens. New regimens including the taxanes have produced a further improvement in risk reduction and are reasonable therapeutic options. The taxanes have been approved for adjuvant therapy in the USA, while European approval is pending. Combined endocrine-chemotherapy is the standard adjuvant treatment in high-risk patients with endocrine-responsive tumours. Endocrine manipulation is usually administered after completion of the chemotherapy programme. For HER2-neu overexpressing tumours, several rapidly accruing trials are exploring the potential additive effect of trastuzumab, a monoclonal antibody directed against the extramembrane portion of the HER2 receptor. Primary chemotherapy is increasingly used in the treatment of locally advanced and operable breast cancer, with increased rates of breast-conserving surgery. A proportion of patients achieve a pathological complete response and these patients have significantly better long-term outcomes. Twenty-five to forty percent of breast cancer patients develop distant metastases. At this stage the disease is incurable; however, treatments can assure a significant prolongation of survival, symptomatic control and maintenance of quality of life. In the case of hormone receptor positivity and in the absence of visceral, life-threatening disease, endocrine manipulation is the treatment of choice. Active treatments include tamoxifen, ovarian ablation, aromatase inhibitors, pure anti-oestrogens and progestins. Aromatase inhibitors are the most active agents, but the choice and the sequence of endocrine therapies are also dictated by prior adjuvant treatment. Chemotherapy has to be preferred in cases of receptor-negative tumours, acquired resistance to hormones and aggressive visceral disease. Combination regimens are usually associated with higher response rates and sometimes survival prolongation, and this approach should be recommended in young patients with good performance status and visceral disease. On the other hand, single agents have a better tolerability profile and should be tand should be the treatment of choice when a careful balance between activity and tolerability is needed. For HER2-neu positive tumours, the combination of trastuzumab and chemotherapy is significantly superior to chemotherapy alone in terms of both response rates and survival. Other useful palliative treatments include bisphosphonates for the control of metastatic bone disease and radiotherapy for painful bone lesions or local relapses.
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PMID:The curability of breast cancer and the treatment of advanced disease. 1510 48

Patients undergoing resection of hepatic metastases of colorectal cancer have a high risk of extrahepatic recurrence, most likely caused by early tumor cell dissemination or the manipulation of liver tumors during surgical resection. Using immunocytochemistry, we studied 47 patients for cytokeratin (CK)-positive (+) cells in: a) bone marrow (BM) samples to determine whether tumor cell dissemination had already occurred before surgery; and b) blood samples directly taken from the hepatic vein before and during surgery of liver metastases. In addition, normal and malignant liver tissues were evaluated for markers known to be involved in tumor progression and metastasis [urokinase plasminogen activator (uPA), Her-2/neu, epidermal growth factor receptor (EGF-R)] using sandwich enzyme immunoassays. CK+ cells were detected in the BM of 26/47 patients (55%), in blood samples of 14/47 patients (30%) before surgery and 11/47 patients (23%) during surgery with a median detection rate of 1 (range, 1-14) CK+ cell per 4x10(6) MNC. No CK+ cells were found in 15/47 patients (32%) in any sample studied. Tumor tissue was obtained from 32/47 patients and normal liver tissue from 24/32 patients. While no differences were found for EGF-R and Her-2/neu, a 9-fold higher expression of uPA could be demonstrated in tumor tissue of 20/32 patients (63%) compared to normal liver tissue. When all obtained results were correlated with clinical outcome, neither the detection of CK+ cells nor the expression pattern in the tumor tissue, or the combination of both, was predictive for extrahepatic recurrence or overall survival after a mean observation time of 43 months (range, 26-54 months). Although uPa is overexpressed in liver metastases of colorectal cancer, and dissemination of CK+ cells during surgery of these metastases is a frequent event in colon cancer, these findings do not predict extrahepatic recurrence. Further characterization of single cells, especially those spread during surgery, will help to identify those patients with an increased risk of later relapse.
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PMID:Tumor cell dissemination in colon cancer does not predict extrahepatic recurrence in patients undergoing surgery for hepatic metastases. 1639 68

In this study, we investigated the expression level of Ras-homologous (Rho) GTPases and the Rho guanine exchange factor (GEF) T-cell lymphoma invasion and metastasis 1 (Tiam1) in breast tumor specimens (n=106) by immunohistochemistry. Rho and Rho-GEF expression scores were compared to clinically established diagnostic and prognostic parameters. We found that RhoA and RhoB scores slightly increased with tumor grade, whereas the Rac1 score remained unaffected. The most significant effects were observed for the Rac1-specific GEF Tiam1. Tiam1 expression scores significantly decreased with the increase in tumor grade, tumor spreading and proliferation. Furthermore, Tiam1 expression was inversely related to the plasminogen activator inhibitor (PAI-1) and estrogen receptor (ER) expression but not the progesterone receptor (PR) and urokinase plasminogen activator (uPA). A low Tiam1 expression was associated with p53 positivity without being related to HER2/neu status. The data show that Tiam1 expression decreases with the progression of breast carcinomas and is inversely associated with several established breast tumor markers. Therefore, we suggest that Tiam1 counteracts the progression of breast carcinomas and is suitable as a novel breast tumor marker.
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PMID:Progression of breast tumors is accompanied by a decrease in expression of the Rho guanine exchange factor Tiam1. 1908 65


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