Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In breast cancer, about 35% of patients without any clinical signs of overt distant metastases already have disseminated tumor cells in bone marrow aspirates at the time of primary therapy. A significant prognostic impact of these disseminated tumor cells has been shown by many international studies: patients with tumor cells in their bone marrow have a significantly worse prognosis than those without them. Even in malignancies where the skeletal system is not a preferred location for distant metastasis, such as ovarian cancer, early presence of minimal residual disease (MRD) is correlated with poor patient outcome. Thus, besides analysis of the primary tumor, detection of MRD can be used for assessment of patient prognosis and for prediction or monitoring of response to systemic therapy. Disseminated tumor cells are also the targets for novel tumor biological therapy approaches such as specific antibody-based therapies against target cell-surface antigens such as HER2, Ep-CAM (17-1A), and uPA-R. In breast cancer, a first antibody-based tumor therapy against HER2 (Herceptin) has already been approved for clinical use in recurrent disease. However, patient selection for such tumor biological therapies becomes rather difficult due to phenotype changes, which may manifest themselves as differences between primary lesion and disseminated tumor cells. Therefore, not only identification of disseminated tumor cells but even more so their characterization at the protein and gene levels have become increasingly important. In conclusion, characterization of tumor biological properties of disseminated tumor cells allows identification of patients with breast cancer or gynecological malignancies at risk for relapse who are likely to benefit from systemic treatment and/or novel tumor biological therapy approaches.
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PMID:Minimal residual disease in breast cancer and gynecological malignancies: phenotype and clinical relevance. 1279 Mar 24

The plasminogen activator inhibitor-1 (PAI-1) blocks the activation of plasmin(ogen), an extracellular protease vital to cancer invasion. PAI-1 is like the corresponding plasminogen activator uPA (urokinase-type plasminogen activator) consistently expressed in human breast cancer. Paradoxically, high levels of PAI-1 as well as uPA are equally associated with poor prognosis in cancer patients. PAI-1 is thought to play a vital role for the controlled extracellular proteolysis during tumor neovascularization. We have studied the effect of PAI-1 deficiency in a transgenic mouse model of metastasizing breast cancer. In these tumors, the expression pattern of uPA and PAI-1 resembles that of human ductal breast cancer and plasminogen is required for efficient metastasis. In a cohort of 63 transgenic mice that were either PAI-1-deficient or wild-type sibling controls, primary tumor growth and vascular density were unaffected by PAI-1 status. PAI-1 deficiency also did not significantly affect the lung metastatic burden. These results agree with the virtual lack of spontaneous phenotype in PAI-1-deficient mice and humans and may reflect that the plasminogen activation reaction is not rate limiting for tumor vascularization and metastasis, or that there is a functional redundancy between PAI-1 and other inhibitors of the uPA/plasmin system, masking the effect of PAI-1 deficiency.
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PMID:Metastasis of transgenic breast cancer in plasminogen activator inhibitor-1 gene-deficient mice. 1285 75

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

uPA and PAI-1 are the first novel tumor biological prognostic factors in breast cancer for which the prognostic impact has been validated at the highest level of evidence and hence all evaluation criteria for transfer into clinical practice have been fullfilled. Breast cancer patients with high uPA and/or PAI-1 levels in their primary tumor tissue have a significantly lower chance for cure than patients with low levels of both uPA and PAI-1. Our research that was honored with the Schmidt-Matthiesen-Award 2002 shows for the first time that uPA and PAI-1 are not only prognostic factors but also have a predictive impact with regard to response to adjuvant chemotherapy. Patients with high uPA/PAI-1 derive a significantly greater benefit from adjuvant chemotherapy than patients with low uPA/PAI-1. Benefit from adjuvant endocrine therapy is independent of uPA/PAI-1 status. The resulting question about the optimal chemotherapy for patients with high uPA/PAI-1 is currently being addressed in Germany by the NNBC-3 trial in node-negative breast cancer (AGO, EORTC-RBG) as well as the ADEBAR trial in patients with 4 or more involved axillary lymph nodes. Moreover, our results suggest the use of novel therapeutic agents interfering with the uPA system together with conventional chemotherapy in patients with high uPA/PAI-1 already in early stage disease.
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PMID:[u-Plasminogen activator (urinary plasminogen activator, urokinase) (uPA) and its PA-1 type 1 inhibitor are not only prognostically but also predictively significant and support clinical decisions on therapy in primary carcinoma of the breast]. 1456 18

A prominent phenotype of plasmin deficiency in mice is reduced metastasis in the MMTV-PymT transgenic breast cancer model. Proteolytically active plasmin is generated from inactive plasminogen by one of 2 activators, uPA or tPA. We now find that uPA deficiency alone significantly reduces metastasis >7-fold in the MMTV-PymT model. We studied a cohort of 55 MMTV-PymT transgenic mice, either uPA-deficient or wild-type controls. Tumor incidence, latency, growth rate and final primary tumor burden were not significantly affected by uPA deficiency. In contrast, average lung metastasis volume was reduced from 1.58 mm(3) in wild-type controls to 0.21 mm(3) in uPA-deficient mice (p = 0.023). Tumor cell dissemination to brachial lymph nodes was also reduced from 53% (28/53) in wild-type controls to 31% (17/54) in uPA-deficient mice (p = 0.032). Mice without plasminogen display a severe pleiotropic phenotype. By comparison, spontaneous phenotypes are modest in uPA-deficient mice, probably because they still have active tPA. We show that metastasis is strongly and selectively decreased in uPA-deficient mice, suggesting that uPA-directed antimetastatic therapy would be efficacious and have limited side effects.
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PMID:Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice. 1547 5

Combined determination of urokinase-type plasminogen activator (uPA) and its inhibitor, activator inhibitor type 1 (PAI-1), supports risk-adapted individualized therapy concepts, particularly in node-negative breast cancer. The prognostic impact of both factors in primary breast cancer was substantiated by a pooled analysis of > 8000 patients with breast cancer and a multicenter prospective randomized therapy trial in node-negative breast cancer; findings achieved the highest level of evidence for tumor biomarkers. Patients with node-negative breast cancer with low antigen levels of uPA and PAI-1 in their primary tumor tissue have a very good prognosis and therefore may be spared the burden of adjuvant chemotherapy, whereas those with elevated uPA/PAI-1 antigen levels carry an increased risk of disease recurrence. Recent retrospective analysis of > 3000 patients indicated that patients with breast cancer with high uPA/PAI-1 values derive a significantly greater benefit from adjuvant chemotherapy than patients with low uPA/PAI-1 levels. Similarly, in the multicenter prospective Chemo N0 trial, administration of cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy led to a substantial reduction in risk of disease recurrence in patients with high uPA/PAI-1. However, benefit from adjuvant endocrine therapy appears to be independent of a patient's uPA/PAI-1 status. In metastatic breast cancer, retrospective studies showed that elevated uPA or PAI-1 present in the primary tumor tissue are associated with a poor response to later palliative endocrine therapy. These findings suggest that high levels of uPA and/or PAI-1 do reflect an aggressive phenotype that may be overcome or suppressed by early systemic therapy in the adjuvant setting but may be too advanced for response to palliative therapy at a later stage.
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PMID:Urokinase-type plasminogen activator and its inhibitor type 1 predict disease outcome and therapy response in primary breast cancer. 1558 71

Pancreatic carcinomas express high levels of urokinase-type plasminogen activator (uPA) and its receptor (uPAR), both of which mediate cell migration and invasion. We investigated the hypotheses that (a) insulin-like growth factor-I (IGF-I)- and hepatocyte growth factor (HGF)-mediated migration and invasion of human pancreatic carcinoma cells require uPA and uPAR function and (b) inhibition of uPAR inhibits tumor growth, retroperitoneal invasion, and hepatic metastasis of human pancreatic carcinomas in mice. Using transwell assays, we investigated the effect of IGF-I and HGF on L3.6pl migration and invasion. We measured the induction of uPA and uPAR following treatment of cells with IGF-I and HGF using immunoprecipitation and Western blot analysis. The importance of uPA and uPAR on L3.6pl cell migration and invasion was studied by inhibiting their activities with amiloride and antibodies before cytokine treatment. In an orthotopic mouse model of human pancreatic carcinoma, we evaluated the effect of anti-uPAR monoclonal antibodies with and without gemcitabine on primary tumor growth, retroperitoneal invasion, and hepatic metastasis. IGF-I and HGF mediated cell migration and invasion in L3.6pl cells. In addition, IGF-I and HGF induced uPA and uPAR expression in L3.6pl cells. In vitro, blockade of uPA and uPAR activity inhibited IGF-I- and HGF-mediated cell migration and invasion. Treatment of mice with anti-uPAR monoclonal antibody significantly decreased pancreatic tumor growth and hepatic metastasis and completely inhibited retroperitoneal invasion. Our study shows the importance of the uPA/uPAR system in pancreatic carcinoma cell migration and invasion. These findings suggest that uPAR is a potential target for therapy in patients with pancreatic cancer.
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PMID:Targeting of urokinase plasminogen activator receptor in human pancreatic carcinoma cells inhibits c-Met- and insulin-like growth factor-I receptor-mediated migration and invasion and orthotopic tumor growth in mice. 1614 Sep 45

Proteases are crucial for the spread of cancer cells from a primary tumor to the site of secondary growth. This study examined the ability of IFNgamma and TNFalpha to stimulate a better invasiveness in B16 murine melanoma cells, and investigated whether this enhanced ability was related to a higher expression of protease activities, such as urokinase plasminogen activator (uPA) and its receptor (uPAR), and matrix metalloproteinases 2 and 9 (MMP-2, MMP-9). We found that murine melanoma cells enhanced their lung-colonizing potential in vivo and invasiveness through Matrigel-coated filters upon costimulation with IFNgamma and TNFalpha; neither IFNgamma nor TNFalpha alone, at the dose used in the experiments, was able to elicit a change in the invasive/metastatic efficiency of melanoma cells. The invasive phenotype of murine melanoma cells stimulated with IFNgamma and TNFalpha was characterized by an enhanced uPA/uPAR and MMP-9 expression: TNFalpha promoted MMP-9 mRNA expression and pro-MMP-9 protein secretion, and the costimulation with IFNgamma and TNFalpha was required to potentiate the expression of mRNA and protein for uPAR, and to induce a redistribution of uPA from the soluble to the cell body-associated form. Both monoclonal antibodies, anti-uPAR and anti-MMP-9, caused a significant reduction of invasiveness in IFNgamma/TNFalpha-stimulated melanoma cells. These results indicate that invasiveness in B16 murine melanoma cells can be regulated in a cytokine-specific fashion and is dependent on the synergism between the uPA/uPAR system and MMP-9.
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PMID:Cytokine-dependent invasiveness in B16 murine melanoma cells: role of uPA system and MMP-9. 1646 34

In epithelial ovarian cancer, the high mortality rate is usually ascribed to late diagnosis, since these tumors commonly lack early-warning symptoms, but tumor-associated biomarkers useful for prognosis or therapy response prediction are in short supply. However, members of the tissue kallikrein serine protease family, the serine protease uPA and its inhibitor PAI-1, are associated with tumor progression of ovarian cancer. Therefore, we used ELISA to determine uPA, PAI-1, and tissue kallikreins hK5-8, 10, 11, and 13 in extracts of 142 primary tumor tissue specimens from ovarian cancer patients and studied the strength of association between protein expression levels of these tumor tissue-associated factors. uPA, PAI-1, hk5, and hk8 were related to FIGO stage; hK5 expression was higher in FIGO III/IV than in FIGO I/II patient tissues. PAI-1 and hk5 differed significantly according to nuclear grading; expression of hK5 was higher in G3 than in G1/2 tumors. Associations between uPA, PAI-1, and the tissue kallikreins were weak. There were strong pairwise correlations within the cluster of tissue kallikreins hK5, 6, 7, 8, 10, and 11, but their bivariate distributions depended on nuclear grading. These results support the notion that several tissue kallikreins are co-expressed in ovarian cancer patients, substantiating the existence of a steroid hormone-driven tissue kallikrein cascade in this disease.
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PMID:Disease processes may be reflected by correlations among tissue kallikrein proteases but not with proteolytic factors uPA and PAI-1 in primary ovarian carcinoma. 1689 83

Cysteine cathepsins are a family of lysosomal proteases that are often upregulated in various human cancers, and have been implicated in distinct tumorigenic processes such as angiogenesis, proliferation, apoptosis and invasion. During cancer progression, cathepsins are often translocated to the cell surface of tumor cells or are secreted into the extracellular milieu, where they can promote tumor invasion through several possible mechanisms. First, they can directly cleave components of the extracellular matrix and basement membrane, essentially clearing a path for the migration of tumor cells away from the primary tumor mass. Second, at the cell membrane, cathepsins can direct a proteolytic cascade in which they activate other proteases such as matrix metalloproteinases and urokinase plasminogen activator, which in turn promote invasion. Finally, cleavage of the cell adhesion protein, E-cadherin, at the cell surface can disrupt adherens junctions and thus facilitate cancer cell migration and invasion. Therefore, cathepsins are now emerging as major players in tumor progression, making them potential drug targets for a wide range of human cancers.
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PMID:Cysteine cathepsins and the cutting edge of cancer invasion. 1724 12


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