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)

Tumor progression to the stage of metastasis may result in part from the selection of certain primary tumor cell clones which are phenotypically competent for survival, invasion, and growth at secondary sites. Selection for traits such as loss of growth inhibitory responses, acquisition of increased adhesiveness, increased local immunosuppression, and enhanced motility and collagenase activities likely contribute to cancer progression and may be regulated through the action of growth factors. The transforming growth factors (TGF-beta) family of growth factors has often been associated with these traits and tumor progression; therefore, elimination or subversion of TGF-beta-responsive pathways should be considered as a mechanistic framework for metastatic events. In this report, we have compared growth and extracellular matrix responses to TGF-beta in six metastatic and six primary tumor-derived cell lines in a mouse model of prostate cancer. We have found that tumor cell lines derived from focal pulmonary metastasis secreted relatively greater quantities of total TGF-betas, lost most or all TGF-beta1 growth inhibition, but responded to TGF-beta1 through induction of the type IV collagenase matrix metalloproteinase-9, whereas cell lines derived from tumors which proliferated at the primary site retained the growth inhibition but lacked collagenase activity. Synthesis of another extracellular matrix protein, plasminogen activator inhibitor 1, was stimulated by TGF-beta1 in both primary as well as metastatic tumors. These results suggest that acquisition of differential responses to the TGF-beta family could result in phenotypic traits which facilitate tumor metastasis from certain primary site clones.
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PMID:Transforming growth factor beta1 stimulates contrasting responses in metastatic versus primary mouse prostate cancer-derived cell lines in vitro. 876 34

A serpin was identified in normal mammary gland by differential cDNA sequencing. In situ hybridization has detected this serpin exclusively in the myoepithelial cells on the normal and noninvasive mammary epithelial side of the basement membrane and thus was named myoepithelium-derived serine proteinase inhibitor (MEPI). No MEPI expression was detected in the malignant breast carcinomas. MEPI encodes a 405-aa precursor, including an 18-residue secretion signal with a calculated molecular mass of 46 kDa. The predicted sequence of the new protein shares 33% sequence identity and 58% sequence similarity to plasminogen activator inhibitor (PAI)-1 and PAI-2. To determine whether MEPI can modulate the in vivo growth and progression of human breast cancers, we transfected a full-length MEPI cDNA into human breast cancer cells and studied the orthotopic growth of MEPI-transfected vs. control clones in the mammary fat pad of athymic nude mice. Overexpression of MEPI inhibited the invasion of the cells in the in vitro invasion assay. When injected orthotopically into nude mice, the primary tumor volumes, axillary lymph node metastasis, and lung metastasis were significantly inhibited in MEPI-transfected clones as compared with controls. The expression of MEPI in myoepithelial cells may prevent breast cancer malignant progression leading to metastasis.
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PMID:Suppression of breast cancer growth and metastasis by a serpin myoepithelium-derived serine proteinase inhibitor expressed in the mammary myoepithelial cells. 1009

In 1991, our group was the first to report the prognostic strength of plasminogen activator inhibitor type 1 (PAI-1) in primary breast cancer. The prognostic impact of invasion markers PAI-1 and urokinase-type plasminogen activator (uPA) on disease-free survival (DFS) and overall survival (OS) in breast cancer has since been independently confirmed. We now report on the prognostic impact of PAI-1 and uPA after long-term median follow-up of 77 months for our cohort (n = 316). Levels of uPA, PAI-1, and cathepsin D were determined in tumor tissue extracts by immunoenzymatic methods. S-phase fraction (SPF) was measured flowcytometrically in paraffin sections. Using log-rank statistics, optimized cutoffs were found for PAI-1 (14 ng/mg), uPA (3 ng/mg), cathepsin D (41 pmol/mg), and SPF (6%). In all patients, various factors (PAI-1, uPA, nodal status, SPF, cathepsin D, grading, tumor size, hormone receptor status) showed significant univariate impact on DFS. In Cox analysis, only nodal status (p < 0.001, RR: 3.1) and PAI-1 (p < 0.001, RR: 2.7) remained significant. In node-negative patients (n = 147), PAI-1, uPA, and SPF had significant univariate impact on DFS, whereas in Cox analysis, only PAI-1 was significant. PAI-1 was also significant for DFS within subgroups defined by established factors. In CART analysis, uPA enhanced the prognostic value of PAT-1 and nodal status for determination of a very-low-risk subgroup. For OS, only lymph node status and PAI-1 were significant in multivariate analysis. PAI-1 levels in the primary tumor were also a significant prognostic marker for survival after first relapse in both univariate and multivariate analysis.
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PMID:Invasion marker PAI-1 remains a strong prognostic factor after long-term follow-up both for primary breast cancer and following first relapse. 1042 5

The plasmin activation system plays a key role in extracellular matrix degradation in many malignant tumors. Because no data are available on the involvement of the plasmin activation system in matrix degradation by thyroid carcinoma, the present study was performed using follicular thyroid carcinoma cell lines obtained from a primary tumor (FTC-133) and metastases (FTC-236 and FTC-238) of one patient. Matrix degradation by these cell lines was studied assessing the release of radioactivity from S35-methionine labeled extracellular matrix coated onto plastic. The involvement of constituents of the plasmin activation system as well as matrix metalloproteinases (MMPs), another class of proteolytic enzymes, which can be activated by plasmin, were assessed by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and zymography. In the matrix degradation experiment, S35 release by FTC-133 was significantly higher than FTC-236 and FTC-238. S35 degradation could be inhibited by the plasmin inhibitor aprotinin and by anti-human urokinase-type plasminogen activator (uPA) antibody, indicating the involvement of the plasmin activation system. Matrix degradation could also be inhibited by the MMP inhibitor marimastat, thus demonstrating the involvement of MMPs in matrix degradation by these cell lines. Zymographic assays revealed activity of uPA in all cell lines. However, in contrast with FTC-236 and FTC-238, no plasminogen activator inhibitor (PAI) or PAI1 mRNA were found in FTC-133. Therefore, the differences in PAI activity as observed between the cell lines may originate from differences in PAI1 gene transcription. Differences in PAI1 expression did not affect the attachment of these cell lines to vitronectin. We conclude that the plasmin activation system is involved in extracellular matrix degradation by these metastatic follicular thyroid carcinoma cell lines. Differences in extracellular matrix degradation between the cell lines correspond with differences in PAI1 gene expression, indicating the significance of PAI1 in extracellular matrix degradation by metastatic follicular thyroid carcinoma.
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PMID:Degradation of extracellular matrix by metastatic follicular thyroid carcinoma cell lines: role of the plasmin activation system. 1052 70

The objective of the present study was to measure preoperative plasma tissue inhibitor of metalloproteinase (TIMP)-1 levels in colorectal cancer patients and relate these values to clinical and biochemical patient characteristics. TIMP-1 levels were determined by ELISA in EDTA plasma samples collected preoperatively from 588 colorectal cancer patients. Plasma TIMP-1 levels were distributed with a median value of 141.1 microg/liter (range, 53.7-788.7 microg/liter). Whereas no significant differences were found in the median plasma TIMP-1 levels among patients with Dukes' stage A, B, and C disease, patients with Dukes' stage D disease had significantly higher plasma TIMP-1 levels (P < 0.0001); however, high plasma TIMP-1 levels were not restricted to advanced disease. A relatively weak correlation between plasma TIMP-1 level and age was found (r = 0.35; P < 0.0001). There was no significant difference in TIMP-1 levels between males and females (P = 0.97). Univariate analysis demonstrated an increasing risk of mortality with increasing TIMP-1 levels [scored as the log(e)(TIMP-1); hazard ratio = 3.3; 95% confidence interval, 2.6-4.2; P < 0.0001]. Including covariates (Dukes' stage, primary tumor location, gender, age, plasminogen activator inhibitor type 1, and soluble urokinase plasminogen activator receptor) in a multivariate analysis, TIMP-1 was retained in the final model (hazard ratio = 2.5; 95% confidence interval, 1.7-3.7; P < 0.0001). This study showed a highly significant association between preoperative plasma TIMP-1 levels and survival in colorectal cancer patients, with higher plasma TIMP-1 levels being associated with poor outcome. Independent of clinical parameters including Dukes' stage, plasma TIMP-1 levels were found to strongly predict prognosis of colorectal cancer patients. Additional studies are needed to validate the clinical usefulness of plasma TIMP-1 measurements.
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PMID:High preoperative plasma tissue inhibitor of metalloproteinase-1 levels are associated with short survival of patients with colorectal cancer. 1110 46

The investigation of molecular and genetic changes in gastric cancer has brought new insights into the pathogenesis of the disease. Knowledge of the genetic abnormalities and altered molecules could be used for differential diagnosis in case of an unknown primary tumor, allows their evaluation as prognostic factors, and could open novel avenues for more specific clinical interventions. Clinically relevant molecules whose expression or structure is altered include the plasminogen activator and its inhibitor plasminogen activator inhibitor type 1, the cell cycle regulator cyclin E, epidermal growth factor, the apoptosis inhibitor bcl-2, the cell adhesion molecule E-cadherin, and the multifunctional protein beta-Catenin. In addition, genetic instability is commonly seen. Gene amplification and protein overexpression of the growth factor receptors c-erbB2 and K-sam may be prognostic factors for intestinal- and diffuse-type gastric cancer, respectively. There has long been evidence for a genetic predisposition to gastric cancer by epidemiological studies and case reports. Very recently, germ line mutations of E-cadherin have been identified that are responsible for a dominantly inherited from of diffuse-type gastric cancer and could be used to identify individuals that are at high risk. The clinical implications of the recent findings for diagnosis, prognosis, therapy, and risk assessment are discussed.
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PMID:The use of molecular biology in diagnosis and prognosis of gastric cancer. 1152 6

The content of urokinase- and tissue-type plasminogen activators and plasminogen activator inhibitor PAI-1 in the cytosol of primary and metastatic melanomas and benign skin pigment neoplasms was estimated by enzyme immunoassay. It was shown that local growth and invasion of melanomas are related to suppressed expression of tissue plasminogen activator. The content of urokinase plasminogen activator increases in patients with distant metastases and large thickness of the primary tumor.
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PMID:Tissue- and urokinase-type plasminogen activators and type 1 plasminogen activator inhibitor in melanomas and benign skin pigment neoplasms. 1168 50

Risk assessment and prediction of response to treatment are prerequisites for individualized adjuvant therapy decisions in breast cancer. The strong prognostic impact of the two invasion factors urokinase-type plasminogen activator (uPA) and its inhibitor, plasminogen activator inhibitor type 1 (PAI-1), in breast cancer has recently been validated at level-I evidence. This article considers the predictive impact of uPA/PAI-1 on response to adjuvant chemo- and endocrine therapy in 3424 primary breast cancer patients from two different data sets. uPA and PAI-1 antigen levels were measured by ELISA in primary tumor tissue extracts. After a median follow-up of 83 months, uPA/PAI-1 has a significant impact on disease-free survival in Cox multivariate analysis (P < 0.001; hazard ratio, 2.0; 95% confidence interval, 1.8-2.3). Patients with high uPA/PAI-1 levels benefit more strongly from adjuvant chemotherapy than those with low levels. This effect is seen as a significant interaction between chemotherapy and uPA/PAI-1 for the entire collective (P < 0.003; hazard ratio, 0.68; 95% confidence interval, 0.53-0.88) and separately within nodal subgroups. This enhanced benefit in the high uPA/PAI-1 patients occurs over and above the significant impact of both therapies in all patients. We find no corresponding significant interaction between endocrine therapy and uPA/PAI-1; i.e., no significant difference in benefit between patients with high and low uPA/PAI-1. In conclusion, uPA and PAI-1 levels in primary tumor tissue provide clinically relevant information on relapse risk and treatment response that will help to tailor adjuvant therapy concepts in breast cancer, accounting for individual biological tumor characteristics.
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PMID:Enhanced benefit from adjuvant chemotherapy in breast cancer patients classified high-risk according to urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (n = 3424). 1218 17

Invasion factors urokinase-type plasminogen activator (uPA) and its plasminogen activator inhibitor (PAI-1) are the only novel tumor biological prognostic factors validated at the highest level of evidence with regard to their clinical utility in breast cancer. Antigen levels of both factors present in extracts of primary tumor tissue are determined by standardized, quality-assured enzyme-linked immunosorbent assays. Numerous studies showed that patients with low levels of uPA and PAI-1 have a significantly better survival than patients with high levels of either factor. Recently, these data have been validated by a European Organization for Research and Treatment of Cancer pooled analysis comprising more than 8000 breast cancer patients. The particular combination of both factors, uPA/PAI-1 (both low vs. either or both factors high), outperforms the single factors as well as other traditional prognostic factors with regard to risk group assessment, particularly in node-negative breast cancer. Node-negative breast cancer patients with low levels of uPA and PAI-1 have a very good prognosis and, as such, may be candidates for being spared the burden of adjuvant chemotherapy. In contrast, node-negative patients with high uPA/PAI-1 are at a substantially increased risk of relapse, comparable to that of patients with > or = 3 involved axillary lymph nodes. First results from a multicenter prospective randomized therapy trial in node-negative breast cancer (Chemo N(0)) as well as recent retrospective analyses indicate that these high-risk patients benefit from adjuvant chemotherapy. Thus, combined determination of the invasion factors uPA and PAI-1 supports risk-adapted individualized therapeutic strategies in patients with primary breast cancer, particularly in those with node-negative breast cancer.
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PMID:Clinical utility of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 determination in primary breast cancer tissue for individualized therapy concepts. 1219 77

Tumor cell metastasis can be suppressed by the attenuation of proteolytic and angiogenic events that are mediated by tumor and endothelial cells. Combinations of specific inhibitors directed to separate stages of the metastatic cascade may improve the potential for adjuvant therapies. Amiloride is an effective plasminogen activator inhibitor, while celecoxib is a cylcooxygenase-2 inhibitor. In vitro invasion assays were used to assess the effect of each inhibitor on the cellular invasion of MATB rat mammary carcinoma cells. Individually, both amiloride and celecoxib impeded cellular invasion in a dose-dependent manner. Combinations consistently exerted a significant inhibitory response (91 to 99%). These inhibitors were administered alone and in combination to evaluate their efficacy in the prevention of pulmonary metastases from a primary rat mammary carcinoma. Amiloride and celecoxib, alone and in combination, consistently showed no effect on the growth of primary tumors. The combined inhibitors were able to reduce significantly the growth of local recurrences following primary tumor excision and metastatic incidence rates. Numbers of pulmonary metastases were reproducibly and significantly decreased with the administration of amiloride and celecoxib, alone and in combination. Celecoxib alone was most effective with a reduction in 98% of the metastases, yet distinctions were observed in the results with respect to the local recurrences, blood levels for the inhibitors and tissue production of prostaglandin E2. These data demonstrate the potential use for celecoxib, alone and in combination with amiloride, in the suppression of metastases.
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PMID:Control of pulmonary metastases of rat mammary cancer by inhibition of uPA and COX-2, singly and in combination. 1555 90


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