Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Urokinase plasminogen activator (uPA) is a proteolytic enzyme implicated in cancer invasion and tumor progression. Urokinase PA and its inhibitor (PAI-1) appear to be new and independent prognostic markers in breast cancer. To investigate how uPA- and PAI-1-levels correlate with angiogenesis and tumor vessel invasion, we counted microvessels and their tumor invasion and determined the uPA- and PAI-1 levels in 42 primary invasive breast carcinomas. 20 Patients had no lymph node metastasis at the time of surgery, while 22 patients had positive nodes. Using light microscopy, we highlighted the vessels by staining their endothelial cells immunocytochemically for CD31 and Factor VIII. After gaining tumor tissue extracts, we determined the uPA- and PAI-1-levels by ELISA. A positive correlation between microvessel density, angioinvasion and uPA- and PAI-1-levels was found. We speculate that high uPA levels may induce tumor neovascularisation, angioinvasion and may cause tumor progression and metastasis. The degradation of the vessel wall by uPA causes a leak. This wall defect may, on the one hand, be the stimulus for endothelial cell proliferation and formation of new blood vessels and, on the other hand, it may be the place of tumor cell entry.
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PMID:Urokinase plasminogen activator induces angiogenesis and tumor vessel invasion in breast cancer. 747 58

Proteolytic enzymes are required to mediate tumor cell invasion of adjacent tissues and spread of primary tumors to distant sites. Our objective was to examine the activities and molecular forms of plasminogen activator (PA) and matrix metalloproteases (MP) in primary and secondary growths of SC tumors of three human prostatic cell lines (Du-145, PC-3, and 1-LN-PC-3-1A [1-LN], a subline of PC-3) grown in nude mice. The plasminogen activator activities were 1.7 +/- 1.3 (+/- SD), 6.2 +/- 2.8, and 11.5 +/- 4.2 for Du-145, PC-3, and 1-LN in primary SC tumors, respectively. Urokinase was the predominant molecular form of PA found in each tumor as determined from its molecular size (predominantly 54 kDa with a minor activity of 33 kDa) and sensitivity to amiloride. Prominent MP activities of approximately 68, 76, and 96 kDa as well as lesser activities of about 56, 59, 63, 84, 165, and 180 kDa were found in 1-LN tumors, whereas only less active MP of 59, 68, and 96 kDa were detected in the parental PC-3 cells. Du-145 tumors expressed MP activities of 59 and 96 kDa. Treatment of 1-LN tumor extracts with p-aminophenylmercuric acetate (APMA) significantly reduced the MP activities of 76 and 165 kDa while increasing activities of 56, 59, 65, 68, and 84 kDa. The 76 and 165 kDa MP activities thus appear to be prominent proenzyme forms of MP expressed in the 1-LN tumor. Secondary growths of tumor were subsequently found near the site of initial injection of PC-3 and 1-LN cells following removal of the primary tumor. There was a 42% increase in PA activity in the PC-3 secondary tumors, but only an 8% increase in 1-LN secondary tumors. However, there was no difference in the activities or number of molecular forms of MP in extracts of PC-3 or 1-LN primary or secondary tumors. The substantial expression of MP activities in the more aggressive 1-LN subline of the human prostatic PC-3 cell line indicates that induction of certain MP may be an important regulatory event in prostate tumor progression.
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PMID:Plasminogen activator and metalloprotease activities of Du-145, PC-3, and 1-LN-PC-3-1A human prostate tumors grown in nude mice: correlation with tumor invasive behavior. 795 14

We have examined the role of urokinase receptor (uPAR) in tumor invasion and metastasis by developing a homologous model of uPAR overexpression in a rat breast cancer cell line (Mat B III) using gene transfer technique. Control (pRc-CMV) and experimental plasmid (pRc-uPAR-S) were transfected into Mat B III cells by using Lipofectin reagent. Levels of uPAR production were accessed by Northern blotting, immunofluorescence, receptor binding and ELISA. At least 3 experimental clones (pRc-uPAR-S), expressing 3- to 5-fold higher levels of uPAR than control (pRc-CMV), were selected for further analysis. Experimental cells overexpressing uPAR showed a 4-to 5-fold higher invasive capacity compared with control cells in a Boyden chamber invasion assay. Both control and experimental cells (1 x 10(6) cells) were injected into the mammary fat pad of syngeneic female Fischer rats. Animals were sacrificed at timed intervals and evaluated for the development of tumor growth and metastasis. Animals receiving cells overexpressing uPAR had significantly larger tumor volume and weight throughout our study. Furthermore, due to increased uPAR expression, experimental animals developed large metastatic lesions in liver, spleen and lymph nodes. Our results therefore demonstrate the role of uPAR in tumor progression, due to its ability to localize uPA within the tumor cell milieu.
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PMID:Overexpression of urokinase receptor in breast cancer cells results in increased tumor invasion, growth and metastasis. 870 19

Extravasation and intravasation of solid malignant tumors is controlled by attachment of tumor cells to components of the basement membrane and the extracellular matrix, by local proteolysis and tumor cell migration. Strong clinical and experimental evidence has accumulated that the tumor-associated serine protease plasmin, its activator uPA (urokinase-type plasminogen activator), the receptor uPA-R (CD87), and the inhibitors PAI-1 and PAI-2 are linked to cancer invasion and metastasis. In cancer, increase of uPA, uPA-R, and/or PAI-1 is associated with tumor progression and with shortened disease-free and/or overall survival in patients afflicted with malignant solid tumors. uPA and/or its inhibitor PAI-1 appear to be one of the strongest prognostic markers so far described. Strong prognostic value to predict disease recurrence and overall survival has been documented for patients with cancer of the breast, ovary, cervix, endometrium, stomach, colon, lung, bladder, kidney, brain, and soft-tissue. Due to the strong correlation between elevated uPA and/or PAI-1 values in primary cancer tissues and the tumor invasion/ metastasis capacity of cancer cells, proteolytic factors have been selected as targets for therapy. Various very different approaches to interfere with the expression or reactivity of uPA or CD87 at the gene or protein level were successfully tested including antisense oligonucleotides, antibodies, enzyme inhibitors, and recombinant or synthetic uPA and uPA-R analogues.
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PMID:Clinical impact of the plasminogen activation system in tumor invasion and metastasis: prognostic relevance and target for therapy. 919 68

Membrane vesicles are shed by tumor cells both in vivo and in vitro. Although their functions are not well understood, it has been proposed that they may play multiple roles in tumor progression. We characterized membrane vesicles from human HT1080 fibrosarcoma cell cultures for the presence of proteinases involved in tumor invasion. By gelatin zymography and Western blotting, these vesicles showed major bands corresponding to the zymogen and active forms of gelatinase B (MMP-9) and gelatinase A (MMP-2) and to the MMP-9. tissue inhibitor of metalloproteinase 1 complex. Both gelatinases appeared to be associated with the vesicle membrane. HT1080 cell vesicles also showed a strong, plasminogen-dependent fibrinolytic activity in 125I fibrin assays; this activity was associated with urokinase plasminogen activator, as shown by casein zymography and Western blotting. Urokinase was bound to its high affinity receptor on the vesicle membrane. Addition of plasminogen resulted in activation of the progelatinases associated with the vesicles, indicating a role of the urokinase-plasmin system in MMP-2 and MMP-9 activation. We propose that vesicles shed by tumor cells may provide a large membrane surface for the activation of membrane-associated proteinases involved in extracellular matrix degradation and tissue invasion.
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PMID:Urokinase plasminogen activator and gelatinases are associated with membrane vesicles shed by human HT1080 fibrosarcoma cells. 920 45

Urokinase (urokinase plasminogen activator, uPA) and its cell surface receptor (uPA receptor, uPAR) play an important role in a variety of physiological and pathological processes requiring cell migration and tissue remodeling. Using our syngeneic model of uPAR overexpression by the rat breast cancer cell line Mat B-III, we have examined the ability of the nonsteroidal antiestrogen, tamoxifen (TAM), and of a selective synthetic inhibitor of uPA, 4-iodo benzo[b]thiophene-2-carboxamidine (B-428), to inhibit expression of uPA and uPAR as well as cell growth, invasion, and metastasis of wild-type Mat B-III cells and of cells overexpressing uPAR (Mat B-III-uPAR). Both TAM and B-428 inhibited uPAR gene transcription, mRNA expression, protein production and also decreased the proliferative and invasive capacity of Mat B-III and Mat B-III-uPAR. The effects of TAM and B-428 were more pronounced when these agents were tested in combination. Both control and experimental cells (1 x 10(6) cells) were inoculated orthotopically into the mammary fat pad of syngeneic female Fisher rats, and animals were infused i.p. with either TAM and B-428 alone or in combination for 2 weeks. Control animals receiving vehicle alone developed large tumors and macroscopic metastases to lungs, liver, and lymph nodes. In contrast to this, experimental animals receiving TAM and B-428 showed a significant decrease in primary tumor volume and metastases. Combination therapy had especially marked effects in blocking progression of the primary tumor in experimental animals inoculated with highly aggressive Mat B-III-uPAR cells. These results underscore the utility of anti-proteolytic agents (B-428) in addition to standard hormone therapy (TAM) in advanced breast cancer patients where the uPA/uPAR system plays a key role in tumor progression.
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PMID:Prevention of breast cancer growth, invasion, and metastasis by antiestrogen tamoxifen alone or in combination with urokinase inhibitor B-428. 927 32

Recent studies have shown that urokinase (uPA) is an independent prognostic marker in breast cancer. uPA plays a key role in the degradation of tumor matrix and promotes tumor progression. Macrophage expression of uPA appears to be important in this context. Our objective in the present study was to provide evidence that tumor growth factor-beta (TGF-beta) released from breast cancer cells markedly up-regulates uPA expression in tumor-associated macrophages (TAMs). TAMs from 32 breast carcinomas were cultured. Blood monocytes from healthy donors and breast cancer patients as well as tissue macrophages from patients with fibrocystic changes of the breast were also examined. After TGF-beta incubation, uPA levels were tested by ELISA, and uPA mRNA levels were determined by Northern blot analysis. TGF-beta receptor and uPA cell surface fluorescence intensities were determined by flow cytometry; TGF-beta receptors were determined by Western blot analysis. Protein kinase-C dependence was also examined, and immunohistochemical stainings for uPA and TGF-beta were performed. We have demonstrated that TGF-beta markedly up-regulates basal uPA expression (mRNA and protein) in TAMs but only modestly increases uPA production in blood monocytes and tissue macrophages. Exposure of macrophages to TGF-beta1 led to a rapid and sustained increase in uPA mRNA levels, which was independent of de novo protein synthesis and completely inhibited by actinomycin D. H7 markedly reduced the ability of TGF-beta to stimulate uPA expression. Likewise, okadaic acid potentiated the ability of TGF-beta to up-regulate macrophage uPA expression. We suggest that TAMs are more responsive to TGF-beta stimulation than are blood monocytes and tissue macrophages because of different TGF-beta receptor densities. TGF-beta stimulates transcription of the uPA gene, increases uPA-mRNA stability, and activates uPA expression via protein kinase-C-dependent mechanisms. The ability of TGF-beta to induce macrophage uPA expression may provide an indirect mechanism by which this growth factor stimulates angiogenesis. It may be, therefore, that TAMs promote tumor progression and tumor angiogenesis.
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PMID:Transforming growth factor-beta stimulates urokinase expression in tumor-associated macrophages of the breast. 946 Nov 22

Despite our recent advances in characterizing the molecular basis of breast and prostate cancer and their early detection with the aid of new imaging and diagnostic techniques, these cancers continue to be the leading causes of cancer-related deaths. This limited success in achieving our ultimate goal of cancer control is due to our inability to block the production of various factors produced in the later stages of these cancers that cause this high rate of mortality. A key requirement in the complex process of tumor invasion is the ability of tumor cells to produce and recruit growth factors and proteolytic enzymes within the tumor cell environment to promote neovascularization, tumor growth and promote extracellular matrix (ECM) degradation to facilitate tumor metastasis. One such protease, urokinase (uPA), has been strongly implicated in the progression of several malignancies including breast and prostate cancer. Along with uPA, its cell surface receptor (uPAR) is also believed to be involved due to its ability to recruit uPA within the tumor cell environment. In recent years, novel in vivo models of breast and prostate cancer have been developed which have clearly demonstrated the significance of uPA and uPAR in the invasion and metastases of these hormone-dependent cancers. The availability of these in vivo models has now permitted us to evaluate the molecular, chemical and immunotherapeutic strategies targeted against the uPA/uPAR system. This review describes the mechanism of uPA actions in tumor progression and analyses the usefulness of these in vivo models to authenticate uPA/uPAR as a therapeutic target and evaluates the benefits of blocking uPA/uPAR interactions alone or in combination with currently available treatment modalities against this cancer. Based on these results, there is an urgent need to develop and optimize strategies which will ultimately allow us to control the progression of these malignancies and enhance our ability to effectively manage these patients.
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PMID:Role of urokinase (uPA) and its receptor (uPAR) in invasion and metastasis of hormone-dependent malignancies. 949 55

This study was aimed at testing the hypothesis that the expression of proteases essentially produced by reactive stromal cells (stromelysin-3 [ST3], gelatinase A [GELA], and urokinase [uPA]) is predictive of prognosis in patients with breast cancer. This was a study of patients with node-positive and node-negative breast cancer diagnosed from 1980 to 1986 and with an average of 10 years follow-up. ST3 (665 cases), GELA, and uPA (575 cases each) expression was obtained by in situ hybridization on formalin-fixed, paraffin-embedded material using mRNA antisense probes. ST3 was expressed by 86.6% of the cases; GELA, 77.7%; and uPA, 64.7%. A significant correlation (P < .05) was found between high (more than 10%) ST3 expression and a younger age, lymph node involvement, poor nuclear grade, ductal histology, aneuploidy, and HSP-27 expression. High GELA expression was significantly associated with c-erbB2, ductal histology, and HSP-27 expression. High uPA expression correlated with poor nuclear grade, ductal histology, lack of estrogen and progesterone receptors, and p53 protein accumulation. High level of expression of all three proteases correlated significantly with each other and with cathepsin D expression by reactive stromal cells. By univariate analysis, both ST3 and uPA expression significantly predicted a shorter recurrence-free survival (ST3, P = .0199; uPA, P = .0269). By multivariate analyses, the prognostic significance was lost, most particularly at longer term. This study adds support to the concept that protease expression by reactive stromal cells is related to cancer cell characteristics but that their contribution to cancer progression is marginal.
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PMID:Prognostic significance of stromelysin 3, gelatinase A, and urokinase expression in breast cancer. 974 15

Proteolytic degradation of the extracellular matrix plays a crucial role in both cancer invasion and non-neoplastic tissue remodeling processes. In human cancers the components of matrix degrading protease systems (uPA, uPAR, PAI-1 and MMPs) can be expressed by either the non-neoplastic stromal cells, the cancer cells or both. Studies of the prognostic impact of these components in human cancer and the effect of targeted gene inactivation on cancer metastasis in mice support the assumption that proteases promote cancer progression, independent of whether they are expressed by cancer cells or stromal cells. The pattern of expression of components of protease systems is usually very similar in different cases of the same type of cancer, while it varies between different types of cancer. There are intriguing similarities between the cellular expression pattern of components of protease systems seen in cancer invasion and in certain types of non-neoplastic tissue remodeling. We propose that cancer invasion can be viewed as tissue remodeling gone out of control. The stromal cell involvement in cancer invasion represents a new paradigm with important implications for cancer pathophysiology and cancer therapy.
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PMID:Cancer invasion and tissue remodeling--cooperation of protease systems and cell types. 1019 Feb 88


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