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)

The plasminogen activation system plays an important role in enhancing pericellular proteolysis of tumor invasion/metastasis and in autocrine/paracrine tumor growth stimulation. To investigate the prognostic significance of the plasminogen activation system in human chondrosarcoma, the immunohistochemical expression of urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), plasminogen activator inhibitor, 1 (PAI-1) and 2 (PAI-2) were analyzed in 28 patients with chondrosarcoma. In multivariate survival analysis, histological grade (p = 0.0008) and location (p = 0.02) were independent risk factors for local relapse. For metastasis-free survival, uPA index (p = 0.006) and PAI-2 index (p = 0.04) were independent prognostic factors. PAI-2 index (p = 0.02), uPAR index (p = 0.02) and histological grade (p = 0.03) predicted total survival. These results demonstrated the usefulness of uPA, uPAR and PAI-2 expression as biological prognostic indicator and the importance of the plasminogen activation system in tumor progression and metastasis in chondrosarcoma.
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PMID:Prognostic relevance of urokinase type plasminogen activator, its receptor and inhibitors in chondrosarcoma. 1106 19

Melanoma antigen (MAGE)-A-derived peptides elicit a strong in vitro T-cell response against tumor cells. For determination of MAGE-A1, -2, -3, -4, -6, and -12 expression profile in invasive breast cancer, we developed a multiplex seminested reverse transcription-PCR-method. In total, 18 of 67 (27%) tumors were positive for at least one of these MAGE transcripts, and the expression pattern was heterogeneous: MAGE-A1 was positive in 4 of 67 (6%), MAGE-A2 in 13 of 67 (19%), MAGE-A3 in 7 of 67 (10%), MAGE-A4 in 9 of 67 (13%), MAGE-A6 in 10 of 67 (15%), and MAGE-A12 in 6 of 67 (9%) patients. The MAGE-A transcripts were more frequently expressed in ductal breast carcinomas compared with other histomorphological types. We observed a preferential expression of MAGE-A in patients at a higher risk of recurrence: those harboring tumors with high levels of the protease urokinase-type plasminogen activator and its inhibitor plasminogen activator inhibitor 1, high score of the Ki-67 proliferation antigen, and lesser degree of differentiation. Our findings suggests a potential involvement of MAGE-A in tumor progression, with potential implications for active immunotherapy.
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PMID:MAGE-A gene expression pattern in primary breast cancer. 1155 35

The plasminogen/plasmin system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumour cell migration. High levels of components of the plasminogen activation system, and paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI-1), have been correlated with a poor prognosis for patients with cancers of different types. Recent findings clearly suggest that PAI-1 is essential for capillary sprouting during tumour angiogenesis. Moreover, there is accumulating evidence that both the urokinase receptor and PAI-1 are multifunctional proteins involved not only in extracellular matrix proteolysis but also in cellular adhesion and migration through their binding site for vitronectin. The understanding of whether PAI-1 plays a regulatory role in angiogenesis by tightly controlling proteolytic activity or by influencing cell migration could allow a new anti-angiogenic approach for tumour therapy.
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PMID:[Role of plasminogen activator inhibitor type 1 in tumor angiogenesis]. 1180 82

Maspin, a novel serine protease inhibitor (serpin), suppresses the growth and metastasis of breast tumor in vivo. However, the underlying molecular mechanism is unclear. In the current study, we report the first evidence that endogenous maspin expression in mammary carcinoma cells MDA-MB-435 enhanced staurosporine (STS)-induced apoptosis as judged by the increased fragmentation of DNA, increased proteolytic inactivation of poly-[ADP-ribose]-polymerase (PARP), as well as the increased activation of caspase-8 and caspase-3. In parallel, recombinant maspin did not directly regulate the proteolytic activities of either caspase-3 or caspase-8 in vitro. Consistent with this result, maspin expressing normal mammary epithelial cells underwent more rapid STS-induced apoptosis as compared to breast carcinoma cells. Interestingly, maspin transfectant cells did not undergo spontaneous apoptosis in the absence of STS. Moreover, neither purified maspin protein added from outside nor endogenous maspin secreted to the cell culture media sensitized cells to STS-induced apoptosis. To investigate the structural determinants of maspin in its apoptosis-sensitizing effect, MDA-MB-435 cells were also transfected with maspin/PAI-1 and PAI-1/maspin chimeric constructs resulting from swapping the N-terminal and the C-terminal domains between maspin and PAI-1 (plasminogen activator inhibitor type 1). The resulting stable transfectant clones expressing maspin/PAI-1 and PAI-1/maspin, respectively, did not undergo spontaneous apoptosis, and were similarly inhibited as maspin transfectant cells in motility assay. Interestingly, however, expression of both maspin/PAI-1 and PAI-1/maspin in MDA-MB-435 cells failed to sensitize these cells to STS-induced apoptosis. Taken together, our evidence provides new insights into the complex molecular mechanisms of maspin that may suppress breast tumor progression not only at the step of invasion and motility, but also by regulating tumor cell apoptosis. The sensitizing effect of maspin on apoptosis is to be contrasted by the pro-survival effect of several other serpins.
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PMID:Maspin sensitizes breast carcinoma cells to induced apoptosis. 1203 65

The plasminogen/plasmin system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumor cell migration. High levels of components of the plasminogen activation system, and paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI-1), have been correlated with a poor prognosis for patients with cancers of different types. Recent findings clearly suggest that PAI-1 is essential for capillary sprouting during tumor angiogenesis. Moreover, there is an accumulating evidence that both the urokinase receptor and PAI-1 are multifunctional proteins involved not only in extracellular matrix proteolysis, but also in cellular adhesion and migration through their binding site for vitronectin. The understanding of whether PAI-1 plays a regulatory role in angiogenesis by tightly controlling proteolytic activity, or by influencing cell migration, could allow a new anti-angiogenic approach for tumor therapy.
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PMID:[Role of PAI-1 plasminogen activator inhibitor in tumor invasion and angiogenesis]. 1255 75

The urokinase plasminogen activator (uPA) system consists of the serine protease uPA, its glycolipid-anchored receptor, uPAR and its 2 serpin inhibitors, plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2). Recent findings suggest that the uPA system is causally involved at multiple steps in cancer progression. In particular, uPA has been implicated in remodelling of the extracellular matrix, enhancing both cell proliferation and migration and modulating cell adhesion. Consistent with its role in cancer progression, multiple groups have shown that high levels of uPA in primary breast cancers are independently associated with adverse outcome. Paradoxically, high levels of PAI-1 also correlate with poor prognosis in patients with breast cancer. The prognostic value of uPA/PAI-1 in axillary node-negative breast cancer patients was recently validated using both a prospective randomised trial and a pooled analysis, i.e., in 2 different Level 1 Evidence studies. Assay of uPA and PAI-1 may thus help identify low risk node-negative patients for whom adjuvant chemotherapy is unnecessary. Finally, preclinical studies show that either inhibition of uPA catalytic activity or prevention of uPA binding to its receptor reduces tumor growth, angiogenesis and metastasis.
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PMID:The urokinase plasminogen activator system: role in malignancy. 1475 4

Recent reports suggest that elevated levels of plasminogen activator inhibitor (PAI)-1 may contribute to tumor progression. We have recently shown that antibodies to PAI-1 block the invasive and migratory potential of human fibrosarcoma cells and suppress angiogenesis in vitro. Here we report the in vitro evaluation of a low-molecular-weight modulator of PAI-1, XR5967, on invasion, migration and angiogenesis. XR5967, a diketopiperazine, dose-dependently inhibited the activity of human and murine PAI-1, towards urokinase plasminogen activator (uPA), with IC50 values of 800 nM and 8.3 microM, respectively. This was confirmed by SDS-PAGE, revealing that XR5967 inhibited complex formation between PAI-1 and uPA. This suppression may be caused by XR5967 promoting insertion of the reactive center loop within PAI-1. XR5967 dose-dependently inhibited the invasion of human HT1080 fibrosarcoma cells through Matrigel. Their invasion was reduced by 57% (p<0.001) at 5 microM. HT1080 cell migration was inhibited in a similar manner, indicating that PAI-1 may play an additional role in invasion, which is distinct to its role in the regulation of proteolysis. The potential of XR5967 to inhibit the invasion/migration of human endothelial cells was investigated in an in vitro model of angiogenesis. In this model XR5967 reduced tubule formation by 77% at 5 microM (p<0.001), highlighting a crucial role for PAI-1 in angiogenesis. These data stress the importance of a balanced proteolysis in the processes of invasion, migration and angiogenesis. Our results support the clinical findings and indicate that modulation of PAI-1 activity, with low-molecular-weight inhibitor of PAI-1 activity, may be of therapeutic benefit for the treatment of cancer.
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PMID:XR5967, a novel modulator of plasminogen activator inhibitor-1 activity, suppresses tumor cell invasion and angiogenesis in vitro. 1509 Jul 42

Human kallikrein 5 (KLK5) is a member of the human kallikrein gene family of serine proteases. Preliminary results indicate that the protein, hK5, may be a potential serological marker for breast and ovarian cancer. Other studies implicate hK5 with skin desquamation and skin diseases. To gain further insights on hK5 physiological functions, we studied its substrate specificity, the regulation of its activity by various inhibitors, and identified candidate physiological substrates. After producing and purifying recombinant hK5 in yeast, we determined the k(cat)/K(m) ratio of the fluorogenic substrates Gly-Pro-Arg-AMC and Gly-Pro-Lys-AMC, and showed that it has trypsin-like activity with strong preference for Arg over Lys in the P1 position. The serpins alpha(2)-antiplasmin and antithrombin were able to inhibit hK5 with an inhibition constant (k(+2)/K(i)) of 1.0 x 10(-) (2)and 4.2 x 10(-4) m(-1) min(-1), respectively. No inhibition was observed with the serpins alpha(1)-antitrypsin and alpha(1)-antichymotrypsin, although alpha(2)-macroglobulin partially inhibited hK5 at high concentrations. We also demonstrated that hK5 can efficiently digest the extracellular matrix components, collagens type I, II, III, and IV, fibronectin, and laminin. Furthermore, our results suggest that hK5 can potentially release (a) angiostatin 4.5 from plasminogen, (b) "cystatin-like domain 3" from low molecular weight kininogen, and (c) fibrinopeptide B and peptide beta15-42 from the Bbeta chain of fibrinogen. hK5 could also play a role in the regulation of the binding of plasminogen activator inhibitor 1 to vitronectin. Our findings suggest that hK5 may be implicated in tumor progression, particularly in invasion and angiogenesis, and may represent a novel therapeutic target.
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PMID:Biochemical and enzymatic characterization of human kallikrein 5 (hK5), a novel serine protease potentially involved in cancer progression. 1571 79

Solid tumors synthesize a number of extracellular matrix-degrading proteases that are important for tumor progression. Based on qualitative in situ hybridization studies in human cancer tissue, a range of components involved in proteolysis appear to be expressed by stromal cells rather than cancer cells. We have now used laser capture microdissection and real-time PCR to quantify the mRNA expression of components of matrix-degrading proteolytic systems in cancer and stromal areas of mouse mammary tumors genetically induced by the polyoma virus middle T (PyMT) antigen. We examined the mRNA levels of urokinase plasminogen activator, plasminogen activator inhibitor 1 and the matrix metalloproteases MMP-2, -3, -11, -13 and -14, and found that all these seven genes are predominantly expressed by stromal cells. Our results were qualitatively supported by in situ hybridization analysis of the expression of mRNAs for MMP-2, -3 and -13 in the PyMT tumors. Statistical analyses indicated that the quantitative expression patterns observed in cancer and stromal cells isolated from individual tumors from different PyMT mice are quite reproducible. The methodology described in this study provides excellent tools to study the possible interactions between cancer and stromal cells during the development of breast cancer, and the results suggest that stromal cells are involved in carcinogenesis and tumor progression, which may have important implications for the biology and therapy of cancer.
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PMID:Extracellular protease mRNAs are predominantly expressed in the stromal areas of microdissected mouse breast carcinomas. 1576 Sep 18

In a number of cancer types high tumor tissue levels of plasminogen activator inhibitor type 1 (PAI-1) protein are strongly associated with shorter cancer patient survival. This association has been intriguing since PAI-1 is known to inhibit urokinase plasminogen activator (uPA) that converts plasminogen to plasmin, which is actively involved in tumor progression and invasion. In order to further explore the biological role of PAI-1 in cancer, we have prepared fibroblasts from PAI-1 gene deficient mice and from their wild type littermates. From these fibroblasts fibrosarcoma cell lines were established and characterized. Both types of fibroblasts underwent spontaneous transformation as indicated by aneuploidy, immortalization, clonogenicity in soft agar and tumor formation in vivo. While both PAI-1 deficient and PAI-1 expressing cell lines showed similar proliferation rates in vitro, cells devoid of PAI-1 were significantly more sensitive to apoptotic stimuli. When inoculated subcutaneously into nude mice PAI-1 expressing cells rapidly established tumors, while PAI-1 deficient cells had a significantly longer lag-phase before they started to grow (p<0.0001). The present study suggests that PAI-1, besides its uPA inhibiting function, has a role in cancer progression by protecting tumor cells from undergoing apoptosis.
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PMID:Indication of a role of plasminogen activator inhibitor type I in protecting murine fibrosarcoma cells against apoptosis. 1627 Jun 43


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