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)

Angiogenesis and the extracellular matrix are fundamental to tumor progression from in situ to invasive and metastatic disease. Laminin, a major glycoprotein integrated into basement membranes, is observed in angiogenesis and tumorigenesis. A recent study described an association between melanoma cells and endothelial cells via an amorphous matrix containing laminin. In the current study, we have examined 45 cases of human primary and metastatic melanomas by electron microscopy for the presence of an amorphous matrix. We observed an amorphous matrix without a clearly delineated lamina or basement membrane in 41 of the 45 melanomas studied. 28 cases with tissue blocks available for study were examined by immunohistochemistry for the expression of laminin and type IV collagen. We observed the presence of an angiocentric matrix containing laminin in 24 of the 28 melanomas studied. Since laminin is involved in tumor migration, the presence of laminin between melanoma cells and small vessels suggests a role for this material in periendothelial tumor migration. However, further study is required to characterize the nature of this material and the mechanisms involved.
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PMID:Ultrastructural and immunohistochemical studies of the periendothelial matrix in human melanoma: evidence for an amorphous matrix containing laminin. 1008 97

Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. Urokinase-type plasminogen activator (uPA) is often expressed in human tumors including astrocytic tumors. To elucidate the possible regulation mechanism of uPA gene expression in astrocytic tumors, quantitative RT-PCR was performed to monitor the gene expression of uPA and the transcription factor Ets-1. Expression of uPA and Ets-1 genes was up-regulated in astrocytic tumors, but was not detected in normal brain. Expression levels of uPA correlated with those of Ets-1, and also with the degree of malignancy of the tumors. Glioma cell lines U251, U87, and T98G also expressed both uPA and Ets-1 genes. Expression of a dominant negative mutant of Ets-1, which competitively inhibits Ets-1 function, abolished uPA expression in U251 cells. Parental U251 cells showed invasive growth in 3-dimensional collagen gel, however, cells expressing dominant negative Ets-1 failed to grow invasively in the collagen gel. Treatment of U251 cells with the uPA inhibitor aprotinin also inhibited spreading of cells into collagen gel. These results suggest that Ets-1 plays an essential role in regulation of uPA gene expression, which in turn contributes to the invasive growth of astrocytic tumors.
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PMID:Ets-1 positively regulates expression of urokinase-type plasminogen activator (uPA) and invasiveness of astrocytic tumors. 1021 28

Breakdown of basement membrane (BM) is believed to be an essential step for tumor invasion and metastases. We have previously demonstrated that matrix metalloproteinase-9 (MMP-9), the 92 kDa collagenase expression correlates with metastases in human colorectal cancer (CRC). This study explores the relationship between the 72 and 92 kDa type IV collagenase (MMP-2 and MMP-9) activities and pattern of type IV collagen expression during human colorectal tumorigenesis. Thirty-four CRC patients, including four synchronous adenomas and one synchronous liver metastases, were involved in this study. By immunohistochemical staining, type IV collagen expression was noted to be continuous in the BM of normal mucosa, adenoma and in two cases of carcinoma in situ. Limited or absent type IV collagen staining pattern was seen in 100 (19/19) and 23% (3/13) of CRC with and without metastases, respectively. By double immunostaining, MMP-9 protein expression was noted to localize within areas of limited type IV collagen staining. Similarly, type IV collagen staining was noted to be greatest in areas devoid of MMP-9 expression. Gelatin zymography detected both 92 and 72 kDa proenzyme forms in all CRC and normal mucosa extracts examined. The mean tumor/normal fold increases of the proMMP-2 and proMMP-9 enzyme forms were 1.6+/-0.1 (mean +/- SE) and 2.4+/-0.5 in adenomas, and 2.1+/-0.2 and 4.1+/-0.7 in CRC, respectively. The 62 and 82 kDa bands were present in 63 (12/19) and 74% (14/19) of CRC with metastases, compared with only 20 (3/15) and 33% (5/15) of CRC without metastases, respectively. These differences were significant (P = 0.045 and P = 0.030, respectively). Our results demonstrate that loss of BM type IV collagen along with elevations in MMP-2 and MMP-9 expression, especially the activated forms, occur during colorectal tumorigenesis. Our data suggest that control of type IV collagenase activation may be beneficial in preventing human colorectal tumor progression.
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PMID:Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis. 1033 90

During certain developmental processes, as well as during tumor progression, polarized epithelial cells integrated within multicellular structures convert into scattered, freely migrating fibroblast-like cells. Despite the biological and clinical importance of this phenomenon, the intracellular biochemical cascades that control the switch between the epithelial and mesenchymal phenotypes have not been elucidated. Using Madin-Darby canine kidney (MDCK) cells (clone C7) as a model system, we have assessed the potential role of the mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) cascade in the modulation of epithelial plasticity. When grown in three-dimensional collagen gels, MDCK-C7 cells form spherical cysts composed of polarized epithelial cells circumscribing a central lumen. This morphogenetic behavior is profoundly subverted in MDCK-C7 cells expressing a constitutively active MAPK/ERK kinase 1 (caMEK1) mutant (C7-caMEK1 cells). When suspended in collagen gels, C7-caMEK1 cells assume an elongated fibroblastoid shape and are unable to generate multicellular cysts. In addition, when seeded onto the surface of a collagen gel, C7-caMEK1 cells penetrate extensively into the underlying matrix, unlike wild-type and mock-transfected MDCK-C7 cells, which remain confined to the surface of the gel. Similar changes in morphogenetic and invasive properties are observed in MDCK-C7F cells, a nontransfected, stably dedifferentiated derivative of MDCK-C7 cells that expresses substantially increased ERK2 activity. Both C7-caMEK1 and MDCK-C7F cells but not wild-type or mock-transfected MDCK-C7 cells express activated M(r) 72,000 gelatinase A [matrix metalloproteinase (MMP)-2] as well as elevated levels of membrane type-1 MMP. Synthetic MMP inhibitors as well as recombinant tissue inhibitor of metalloproteinases 2 and 3 suppress the invasion of collagen gels and restore the capacity of C7-caMEK1 cells to form cysts, thereby implicating the membrane type-1 MMP/MMP-2 proteolytic system in epithelial cell invasiveness and loss of multicellular organization. Taken together, our data demonstrate that increased activity of the MEK1-ERK2 signaling module in MDCK-C7 cells is associated with failure of morphogenesis and expression of a highly invasive phenotype. Sustained activation of the MAPK cascade therefore results in the destabilization of the three-dimensional architecture and the conversion of polarized epithelial cells into migrating mesenchymal-like cells.
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PMID:Constitutively active mitogen-activated protein kinase kinase MEK1 disrupts morphogenesis and induces an invasive phenotype in Madin-Darby canine kidney epithelial cells. 1035 13

HARP (heparin affin regulatory peptide), also called pleiotrophin (PTN), belongs to the heparin binding growth factors (HBGFs) family. Several new data suggest a role for HARP during the various stages of angiogenesis. In vivo, HARP is localised in endothelial cells of blood capillaries. In vitro, HARP displays mitogenic activity on endothelial cells, induces the formation of capillary-like structures in collagen gel, and degrades extracellular matrix via stimulation of plasminogen activator activity. HARP is also involved in neoangiogenesis during tumor progression. This review discusses the possible role of HARP in tumor angiogenesis and its therapeutic implications.
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PMID:[Implication of HARP in angiogenesis and possible therapeutic role]. 1037 4

Benign and malignant HaCaT-ras clones, derived from immortalized HaCaT cells were grown as nude mouse surface transplants rendering a human tumor progression model. Searching for malignancy-related alterations, the deposition, localization and mRNA of basement membrane and hemidesmosome components were analysed by immunofluorescence, in situ hybridization and electron microscopy. Initially, at 1 week epithelia of benign and malignant cells revealed a similarly low polarity and an enlarged 'activated basal' compartment, reflected by partial dislocation and extended pericellular staining of the hemidesmosome constituent integrin alpha 6 beta 4 seen by immunofluorescence. Whereas benign grafts eventually normalized, closely resembling grafts of HaCaT cells, malignant growth was correlated with a persisting epithelial activation state and continuing higher expression of alpha 6 (by immunofluorescence and in situ hybridization). The basement membrane components bullous pemphigoid antigen 1, laminin-5 and collagen IV exhibited a largely linear distribution at 1 week. However, in the malignant cell transplants initially minor basement membrane discontinuities became more severe at around 2 weeks, associated with close stromal cell contacts, angiogenesis and invasion. Most striking were basement membrane alterations seen by electron microscopy. At 1 week stretches of basement membrane had developed in malignant transplants, though to a much lesser extent than in benign specimens. With invasion these basement membrane structures mostly disappeared despite persistent although variable immunofluorescence, suggesting high turnover without ultrastructural assembly. The hemidesmosome structures were defective throughout, completely lacking anchoring plaques with keratin filaments, whereas they were still associated with basement membrane deposits. Thus, malignant HaCaT-ras transplants, while initially resembling regenerating wounds, revealed an increasing loss of tissue polarity and basement membrane structures, which seemed to be accelerated upon stromal cell contacts.
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PMID:Defects of basement membrane and hemidesmosome structure correlate with malignant phenotype and stromal interactions in HaCaT-Ras xenografts. 1037 63

Previous studies have shown a correlation between the production of certain matrix metalloproteinases (MMPs), especially the gelatinases, by malignant tumors and the progression of these cancers as they invade and metastasize through the extracellular matrix and basement membranes. However, very few of these studies examined this relationship in human oral cancer in vivo, and none addressed the issue of how combinations of the MMPs may further enhance tumor progression. To determine which MMPs are produced in vivo by human oral cancers, we used specific anti-human-MMP antibodies and immunocytochemistry (ICC) methods to examine oral cancer tissue specimens from 20 surgery patients. The ICC data indicated that 72-kDa (72K-GL) and 92-kDa gelatinases (92K-GL) were produced in vivo by discreet clusters of tumor cells and by stromal fibroblasts, vascular endothelial cells (72K-GL), and PMNs (92K-GL). Some stromal fibroblasts near the tumors also appeared to produce fibroblast-type collagenase (FIB-CL), a finding confirmed by Western blot analysis of media conditioned by oral tumor explant cultures. ICC results indicated that 5 of the 20 tumors coincidentally produced all three MMPs. To examine how the two gelatinases and FIB-CL may interact in vitro to degrade fibrillar type I collagen, a major structural component of the extracellular matrix, we used a modified FIB-CL activity assay. Combinations of the gelatinases and FIB-CL were incubated with a 3H-collagen substrate, with the results compared with the combination of stromelysin-1 (SL-1, a superactivator of FIB-CL) and FIB-CL. 92K-GL caused a nine-fold increase in collagenase activity, equivalent to SL-1, while 72K-GL produced a four-fold increase. These results indicate that human oral cancers produce 92K-GL, 72K-GL, and FIB-CL in vivo and that the gelatinases and FIB-CL cooperate to enhance collagen degradation greatly in vitro.
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PMID:92K-GL (MMP-9) and 72K-GL (MMP-2) are produced in vivo by human oral squamous cell carcinomas and can enhance FIB-CL (MMP-1) activity in vitro. 1040 63

Activation of pro-matrix metalloproteinase (MMP)-2 on the surface of malignant cells by membrane-bound MT1-MMP is believed to play a critical role during tumor progression and metastasis. In this study we present evidence that MT1-MMP plays a key role for the in vitro invasiveness of malignant melanoma. Melanoma cell lines secreted latent MMP-2 when cultured on plastic. However, when cells were grown in floating type I collagen lattices, only high invasive melanoma cells activated proMMP-2. Activation could be inhibited by antibodies against MT1-MMP, by addition of recombinant tissue inhibitor of metalloproteinases (TIMP)-2 and by inhibition of MT1-MMP cleavage. MT1-MMP protein was detected as an inactive protein in all cell lines cultured as monolayers, whereas in collagen gels, active MT1-MMP protein was detected in the membranes of both high and low invasive melanoma cells. Production of TIMP-2 was about 10-fold higher in low invasive cells as compared with high invasive melanoma cells and was further increased in the low invasive cells upon contact to collagen. Thus, in melanoma cells TIMP-2 expression levels might regulate MT1-MMP-mediated activation of proMMP-2. High invasive melanoma cells displayed increased in vitro invasiveness, which was inhibited by TIMP-2. These data indicate the importance of these enzymes for the invasion processes and support a role for MT1-MMP as an activator of proMMP-2 in malignant melanoma.
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PMID:Tissue inhibitor of matrix metalloproteinase-2 regulates matrix metalloproteinase-2 activation by modulation of membrane-type 1 matrix metalloproteinase activity in high and low invasive melanoma cell lines. 1040 57

Furan cholangiocarcinogenesis in rat liver is proving to be a unique and useful animal model for investigating important aspects of the cellular and molecular pathogenesis of cholangiocarcinoma potentially relevant to the human disease. We now describe the first culture model of rat cholangiocarcinoma cells derived from a transplantable cholangiocarcinoma originally induced in the liver of a furan-treated rat. An epithelial cell isolate highly enriched in viable cholangiocarcinoma cells was consistently obtained from transplantable cholangiocarcinoma tissue utilizing a similar procedure to that recently developed by us to establish a new rat hyperplastic bile ductular epithelial cell culture model characterized by the appearance of polarized bile ducts in vitro. Primary cholangiocarcinoma cell cultures could be readily established with these isolated cells and, in addition, we established from one such culture a novel rat cholangiocarcinoma cell line designated C611B. Cultured C611B cholangiocarcinoma cells retained a number of important characteristic features of the carcinoma cells of the parent tumor, including marked expression of the tyrosine kinase growth factor receptor proteins c-Met and c-Neu. Under basal culture conditions, the C611B cell line exhibited a cell doubling time of approximately 24 h and was aneuploid, with a predominant chromosomal count of 43. Moreover, C611B cells on collagen gels were 100% tumorigenic when transplanted into inguinal fat pads of syngeneic rats. All tumors formed at the transplantation site were cytokeratin 19-positive, mucin-producing tubular adenocarcinomas whose histological and phenotypic features closely resembled those of the furan-induced parent transplantable rat cholangiocarcinoma. Based on our findings, we believe that this novel rat cholangiocarcinoma cell culture model can serve as a valuable resource for investigating aberrant growth properties and tumor progression in biliary cancer.
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PMID:Establishment of a novel rat cholangiocarcinoma cell culture model. 1059 Feb 29

Adhesion and signaling by integrins require their dynamic association with nonintegrin membrane proteins. One such protein, the glycolipid-anchored urokinase receptor (uPAR), associates with and modifies the function of the beta(2)-integrin Mac-1 (CD11b/CD18). In this study, a critical non-I-domain binding site for uPAR on CD11b (M25; residues 424-440) is identified by homology with a phage display peptide known to bind uPAR. Recombinant soluble uPAR and cells expressing uPAR bound to immobilized M25, binding being promoted by urokinase and blocked by soluble M25, but not a scrambled control or homologous peptides from other beta(2)-associated alpha-chains. Mac-1, but not a mutated Mac-1 in which M25 was replaced with the homologous sequence of CD11c, co-precipitated with uPAR. In the beta-propeller model of alpha-chain folding, M25 spans an exposed loop on the ligand-binding, upper surface of alphaM, identifying uPAR as an atypical alphaM ligand. Although not blocking ligand binding to Mac-1, M25 (25-100 microM) inhibited leukocyte adhesion to fibrinogen, vitronectin, and cytokine-stimulated endothelial cells. M25 also blocked the association of uPAR with beta(1)-integrins and impaired beta(1)-integrin-dependent spreading and migration of human vascular smooth muscle cells on fibronectin and collagen. These observations indicate that uPAR associates with integrins directly and that disruption of this association broadly impairs integrin function, suggesting a novel strategy for regulation of integrins in the settings of inflammation and tumor progression.
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PMID:Identification of a urokinase receptor-integrin interaction site. Promiscuous regulator of integrin function. 1074 8


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