Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously demonstrated that expression of the cell surface adhesion molecule MCAM/MUC18 correlates directly with the metastatic potential of human melanoma cells. In addition, the progression of human melanoma towards the metastatic phenotype is associated with loss of expression of the tyrosine-kinase receptor c-KIT. This review summarizes our recent data demonstrating that the expression of both genes is regulated by the AP-2 transcription factor. Moreover, we have observed a loss of AP-2 expression in metastatic melanoma cells. Re-expression of AP-2 in the highly metastatic A375SM cells decreased their tumorigenicity and inhibited their metastatic potential in nude mice. MCAM/MUC18 mRNA and protein expression was significantly downregulated while c-KIT expression was upregulated in the AP-2 transfected cells. Since AP-2 also regulates other genes that are involved in the progression of human melanoma such as E-cadherin, MMP-2, p21WAF-1, HER-2, BCL-2, and insulin like growth factor receptor-1, we propose that loss of AP-2 is a crucial event in the development of malignant melanoma.
Cancer Metastasis Rev 1999
PMID:Role of AP-2 in tumor growth and metastasis of human melanoma. 1072 91

In tumor tissue specimens of 27 primary and 17 secondary glioblastomas and the precursor lesions, the immunohistochemical expression patterns of the membrane protein CD44s, the basal lamina proteins laminin, collagen IV, and fibronectin, the lectin galectin-3 recognizing tenascin and N-CAM as well as of the matrix-degrading enzymes matrix metalloproteinase MMP-2 and MMP-9, and cathepsin D were studied. Besides expression of basal lamina proteins in vessels, all glioblastomas and the precursor lesions showed strong immunoreactivity of CD44s, tenascin, galectin-3, and N-CAM which were restricted to solid tumor masses. Present in solid tumor areas, MMP-2, MMP-9 and cathepsin D were also strongly expressed by single tumors cells invading adjacent brain tissue at the infiltrative margin. Neither the expression pattern in primary and secondary glioblastomas nor in the precursor tumors revealed significant differences. There was also no intraindividual constant expression pattern during glioma progression or correlation with malignancy. Restricted expression of CD44s, galectin-3, tenascin and N-CAM in solid tumor masses seems to contribute to homotypic tumor cell adhesion while single tumor cells abolish this expression profile and acquire invasive activities by expression of cathepsin D, MMP-2 and MMP-9.
Invasion Metastasis
PMID:Expression of adhesion factors and degrading proteins in primary and secondary glioblastomas and their precursor tumors. 1072 72

We have previously reported that MMP-2 and MMP-9 are present in rat A-NK cells, and have recently documented that additional MMPs are present in rodent A-NK cells. To our knowledge only proMMP-9 has previously been reported for human NK and A-NK cells. Herein, we report for the first time the presence of MMP-2 and MT1-MMP in human NK cells. The importance of these enzymes for the migration of A-NK cells into tumor metastases is of great potential relevance. MMPs may be rate limiting in A-NK cells, following their adoptive transfer, to traverse basement membrane and accumulate within established cancer metastases, a likely pre-requisite to their cytolytic function. Human NK cells express and produce MMP-2, MMP-9, MT1-MMP and the inhibitor TIMP-1. Moreover, human A-NK cells degrade the extracellular matrix equivalent (Matrigel) in a seemingly IL-2 dependent manner. It is therefore likely that A-NK cell MMPs play crucial roles in contributing to A-NK cell localisation and positioning the cells in vivo to allow for triggering their cytolytic potential.
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PMID:Matrix metalloproteinases of human NK cells. 1075 86

The production of various proteolytic enzymes by tumor cells facilitate the invasion of solid tumors into surrounding tissues. We examined three cell lines (M1Dor, M4Be and M3Da) derived from malignant melanoma which exhibited different abilities to grow in nude mice following subcutaneous grafting. By in vitro invasion assay using Boyden-chambers technique, we found that none of those cell lines were able to invade the Matrigel. Several studies have substantiated the role of matrix metalloproteinases (MMP), mainly gelatinases MMP-9 and MMP-2, in melanoma cell invasion. Each cell line constitutively produced MMP-2 (but not MMP-9) in its latent form only, with stronger production for the most tumorigenic cell line in vivo (M3Da). Integrity of the MMP-2 activation process was studied since MMP-2 was also recovered as zymogen at the cell plasma membrane. All cell lines secreted TIMP-1 and TIMP-2 in a constitutive manner and again, but TIMP-2 production as well as MT1-MMP expression were found inversely related to their tumorigenic potential. Plating cells onto type I or type IV collagen did not trigger pro-MMP-2 activation; on the contrary, conversion of pro-MMP-2 to its active form could be evidenced when melanoma cell lines were seeded in a three dimensional type I collagen lattice.
Clin Exp Metastasis 1999
PMID:Expression and activation of pro-gelatinase A by human melanoma cell lines with different tumorigenic potential. 1076 11

Squamous cell carcinomas of the head and neck are known for their aggressive growth and propensity to metastasize. Invasion is facilitated by matrix metalloproteineases (MMPs). Tissue inhibitors of MMPs (TIMPs) negatively regulate MMP activity. MMP and TIMP expression in head and neck squamous cell carcinomas was determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). qRT-PCR allows measurement of several mRNAs from as little as 4 microg of total cellular RNA. We measured MMP-1, MMP-2, MMP-9, and TIMP-1 expression in 8 specimens of primary tumors and adjacent normal tissue. MMP-1 was overexpressed in 6 of 8 tumors, and MMP-9 was overexpressed in 4 of 7 tumors. MMP-2 was expressed in 3 of 8 tumors and 3 of 8 normal samples. TIMP-1 was expressed in all specimens. This work demonstrates that qRT-PCR can be used to examine expression of specific mRNAs in clinical specimens. Therefore this method provides another tool for the molecular analysis of tumors.
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PMID:Expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases in laryngeal and pharyngeal squamous cell carcinoma: A quantitative analysis. 1079 52

Sixty human brain tumors, classified according to the New World Health Organization (WHO) classification including, grade I schwannomas, meningiomas and pilocytic astrocytomas, grade II astrocytomas, grade III anaplastic astrocytomas, grade IV glioblastomas, grade III anaplastic oligodendrogliomas and grade IV glioblastomas and lung and melanoma metastases were analyzed for the expression of three matrix metalloproteinases (MMPs), two tissue inhibitors of MMPs (TIMPs) and for MMP activity. Some correlation was found between MMP expression and the degree of malignancy. Western blotting analysis revealed a more uniform pattern of distribution of MMP-2 (gelatinase A) than of MMP-9 (gelatinase B) and MMP-12 (metalloelastase) among tumors. MMP-9 levels were found to be significantly higher in grade III anaplastic astrocytomas and anaplastic oligodendrogliomas than those in grade I schwannomas and meningiomas. Anaplastic astrocytomas and Grade IV glioblastomas expressed significantly higher levels MMP-12 than grade I meningiomas. All sixty tumors showed a similar pattern of activity in zymography, proMMP-9 being the major species detected. Interestingly, TIMP-1 and TIMP-2 expression levels were especially low in tumors of grade II and grade III but significantly higher in tumors of grade I, particularly in schwannomas. Taken together, these data suggest that: 1) a balance between MMPs and TIMPs has an important role to play in human brain tumors; 2) TIMP expression may be valuable markers for tumor malignancy.
Clin Exp Metastasis 1999
PMID:Expression of matrix metalloproteinases and their inhibitors in human brain tumors. 1084 54

Evidence suggests that there is an association between the abnormal expression of members of the c-erbB receptor tyrosine kinase family and poor prognosis in head and neck squamous cell carcinomas (HNSCC). Until now, the relative contributions of different c-erbB ligands to HNSCC progression have not been clearly defined. In this paper we examined the effects of ligands with different c-erbB receptor specificities in terms of their stimulation of HNSCC proliferation, expression of matrix metalloproteinases (MMPs) and invasion. Heregulin-beta1 (HRG-beta1; selective c-erbB3/B4 ligand) was found to stimulate proliferation in the majority of cell lines, whereas epidermal growth factor (EGF; EGFR ligand) and betacellulin (BTC; EGFR/B4 ligand) induced variable responses. All three ligands up-regulated multiple MMPs including collagenases, stromelysins, matrilysin and gelatinase B (MMP-9) but had minimal or no effects on gelatinase A (MMP-2), MT1-MMP and tissue inhibitors of MMPs (TIMPs). MMP-9 mRNA was induced to a higher level than other MMPs, although with slower kinetics. HRG-beta1 was less active than EGF and BTC at the optimal concentration (relative potency of EGF:BTC:HRG = 3:4:1). In vitro invasion through Matrigel was also increased by all three ligands in proportion to their MMP up-regulation. A specific anti-EGFR monoclonal antibody (mAb ICR62) inhibited MMP up-regulation, migration and invasion induced by all three ligands, whereas an anti-c-erbB-2 mAb ICR12 inhibited mitogenic and motogenic responses following ligand stimulation but had no effect on MMP expression. These results suggest that c-erbB ligands may differentially potentiate the invasive phenotype of HNSCC via co-operative induction of cell proliferation, migration and proteolysis. The EGFR signalling pathway appears to be the dominant component controlling the proteolytic and invasive phenotype in HNSCC, whereas the c-erbB-2 signalling pathway is responsible, in part, for the mitogenic and motogenic effects of ligands.
Clin Exp Metastasis 1999
PMID:Differential modulation of proliferation, matrix metalloproteinase expression and invasion of human head and neck squamous carcinoma cells by c-erbB ligands. 1084 63

Metastasis of cancer starts with the penetration of cancer cells through the membrane surrounding the cancer focus into the stroma (extracellular matrix). The focal membrane consists of mainly type-IV collagen. An immunochemical study of 28 patients with benign thyroid nodular diseases and 27 patients with papillary carcinoma revealed the fragmentation of type-IV collagen in 4 patients with papillary carcinoma. Matrix metalloprotease (MMP)-2 and MMP-9 are the major enzymes which decompose type-IV collagen, and they have been suggested to be related to cancer metastasis. Therefore, we conducted biochemical and immunohistochemical studies to determine the relationship between these MMPs and the degree of malignancy in thyroid diseases. The concentration of MMP-2 in the serum of patients with papillary carcinoma and patients with benign nodules was 526.0 +/- 96.6 and 522.7 +/- 114.6 ng/ml, respectively, and that of MMP-9 was 53.8 +/- 40.3 and 39.9 +/- 36.0 respectively. There was no significant difference between the two groups in the concentration of either enzyme. The concentration of TIMP-2 in the serum was below the detectable level. On the other hand, the concentration of MMP-2 in the tissue of papillary carcinoma, benign nodules and normal tissue was 12.1 +/- 8.1, 5.7 +/- 4.3, and 0.6 +/- 0.5 ng/mg tissue protein, respectively, and that of MMP-9 was 4.2 +/- 4.1, 2.1 +/- 1.7, and 0.4 +/- 0.3 ng/mg tissue protein, respectively. Concentrations of both enzymes were significantly higher in the papillary carcinoma tissue. Immunohistochemical studies revealed a diffuse granular distribution of MMP-2 in the cytoplasm of the tumor cells. These findings imply that MMP-2 and MMP-9 are related to the degree of malignancy of cancer, especially metastasis.
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PMID:[Study of matrix metalloproteinase-2 and -9 in thyroid papillary cancer]. 1085 37

Matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs) play an important role in cancer cell invasion and metastasis. Recently, it was shown that the presence of activated MMP-2 correlates with melanoma progression in vitro. This activation involves coordinated expression of MMP-2, membrane-type 1 MMP (MT1-MMP), and TIMP-2. To investigate the expression profile of these enzymes in human melanoma, this study used tumour specimens obtained from both a human melanoma xenograft model, consisting of eight melanoma cell lines with different metastatic capacity in nude mice, and 60 fresh human cutaneous melanocytic lesions comprising all stages of melanocytic tumour progression. MT1-MMP and TIMP-2 mRNA and protein were present in all cell lines. Cell surface expression level of MT1-MMP, as determined by flow cytometry, was similar on all cell lines. In addition, western blot analysis revealed that both inactive and active MT1-MMP protein was expressed by all cell lines. MMP-2 mRNA and the pro-enzyme form of MMP-2 were expressed by all cell lines. Remarkably, the presence of functionally active MMP-2 was restricted to the most aggressive cell lines MV3 and BLM. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of RNA isolated from subcutaneous xenografts revealed MT1-MMP and TIMP-2 mRNA expression in all lesions, whereas MMP-2 mRNA could be detected only in xenografts derived from the highly metastatic cell lines 1F6m, MV3, and BLM. Furthermore, immunohistochemistry demonstrated a marked increase of MMP-2 and MT1-MMP in MV3 and BLM xenografts, whereas TIMP-2 expression showed no evident correlation with metastatic capacity. In human cutaneous melanocytic lesions, MMP-2, MT1-MMP, and TIMP-2 mRNA were detectable by RT-PCR in all lesions. Expression of MMP-2 protein was not detectable, either in common and atypical naevi, or in melanoma in situ by immunohistochemistry. In these lesions, heterogeneous expression of MT1-MMP and TIMP-2 was present in melanocytic cells. In contrast, a large number of MMP-2 and MT1-MMP-positive tumour cells were observed in primary melanomas and melanoma metastases. Double staining experiments and immunohistochemistry on serial sections from the same lesions demonstrated that all tumour cells expressing MMP-2 also expressed MT1-MMP and TIMP-2. Finally, zymography of melanoma metastases revealed that MMP-2 was present in its functionally active form. This study demonstrates that expression of MT1-MMP and TIMP-2 and activation of MMP-2 are correlated with tumour progression both in the xenograft model and in human melanocytic lesions, strongly suggesting that these factors are required for melanoma invasion and metastasis formation.
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PMID:Expression and activation of matrix metalloproteinase-2 (MMP-2) and its co-localization with membrane-type 1 matrix metalloproteinase (MT1-MMP) correlate with melanoma progression. 1087 45

The alpha 3 beta 1 integrin is elevated in several types of metastatic tumor and has been associated with increased migration and invasion. Our analysis of a series of mammary carcinomas of different histotypes and their corresponding metastases demonstrated significantly increased expression of alpha 3 beta 1 in the tumor metastases. We therefore studied alpha 3 beta 1 expression of several human breast carcinoma cell lines and its association with the invasive phenotype. The MDA-MB-231 cell line expressed high levels of the beta1, alpha 2, alpha 3, alpha 5, and alpha 6 integrin subunits along with moderate levels of the alpha v beta 3 integrin. This line was highly migratory and the most invasive using a chemo-invasion assay. In contrast, the other lines tested, MDA-MB-145, MCF-7, and SK-BR-3, showed lower migratory and invasive activity and reduced alpha 3 integrin subunit expression. Metalloproteases capable of degrading collagen IV are necessary for the invasive process. RT-PCR showed that MDA-MB-231 cells expressed MMP-9, but not MMP-2, gelatinase/collagenase IV. Gelatin zymography demonstrated that invading MDA-MB-231 cells released high levels of MMP-9 gelatinase activity. A direct role for this gelatinase in MDA-MB-231 cell invasion was confirmed by inhibition of invasion using the metalloprotease inhibitor Batimastat. Treatment of MDA-MB-231 cells with a function-blocking anti-alpha 3 antibody strongly inhibited migration and invasion. This correlated with a marked reduction in MMP-9 activity produced by MDA-MB-231 cells, suggesting a role for alpha 3 beta 1 ligand binding in cell signaling and regulation of extracellular matrix degradation.
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PMID:The alpha 3 beta 1 integrin is associated with mammary carcinoma cell metastasis, invasion, and gelatinase B (MMP-9) activity. 1089 37


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