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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A metastatic colony is the end result of a complex series of steps involving multiple gene products. In some cases, the augmented metastatic potential of certain tumour cells may be due to the increased expression of specific gene products which confer a selective advantage. Transfection of the c-Ha-ras oncogene into suitable recipient cells constitutes a powerful experimental model with which to identify putative gene products augmented in highly metastatic tumour cells compared to their non-metastatic counterparts. Transfection of the activated ras oncogene into 3T3 and 10T1/2 embryo fibroblasts, and adult rat fibroblasts, results in transformants which produce high numbers of spontaneous metastases in nude mice or syngeneic recipients. The ras oncogene will also increase the metastatic aggressiveness of murine tumours with low metastatic potential. However, the ras oncogene will not induce the metastatic phenotype in all recipient cells. Furthermore, specific genes such as adenovirus 2 E1A suppress the ability of ras to induce the metastatic phenotype. Natural 'suppressor' gene products may exist which render certain cells resistant to the induction of metastases by ras. Ras oncogene transfection induces the production of type IV collagenase, motility factors and growth factors. The ras oncogene therefore induces a cascade of gene functions leading to rapid progression to the metastatic phenotype. The mechanism of the induction probably involves complex interactions between the ras p21 product and multiple cellular gene products.
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PMID:Oncogene induction of metastases. 307 39

NIH/3T3 cells transfected with DNA from malignant human tumors produced experimental and spontaneous metastases in nude mice. In contrast, parent or spontaneously transformed NIH/3T3 cells failed to metastasize. The transfected clones contained either activated c-Harvey-ras or N-ras oncogenes. A representative clone (T71-17SA2) which was used to assess selected cellular and host factors relevant to the metastatic process produced lung metastases in 100% of the NIH nude mice recipients, secreted augmented levels of type IV collagenase, and invaded human amnion basement membrane in vitro. Expression of the metastatic phenotype was not related to decreased sensitivity to natural killer cells or macrophage-mediated cytotoxicity. Analysis of the cellular DNA from the T71-17SA2 transfectant and its corresponding metastases, both of which contained activated N-ras oncogenes, revealed a twofold increase in the N-ras-specific DNA sequences in the metastatic cells. Thus, transfection with human tumor DNA containing activated ras oncogenes can induce the complete metastatic phenotype in NIH/3T3 cells by a mechanism apparently unrelated to immune cell killing.
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PMID:NIH/3T3 cells transfected with human tumor DNA containing activated ras oncogenes express the metastatic phenotype in nude mice. 398 18

We have identified a novel membrane-type matrix metalloproteinase (MT-MMP) expressed on the cell surface and inducing activation of pro-gelatinase A in vitro. In this study, we further examined the possibility that MT-MMP is the activator of pro-gelatinase A in tumors as well as in vitro. Expression of MT-MMP mRNA was analyzed by Northern blotting in 58 cases of human lung carcinomas. MT-MMP mRNA expression was increased in tumor tissues compared with adjacent normal tissues. The ratio of MT-MMP mRNA levels in tumor/normal tissues (T/N ratio) was 3.19 +/- 1.62 in 29 cases of adenocarcinoma, 3.09 +/- 1.44 in 24 cases of squamous cell carcinoma, 4.40 +/- 0.47 in 3 cases of large cell carcinoma and 3.63 +/- 2.11 in 2 cases of small cell carcinoma, respectively. Activated gelatinase A, as detected by gelatin zymography, was also predominant in tumors compared with normal tissue counterparts, though the difference in mRNA levels was not significant. The activation ratio of gelatinase A in tumor vs. normal tissues correlated well with that of MT-MMP mRNA expression and with lymph node metastases. Our findings suggest that MT-MMP is indeed the tumor-specific activator of pro-gelatinase A in lung carcinomas and is important to initiate invasion of basement membranes.
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PMID:Activation of the precursor of gelatinase A/72 kDa type IV collagenase/MMP-2 in lung carcinomas correlates with the expression of membrane-type matrix metalloproteinase (MT-MMP) and with lymph node metastasis. 759 10

Loss of negative growth regulation and high invasive potential are neoplastic traits often associated with abnormal expression of matrix metalloproteinases (MMPs). We previously found MMP-3 (stromelysin/transin) was secreted by quiescent rat Schwann cell cultures and expressed potent antiproliferative activity. In the present study we observed that human Schwann cells and cutaneous neurofibroma Schwann cell cultures secreted abundant MMP-3 and their proliferation was inhibited by autologous and rat Schwann cell conditioned media. Antiproliferative activities were depleted by immunoadsorption with anti-stromelysin antibodies. In contrast, plexiform neurofibroma cultures did not secrete MMP-3 and failed to respond to Schwann cell antiproliferative activities associated with MMP-3. Quiescent Schwann cells constitutively secreted low levels of MMP-2 (gelatinase A) and showed a low invasion potential in filter-based assays of basement membrane invasion. Cyclic AMP elevation, which profoundly influences cell differentiation, increased the invasion potential of rat Schwann cells and caused a corresponding increase in secretion of MMP-2. Schwann cells immortalized by protracted elevation of cAMP, as well as a schwannoma cell line (D6P2T), also rapidly invaded a reconstituted basement membrane and over-expressed MMP-2. Similarly, neurofibroma Schwann cells were highly invasive and secreted up to 10-fold more MMP-2 than normal human Schwann cells. Additionally, only cutaneous neurofibroma Schwann cell cultures secreted MMP-9 (gelatinase B) and MMP-1 (interstitial collagenase) and also invaded native type I collagen barriers. Cultures of normal Schwann cells and plexiform neurofibroma tumor expressed little or no MMP-1 and did not invade type I collagen barriers. These results suggest a role for MMPs in the control of proliferation and invasion by Schwann cells and in the formation of peripheral nerve sheath tumors.
Clin Exp Metastasis 1995 Jul
PMID:Differences in proliferation and invasion by normal, transformed and NF1 Schwann cell cultures are influenced by matrix metalloproteinase expression. 760 93

Many enzymes capable of proteolytic degradation of extracellular matrix and basement membranes have been implicated in tumor progression, including the matrix metalloproteinases, cathepsins, plasminogen activators, and heparanase. Matrix metalloproteinases, a family of zinc-dependent proteases, participate in several steps in tumor progression, including invasion, metastasis, and angiogenesis. In this review, we will give a brief overview of this protease family, and we will review in vitro and in vivo evidence implicating a particular metalloproteinase, the 92-kD type IV collagenase/gelatinase (MMP-9 or gelatinase B), as well as other metalloproteinases, in cancer progression. Finally, using recent studies from our laboratory, we will demonstrate the importance of both tumor cell and host stromal cell production of MMP-9 in tumor progression.
Invasion Metastasis
PMID:Metalloproteinases in tumor progression: the contribution of MMP-9. 765 17

The production and local release of various proteolytic enzymes, either by tumor cells or tumor-associated stromal cells, is thought to facilitate the malignant behavior of solid tumors. Human cutaneous melanoma offers an excellent clinical model to study the possible contribution of such proteases to solid tumor progression because melanoma goes through a series of well defined stages in its pathogenesis; moreover, permanent cell lines have been established from these various stages. As a first step to analyzing the gelatinolytic enzymes in melanoma pathology, we examined cell lines derived from early stage primary melanomas in which patients were cured of their disease and compared the results to those obtained with cell lines established from advanced stage primary lesions or metastases (i.e., from patients who eventually succumbed to the disease). We found that 80% of cell lines examined from early stage lesions constitutively produced only the 72-kDa gelatinase A but never the 92-kDa gelatinase B. In contrast, the majority of advanced stage cell lines examined produced both the 72-kDa gelatinase A and the 92-kDa gelatinase B. Advanced stage cell lines that did not constitutively produce the 92-kDa gelatinase B could be induced to do so with transforming growth factor beta, interleukin 1 beta or 12-O-tetradecanoyl-phorbol-13-acetate. In total, 0 of 5 early stage cell lines constitutively expressed the 92-kDa gelatinase B, and only 2 of 5 could be induced to produce this activity. In contrast, all advanced stage cell lines that were evaluated either constitutively or inducibly produced the 92-kDa gelatinase B. To analyze the mechanism by which 92-kDa gelatinase B production is switched on in the advanced stage melanoma cell lines, somatic cell hybrids were constructed using an advanced stage melanoma cell line as one partner and either one of two early stage cell lines as the other. Constitutive production of the 92-kDa gelatinase B in such hybrids was lost and could not be induced in such hybrids. Coculture of the early and advanced stage cell lines failed to recapitulate what was seen after somatic hybridization, and zymographic analysis of lysates from hybrid cell lines demonstrated no 92-kDa gelatinase B activity. Reverse transcription-PCR analysis demonstrated that the loss of 92-kDa gelatinase B production occurred at the level of steady-state mRNA for the enzyme.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The 92-kDa gelatinase B is expressed by advanced stage melanoma cells: suppression by somatic cell hybridization with early stage melanoma cells. 766 94

We transfected mouse 10T1/2 fibroblasts with the H-ras oncogene and isolated lines expressing H-ras. One of the lines exhibited a highly malignant phenotype with the ability to produce large tumors and to colonize the lung after tail vein injection. In addition, the cells of this line showed increased collagenase IV production, directed migration and invasiveness, properties associated with the ability of tumor cells to metastasize. Since cyclic adenosine 3',5'-monophosphate (cAMP) is known to down-regulate ras expression, we exposed the malignant cells (Cl-1) to either N6, 2',0-dibutyryl cAMP (DB-cAMP) or 8-bromo cAMP (8-Br-cAMP), either with or without a phosphodiesterase inhibitor. We found that these treatments reduced the expression of ras, chemotaxis, invasiveness, and lung colonization of the ras-transformed cells. We therefore postulate that the malignancy of some cells may be regulated by alterations in the intracellular cAMP levels by suppressing ras expression and/or by reducing other activities required for the dissemination of tumor cells.
Clin Exp Metastasis 1993 Nov
PMID:Cyclic AMP decreases chemotaxis, invasiveness and lung colonization of H-ras transformed mouse fibroblasts. 769 88

The 92-kD type IV collagenase is a member of the metalloproteinase family which degrades type IV collagen, a major component of basement membrane and is involved in tumor invasion and metastasis. The promoter and adjacent regulatory sequences of the 92-kD type IV collagenase have been identified previously and three cis-acting elements homologous to the binding sites for AP-1, NF-KB and SP-1 proteins contributed to induction of the promoter activity by 12-O-tetradecanoylphorbol 13-acetate (TPA) and tumor necrosis factor (TNF-alpha) in HT1080 cells. To date, no direct correlation between promoter activity and expression of the 92-kD type IV collagenase has been reported in normal or cancer cells. In this study, the effects of the transcriptional stimulation of the 92-kD type IV collagenase gene on the expression of the enzyme in human A2058 melanoma cells was analyzed by zymography experiments. Quantitative immunoblots using a monoclonal antibody that recognized specifically and exclusively the 92-kD type IV collagenase, confirmed that the 92-kD gelatinase was 92-kD type IV collagenase. Stimulation of the promoter activity resulted in increased gelatinase activity in the culture medium of A2058 cells. A direct correlation between TPA- and TNF-alpha-mediated promoter stimulation of the 92-kD type IV collagenase gene and its expression was also demonstrated in the human fibrosarcoma HT1080 cells. Interleukin-1 alpha failed to induce 92-kD gene promoter activity and type IV collagenase expression in melanoma and fibrosarcoma cell lines. Our data demonstrated that TPA- and TNF-alpha-induced 92-kD type IV collagenase promoter stimulation leads to a proportional increase of enzyme expression and secretion and thus could contribute to the activation of the invasive phenotype.
Invasion Metastasis 1993
PMID:Stimulation of the 92-kD type IV collagenase promoter and enzyme expression in human melanoma cells. 786 Feb 22

Metastatic spread depends critically upon the invasiveness of tumor cells, i.e. their ability to breach basement membranes by elaborating and secreting specific proteolytic enzymes such as gelatinase A (MMP-2). Laminin is a major constituent of the extracellular matrix that can trigger production of MMP-2 in metastatic cells, but not in non-metastatic cells. The present study was designed to examine the role of phospholipase D (PLD) and its product, phosphatidic acid, in the intracellular signal transduction mechanisms that mediate induction of MMP-2 by laminin. Here we show that stimulation of tumor cells with laminin results in a time- and dose-dependent activation of PLD. Laminin-induced production of MMP-2 is attenuated by 1-butanol, a competitive substrate of PLD that reduces PLD-catalyzed production of PA. Moreover, phosphatidic acid itself can induce production of MMP-2 in metastatic tumor cells. MMP-2 can also be induced by exposing the cells to exogenous bacterial PLD. Elevated cellular phosphatidic acid induces MMP-2 in metastatic ras-transformed 3T3 fibroblasts but, like laminin, fails to do so in normal cells. These data indicate that laminin-induced activation of PLD and consequent generation of phosphatidic acid are involved in a signal propagation pathway leading to induction of MMP-2 and enhanced invasiveness of metastatic tumor cells.
Clin Exp Metastasis 1995 Mar
PMID:Role of phospholipase D in laminin-induced production of gelatinase A (MMP-2) in metastatic cells. 788 15

Two human ovarian adenocarcinoma cell lines, MCAS-3 and OVISE-3 were found to secrete little of any type of gelatinase in tissue culture. However, when these cell lines were implanted subcutaneously into nude mice the cyst fluids from the resultant tumors contained gelatinase A and/or B. The enzyme activities, especially of gelatinase B, were much higher in the malignant MCAS-3 tumors than in those of the less malignant OVISE-3 tumor cells. To elucidate the origin of gelatinase B in cyst fluids of the MCAS-3 tumors, murine skin fibroblasts (MSF) were isolated from a subcutaneous tumor in a nude mouse and tested for their proteinase secretion in culture. MSF cells, which secreted some gelatinase A and gelatinase B, were induced to secrete high levels of both enzymes, especially gelatinase B, by co-cultivation with MCAS-3 cells. In addition, gelatinase A activity was induced by incubation of MSF cells with the conditioned medium of either MCAS-3 or OVISE-3 cells, whereas gelatinase B was induced only with that of MCAS-3. Although cytokines or growth factors such as IL-1 beta, TGF-beta 1, TNF-alpha or EGF stimulated the secretion of gelatinases A and B from MSF cells, their effects on gelatinase B activity were far less than that of the MCAS-3 conditioned medium. These results indicate that the major part of gelatinase B activity in the cyst fluids of the ovarian tumors is secreted by host interstitial cells stimulated by tumor-derived humoral factors. Similar tumor cell-host cell interactions may be important in the production of various proteinases in other tumor types.
Clin Exp Metastasis 1995 Mar
PMID:Marked induction of gelatinases, especially type B, in host fibroblasts by human ovarian cancer cells in athymic mice. 788 18


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