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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of the mouse skin multistage model of carcinogenesis has aided our understanding of critical target genes in chemical carcinogenesis. The mutagenic activation of the Harvey-ras proto-oncogene has been found to be an early event associated with the initiation of mouse skin tumors by the polycyclic aromatic hydrocarbon 7,12 dimethylbenz[alpha]anthracene and the pure initiator ethyl carbamate (urethane). In contrast to chemical initiation of mouse skin tumors, ionizing radiation-initiated malignant skin tumors have been shown to possess distinct non-ras transforming gene(s). Differential screening of cDNA libraries made from chemically initiated malignant skin tumors has been used to identify a number of cellular gene transcripts that are overexpressed during mouse skin tumor progression. These differentially expressed genes include beta-actin, ubiquitin, a hyperproliferative keratin (K6), a gene whose product is a member of a fatty acid or lipid-binding protein family, and a gene called transin or stromelysin. The overexpression of the stromelysin gene, which encodes a metalloproteinase that degrades proteins in the basement membrane, is hypothesized to play a functional role in malignant tumor cell invasion and metastasis. We believe that the cloning, identification, and characterization of gene sequences that are differentially expressed during tumor progression could lead to the discovery of gene products that either play functional roles in skin tumor progression or in the maintenance of various progressive tumor phenotypes.
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PMID:Differential gene expression during multistage carcinogenesis. 177 1

The process of mouse skin tumor formation is subdivided into three operational stages. These stages include initiation, promotion and progression. Ionizing radiation has been found to be a weak initiating agent in the production of malignant squamous cell carcinomas, a complete carcinogen and an agent effective in causing tumor progression. Four skin tumor histologies have been seen with ionizing radiation: benign papillomas, squamous (SCC) and basal (BCC) cell carcinomas and fibrosarcomas. Distinct non-ras transforming genes have been detected in radiation initiated SCCs. A benign papilloma cell line (308) was used as a model system to study ionizing radiation induced progression. A variant 308 cell line (308 10 Gy 5) derived by irradiation of the parental 308 cell has been characterized. The 308 10 Gy 5 cells unlike the parental 308 cells form malignant tumors in athymic nude mice upon subcutaneous injection. The variant 308 10 Gy 5 cells unlike the parental cells also show by northern analysis high steady state levels of the following gene transcripts: stromelysin, metallothionein II A and the proto-oncogenes c-fos and c-jun. Transient transfection studies with a chimeric mouse stromelysin promoter sequence upstream of a chloramphenicol (CAT) reporter gene into 308 and 308 10 Gy 5 cells indicated that the stromelysin promoter was constitutively active in the 308 10 Gy 5 but not in the 308 cells. The ability to divide the process of carcinogenesis into multiple stages in the mouse skin mode has facilitated mechanistic studies that may elucidate the molecular pathways involved in radiation induced tumor development.
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PMID:Molecular events involved in ionizing radiation induced skin carcinogenesis. 182 59

We have reported that down-modulation of tissue inhibitor of metalloproteinases (TIMP) by means of antisense RNA converts non-tumorigenic Swiss 3T3 cells into malignant cells capable of forming metastasizing tumors in nude mice [Science 243:947 (1989)]. We now describe changes in the expression of specific genes associated with tumor progression of two lines down-modulated with TIMP, LA1 and LA7. Six independent variant cell lines, generated from different primary tumors produced by LA1 and LA7, lacked (like LA1 and LA7) many characteristics of typical transformed cells. However, their tumorigenicity in nude mice was enhanced; tumors appeared with a shorter lag (1-3 weeks versus 8-10 weeks for the parental clones, LA1 and LA7) and grew very rapidly. Increases, substantial in some cases, in the expression of a cysteine proteinase, cathepsin L, and metalloproteinases homologous to rat transin (stromelysin) and transin-2 were characteristic of these variant clones. The mRNA levels encoding the transformation-associated secreted phosphoprotein (osteopontin) and the calcium-binding protein calcyclin were also augmented. No evidence for gene amplification was found, and we did not detect any change in the mRNA levels of the proto-oncogenes that were examined. These novel cell lines represent a new paradigm for the transformed cell. Our data suggest that a reduction in TIMP secretion enhances the cell's oncogenic capacity by altering the extracellular environment in a way conducive to further changes in gene expression necessary for tumor progression.
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PMID:Increased proteinase expression during tumor progression of cell lines down-modulated for TIMP levels: a new transformation paradigm? [corrected]. 206 53

There are several characteristics of stromelysin that suggest that expression of this enzyme may play an important role in tumor invasion and metastasis; the stromelysin gene is expressed in response to stimulation by oncogenes and tumor promoters, and the protein product of this gene is a metalloproteinase capable of degrading multiple components of the extracellular matrix. Experimental evidence to support this hypothesis has been derived from several animal model systems, in which a positive correlation has been observed between stromelysin expression and tumor progression and metastasis. In addition, in vivo experiments in which the levels of TIMP, the tissue inhibitor of metalloproteinases, were altered also strongly suggest a causal role for metalloproteinases in tumor metastases. The expression of active stromelysin in tumor cells requires the fulfillment of several criteria, and this multistep process is reminiscent of the molecular events that are currently understood to contribute to tumor progression and carcinogenesis. Expression of stromelysin mRNA requires both a stimulus, a step which may correspond to the activation of an oncogene in multistep carcinogenesis, as well as the lifting of transcriptional repression, which may correspond to the loss of tumor suppressor function. Both positive and negative modulation of stromelysin transcription appear to utilize pathways that involve the protooncogenes c-fos and/or c-jun. The expression of active stromelysin enzyme also requires conversion of the proenzyme to an active form, and a proper balance between the expression of inhibitors and the levels of active enzyme. The multiple levels of stromelysin regulation support the concept of multistep carcinogenesis and may provide a tool for further understanding of the molecular nature of the events that lead to tumor progression, invasion, and metastasis.
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PMID:Stromelysin in tumor progression and metastasis. 209 83

Transin is an oncogene-inducible protein which has been shown to be the rat homologue of an extracellular matrix-degrading metalloproteinase known as stromelysin. The activity of transin/stromelysin is regulated at several levels: (1) at the transcriptional level, it is positively regulated by oncogenes, tumor promoters, and certain growth factors, and is negatively regulated by several agents including glucocorticoids and transforming growth factor-beta; (2) the protease activity is produced by processing of an inactive precursor form to an active enzyme; and (3) total protease activity is modulated by activity of tissue inhibitors of metalloproteinases (TIMPs). The association of transin/stromelysin expression with tumor progression suggests that it plays an important role in cancer.
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PMID:Stromelysin/transin and tumor progression. 210 88

We examined the effects of epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) on EGF receptor (EGFR) phosphorylation and the expression of mRNAs for oncogenes, growth factors, their receptors and metalloproteinase genes by MKN-28 gastric carcinoma cells which express EGF, TGF-alpha and EGFR genes. Both EGF and TGF-alpha stimulated EGFR phosphorylation, EGF and TGF-alpha induced FOS, MYC and ERBB-2 oncogene expression. Interestingly, EGF increased the expression of mRNAs for TGF-alpha and EGFR. On the other hand, TGF-alpha increased TGF-alpha mRNA but decreased the expression of mRNAs for EGFR and TGF-beta. Furthermore, mRNAs for interstitial collagenase, stromelysin and procollagen type I genes were also enhanced after treatment with EGF and TGF-alpha. These results indicate that EGF and TGF-alpha successively evoke cascade phenomena which favor tumor progression, invasion and extracellular matrix formation, acting as autocrine growth regulators for gastric carcinomas.
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PMID:Induction of growth factor-receptor and metalloproteinase genes by epidermal growth factor and/or transforming growth factor-alpha in human gastric carcinoma cell line MKN-28. 216 68

It has been proposed that tumor progression is a selective process and that only a minority of tumor cells survive this selection because they possess the phenotypic traits necessary for metastasis and organ colonization. Both proteases and extracellular matrix proteins have been implicated in invasion and metastasis formation. To examine the nature of the selection process, we transformed 10T1/2 fibroblasts with T24 H-ras and the neoR gene and selected a clonal line expressing the mutant ras gene. After i.v. injection of this line into syngeneic C3H/HeN mice, tumor cells were recovered from lungs by enzymatic treatment and selective outgrowth in G418. Less than one of 10(3) cells survived in the lung 30 min after inoculation, and these exhibited a unique phenotype. This was characterized by a propensity to lodge in the lung on reinjection; markedly enhanced mRNA levels of procollagen alpha 2(I), procollagen alpha 1(III), and fibronectin; and decreased levels of laminin, major excreted protein (procathepsin L), transin, and H-ras. Between 1 and 9 days after tumor injection, the phenotype of the cells surviving in the lung changed dramatically and exhibited a pattern of gene expression with increased protease and low matrix protein mRNA levels. This coincided with a 26-fold increase in the ability to colonize lungs on i.v. injection. Both the phenotype characterized by its propensity to arrest in the lung and that showing enhanced metastatic ability were unstable on prolonged in vitro culture. We hypothesize that two selection events have occurred. The first is for lung arrest and implantation of variants of the injected tumor with high matrix protein and low protease levels. A second selection then occurs for tumor cells that carry a favorable phenotype for invasion and proliferation which is associated with low matrix protein and high protease gene expression. These two phenotypes are represented within a clonal population of recently transformed tumor cells.
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PMID:Transient alterations in the expression of protease and extracellular matrix genes during metastatic lung colonization by H-ras-transformed 10T1/2 fibroblasts. 219 71

Transin mRNA encodes a secreted metalloprotease which is transcriptionally induced in Rat-1 cells by epidermal growth factor (EGF) and a number of oncogenes. A role for transin in tumor progression is suggested by its overexpression in malignant and metastatic tumors compared to their benign counterparts. In an effort to elucidate mechanisms by which elevated transin expression may be inhibited, it has been determined that both transforming growth factor type beta 1 (TGF beta 1) and increased levels of intracellular cyclic 5'-adenosine monophosphate (cAMP) inhibit EGF and oncogene induction of transin mRNA. The inhibition of transin mRNA occurred at the level of transcription as demonstrated by nuclear run-on assays. EGF binding studies in Rat-1 cells showed no significant effect of cAMP or TGF beta 1 on EGF receptor number or affinity. We have also examined the effects of cAMP and TGF beta 1 on oncogene-induced transin using Rat-1 cells transformed by temperature-sensitive mutants of v-src and K-ras oncogenes. Both inhibitors prevented the induction of transin RNA as well as decreased the levels of transin once elevated at the permissive temperature. Despite the similarities in the actions of TGF beta 1 and cAMP on transin gene expression, TGF beta 1 treatment did not significantly elevate intracellular cAMP levels, thus making it unlikely that cAMP is a second messenger system for TGF beta 1 action. These studies suggest that the inhibitory effects of cAMP and TGF beta 1 occur by distinct pathways at the level of gene regulation.
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PMID:Transforming growth factor beta 1 and cAMP inhibit transcription of epidermal growth factor- and oncogene-induced transin RNA. 284 55

To determine the role of a specific member of the metalloproteinase family, stromelysin-1, in mammary carcinogenesis and tumor progression, transgenic mice expressing activated rat stromelysin-1 under the control of the mouse mammary tumor virus promoter/enhancer were treated with the carcinogen 7,12-dimethylbenzanthracene (DMBA) to induce mammary tumors. Surprisingly, the expression of stromelysin-1 during the time of DMBA treatment reduced the number of mice developing mammary tumors, in particular adenoacanthomas, from 65 to 32% (P = 0.02). In contrast, when transgenic mice expressing both transforming growth factor alpha and stromelysin-1 under the control of the mouse mammary tumor virus long terminal repeat were treated with DMBA, there was no significant difference in the number of mice that developed tumors compared to transforming growth factor alpha controls. A 4-fold increase in the number of apoptotic cells was detected in stromelysin-1 transgenic mice compared to littermate controls at the time of DMBA administration, suggesting that the reduction in DMBA-induced tumorigenicity is likely to be due, at least in part, to an increased rate of cell turnover in stromelysin-1 transgenic mice. When malignant adenocarcinomas developed in the stromelysin-expressing mice, there was no detectable alteration in the extent of invasion or in the metastatic potential of these tumors compared to tumors from control mice. These results suggest that the expression of a single metalloproteinase, stromelysin-1, is insufficient for the progression of mammary adenocarcinomas to an invasive and metastatic phenotype, but that matrix degradation by metalloproteinases can alter basic processes of cell proliferation and apoptosis.
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PMID:Decreased tumor formation in 7,12-dimethylbenzanthracene-treated stromelysin-1 transgenic mice is associated with alterations in mammary epithelial cell apoptosis. 788 42

The metalloproteinase matrilysin is widely expressed in the epithelial tumor cells of malignant colorectal adenocarcinomas. Approximately 50% of benign adenomas also express low levels of matrilysin that is focally localized. The expression of stromelysin-1, stromelysin-3, and gelatinase A was observed in the stromal component of several carcinomas and was not present in adenomatous tissue. The expression of interstitial collagenase and gelatinase B was observed in occasional adenomas and carcinomas. Stromelysin-2 transcripts were not detectable in any of the samples examined. Tissue inhibitor of metalloproteinase-1 gene expression was widespread and was observed in both epithelial and stromal cells of adenomas and carcinomas. These results indicate that matrilysin gene expression is an early event in colorectal tumorigenesis and that the expression of stromelysin-1, stromelysin-3, and gelatinase A is primarily a late event. The observed gene expression patterns suggest that matrilysin may participate in early events in tumor progression and that multiple members of the metalloproteinase family may work in concert to facilitate late-stage tumor invasion and metastasis.
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PMID:Expression and localization of matrix-degrading metalloproteinases during colorectal tumorigenesis. 806 80


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