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

Cohorts of 4- to 5-wk-old female Fischer 344 rats received four biweekly 1.5-mg doses of N-methyl-N-nitrosourea (MNU) intravesically and were sacrificed at various intervals. By 13 wk after initiation of the carcinogen, all animals have flat epithelial atypia and/or papillary transitional cell bladder carcinomas, and 67% of the lesions are histological Grade II or III. By 20 wk, 83% have gross bladder wall muscle-invasive tumors that eventually kill the host. There was no gross evidence of visceral metastases in any animal. This rat model of transitional cell carcinoma of the bladder is useful because: (a) all animals develop progressive neoplastic changes in situ within 4 mo after initiation of MNU treatment; (b) these lesions progress to grossly detectable bladder tumors which invade the bladder wall and kill the host; (c) this full progression of bladder epithelial cells from atypical hyperplasia through flat carcinoma in situ to transitional cell carcinoma occurs at discrete time points; (d) the histology of the grossly detectable tumors is that of invasive transitional cell carcinomas; and (e) no leukemias, breast cancers, lymphomas, or other non-bladder tumors are induced. Six MNU-induced bladder wall-invasive tumors were karyotyped, and all tumors were diploid with 42 chromosomes. Three of the tumors had apparently normal karyotypes, while three tumors had karyotypes containing one or more cytogenetic structural markers. One of these markers (i.e., 8p+) was observed in two of the three tumors. The level of expression of total ras p21 (N-, Ki-, and Ha-ras p21) and codon 12-mutated c-Ha-ras p21 (i.e., glycine to glutamic acid mutation in codon 12) in a series of these MNU-induced bladder tumors was determined by Western blot analysis. No increase in the total ras p21 nor any expression of codon 12-mutated c-Ha-ras p21 was detected in any of these tumors.
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PMID:Characterization of an N-methyl-N-nitrosourea-induced autochthonous rat bladder cancer model. 220 31

The development of cancer is a multistage process. The activation of proto-oncogenes and the inactivation of tumor suppressor genes play a critical role in the induction of tumors. Using human cell model systems of carcinogenesis, we have studied how oncogenes, tumor suppressor genes, and recessive cancer susceptibility genes participate in this multistep process. Normal human cells are resistant to the transforming potential of oncogenes, such as ras oncogenes, which are activated by specific point mutations. Since as many as 40% of some tumor types contain activated ras oncogenes, a preneoplastic transition in multistage carcinogenesis must involve changing from an oncogene-resistant stage to an oncogene-susceptible stage. The analysis of such critical steps in carcinogenesis using rodent systems has usually not represented the human disease with fidelity. In order to study this carcinogenic process, we have developed human cell, in vitro systems that represent some of the genetic changes that occur in cellular genes during human carcinogenesis. Using these systems, we have learned some of the functions of dominant activated-transforming oncogenes, tumor suppressor genes, and cellular immortalization genes and how they influence the carcinogenic process in human cells. Using our understanding of these processes, we are attempting to clone critical genes involved in the etiology of familial cancers. These investigations may help us to develop procedures that allow us to predict, in these cancer families, which individuals are at high risk for developing cancer.
Cancer Metastasis Rev 1990 Jul
PMID:The current state of oncogenes and cancer: experimental approaches for analyzing oncogenetic events in human cancer. 220 69

Metastasis is a complex process which results in the growth of tumor cells at sites distant from the primary neoplasm. It is likely that many of the large number of biological changes associated with metastatic ability are controlled through alterations in the expression of a relatively small number of key genes usually referred to as cellular oncogenes and tumor suppressor genes. These genes are normally required for the regulation of growth-related processes in the cell, and alterations through mutations and/or expression are important in establishing metastatic properties of malignant cells. In this article, we review evidence indicating that oncogenes play an important role in metastatic spread, and we have placed emphasis on studies with the ras oncogenes. Metastatic progression is dependent upon an accumulation of multiple genetic changes in malignant cells. Therefore, we have also briefly addressed the related questions of altered growth factor regulation, and the cooperative interactions observed between dominantly acting oncogenes and between these genes, and tumor suppressor genes.
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PMID:Genetic regulation of metastatic progression. 224 Nov

Transfection of rat mammary (Rama) 37 epithelial cells which yield non-metastasizing adenomas in syngeneic Wistar-Furth rats with a drug resistance plasmid containing both the neo gene and EJ-ras-1 (pSV2neo.ras) or with pSV2neo and a plasmid encoding the large T Antigen (pLT214) of polyoma virus yields drug-resistant transformants with a frequency of 10(-5). Representative transformants have been propagated in neo-selecting medium to yield various cell lines. The 7 lines transfected with pSV2neo.ras (EJ1 set) and the 10 lines co-transfected with pSV2neo and pLT214 (LT1 set) all produce tumours at subcutaneous (s.c.) sites with a shorter median latent period than tumours produced by the parental Rama 37 cells. In addition, the LT1 set of transformants yields a higher incidence of tumours than the Rama 37 cells. No metastases are produced when any of the oncogene transformants are inoculated s.c. into rats. However, when an EJ1 representative is inoculated intravenously (i.v.), tumour deposits are found in the lungs of the host animals. In contrast, other Rama 37 variants that metastasize from s.c. sites fail to produce any metastases when inoculated i.v. The oncogene transfectants contain integrated DNA that hybridizes to neo and to the requisite oncogenic DNAs; the pattern of hybridizing bands to the transfected genes and their expression as mRNA is complex, and is presented in detail.
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PMID:Transfection of a non-metastatic diploid rat mammary epithelial cell line with the oncogenes for EJ-ras-1 and polyoma large T antigen. 224 94

In order to evaluate the relevance of protooncogene alterations in gastric cancer and to specifically relate these alterations to types and stages of the neoplasia, we studied oncogenes of possible interest in gastric tumors with different clinical parameters. Fifty DNAs from primary gastric adenocarcinoma were analyzed, by the Southern blotting technique, for the presence of amplification or rearrangements of seven different protooncogenes: c-myc, c-erbB2, c-Ki-ras, c-Ha-ras, c-N-ras, hst, and c-mos. All the tumors analyzed were histologically classified and staged. Amplification of the following genes was found: c-myc (2 of 50), hst (3 of 50), c-erbB2 (3 of 50), and c-Ki-ras (5 of 50). The simultaneous amplification of hst (3 cases), c-myc (1 of 3), or c-Ki-ras (2 of 3) was observed. Analysis of DNAs from atrophic and metaplastic gastric mucosa (which can be regarded as preneoplastic lesions) of the 10 patients showing gene amplification demonstrated that this was limited to neoplastic cells. Considering protooncogene amplification in general (i.e., involving different genes and occurring to different degrees) and clinical parameters of tumors, we found a statistically significant association between amplification and both tumor progression and presence of metastases. Therefore, at least for the genes analyzed, amplification is a relatively infrequent phenomenon and represents a late event in the temporal development of gastric cancer.
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PMID:Heterogeneous protooncogene amplification correlates with tumor progression and presence of metastases in gastric cancer patients. 225 24

This manuscript reviews the molecular aspects of tumor cell invasion of extracellular matrix. The changes in cell:substrate and cell:cell receptors that characterize motile cells are discussed for their importance not only in mediating invasive cell behavior, but also as diagnostic markers for invasive potential. Autocrine motility and scatter factors probably have key roles in initiating migratory behavior, while specific and non-specific extracellular matrix alterations can facilitate cell locomotion. The manuscript reviews reported changes, such as induction of cell motility, matrix degrading enzymes, and invasive/metastatic potential, which can follow transfection with ras oncogenes, and details the key roles of metalloproteinases, heparanase, and plasminogen activator in matrix degradation. Enzymatic inhibitors of initial steps in extracellular matrix degradation, such as rTIMP, and synthetic blockers of adhesive steps in tumor cell invasion represent types of reagent with potential as anti-metastatic agents. Their potential usefulness may be increased if they can be incorporated into a novel, long-term, non-traditional delivery system.
Cancer Metastasis Rev 1990 Sep
PMID:Cell-matrix interactions during tumor invasion. 225 11

Basic FGF (bFGF) and acidic FGF (aFGF) are multipotential factors that stimulate and support proliferation, migration and differentiation. Both bFGF and aFGF are non-secreted growth factors consistent with the lack of a signal peptide. However, bFGF and aFGF are deposited in extracellular matrix (ECM) suggesting that an alternative mechanism for FGF release exists. Four oncogenes, int-2, hst/K-fgf, FGF-5 and FGF-6 have been isolated that are highly homologous to aFGF and bFGF. Unlike bFGF and aFGF, they possess signal peptides and are secreted. These oncogenes transform cells and induce tumors, ostensibly via an autocrine mechanism. The involvement of bFGF and aFGF in autocrine transformation has been clarified by studies using FGF cDNA transfection. NIH-3T3 cells transfected with native bFGF cDNA and expressing 20 to 100 times as much bFGF as parental 3T3 cells acquire an enhanced proliferation rate and higher saturation density. NIH cells transfected with a construct in which bFGF cDNA is altered by addition of a signal peptide, undergo autocrine transformation and exhibit morphological and biochemical alterations characteristic of highly transformed cells. Injection of cells expressing native bFGF even at levels 100 times greater than parental 3T3 cells fails to induce tumors or lung metastasis in syngeneic mice. Signal peptide bFGF-transected cells on the other hand, acquire a high tumorigenic and metastatic potential with tumor incidence and numbers comparable to those induced by ras transformed cells. Acquisition of a signal peptide converts bFGF into a transforming protein analogous to FGF-related oncogenes which naturally have signal peptide sequences.
Cancer Metastasis Rev 1990 Nov
PMID:Autocrine regulation of cell growth and transformation by basic fibroblast growth factor. 229 36

Invasion of normal tissues is a complex process which requires active locomotion of malignant cells. Recent studies have identified a group of proteins which appear to be specific regulators of cell movement. Various strains and lines of fibroblast-like and vascular smooth muscle cells release into culture medium a unique protein activity which causes contiguous sheets of normal epithelial cells (e.g., Madin-Darby canine kidney, MDCK, cells) to spread and separate into individual cells (i.e., to scatter). Crude conditioned medium and partially purified MDCK scattering activity derived from human iliac artery smooth muscle cells (HIAS) scattered several lines of human squamous carcinoma cells (FaDu and A253) and markedly stimulated migration of carcinoma cells out of multicellular spheroids onto plastic culture surfaces. The scattering activities for MDCK and carcinoma cells showed similar sensitivities to temperature, trypsin treatment, and alteration of pH; both activities were blocked in the presence of cycloheximide. Unlike HIAS-derived factor, a similar MDCK scattering factor derived from ras-transformed NIH 3T3 cells did not scatter human carcinoma cells. These findings indicate that specific normal tissue-derived proteins may affect the mobility of tumor cells. Further studies of such proteins may yield insights into the mechanisms of tumor cell locomotion and tumor invasion.
Invasion Metastasis 1990
PMID:Smooth muscle-derived factor stimulates mobility of human tumor cells. 230 25

The experiments in this study were designed to test the hypothesis that natural killer (NK) cells play a role in host surveillance against early neoplastic changes in the malignant process. C3H 10T1/2 mouse fibroblasts were transfected with a pSV2-neo plasmid vector which contains EJ, the mutated c-Ha-ras, regulated by its own promoter. Control cells were transfected with pSV2-neo alone and did not contain the ras gene. Oncogene-transfected cells were compared with control cells for lung colony formation following tail vein injection into C3H mice. Intravenous injection of ras-transfected 10T1/2 cells induced marked lung colony formation in vivo, whereas C3H 10T1/2 parental lines or 10T1/2 cells transfected with pSV2-neo alone induced no lung colonies in C3H mice. The colonising potential of ras transfectants could be decreased by augmentation of NK activity by injection of polyinosinic cytidylic acid and increased by depletion of NK effectors with anti-asialo GM1. Experiments with beige mice demonstrated that the mortality of syngeneic, NK-deficient C3H-bg/bg mice injected with ras tranfectants was significantly greater than similarly treated NK-normal C3H(-)+/bg littermate controls. The results support the view that NK cells are capable in vivo of recognizing early defined stages in the neoplastic process initiated by oncogenes.
Clin Exp Metastasis
PMID:The in vivo clearance of Ha-ras transformants by natural killer cells. 240 89

The role of ras oncogenes in the pathogenesis of renal cell carcinoma is unclear. We have previously shown that insertion of a mutated ras oncogene into cultured human proximal tubular cells, the normal counterpart of renal cell carcinomas, initiates a series of transformation events which results in cells possessing a renal cancer phenotype. These data suggested a role for mutated ras genes in the initiation and maintenance of this disease. Therefore, to assess the involvement of ras genes in renal carcinogenesis, 51 primary and metastatic renal carcinomas, including three oncocytomas, were analyzed for point mutations in codons 12, 13 and 61 of the Ha-ras, Ki-ras and N-ras proto-oncogenes using polymerase-catalyzed chain reaction methodology. A mutated Ha-ras gene was found in one renal cancer metastatic to lung for an overall incidence of 2%. These data indicate that ras oncogenes, activated by point mutations, do not play a major role in the initiation, maintenance or metastases of renal carcinomas.
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PMID:Infrequent ras oncogene point mutations in renal cell carcinoma. 240 98


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