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

Short-term maintenance of fetal rat colonic tissue in vitro has been demonstrated using a collagen matrix organ culture system. The introduction of single (v-myc, v-rasH, v-src) oncogenes or combinations of oncogenes (v-myc/rasH, v-myc/src) into normal colon mucosal elements was established using retroviral vectors, resulting in enhanced proliferation and migration of epithelial cells from the lumen of tissue implants. Expression of a single oncogene in normal colon epithelium did not result in the establishment of cell lines. In contrast, expression of cooperating oncogenic elements resulted in cell lines in greater than 80% of experiments, revealing different morphological characteristics dependent upon the oncogene combination used. Confirmation of the expression of viral transcripts was determined using Northern blot analysis and viral oncoprotein expression using Western blot analysis (p21) and an immunoprecipitation kinase assay (src). Expression of keratin filaments was lost following passaging of cell lines but could be induced by the myc/ras transformants by growth on Rat-1 feeder layers. This induction phenomenon was not observed with myc/src lines, and although these expressed high levels of sucrase isomaltase the epithelial origin of these cells is unclear. Karyotypic analysis performed on three myc/ras-transformed cell lines revealed a normal chromosome complement associated with transformation. In this report we describe a novel in vitro transformation system for normal rat colonic epithelium mediated by the introduction of oncogene elements using different retroviral vector constructs. The potential to generate cell lines representing different stages of neoplastic progression using relevant genetic components presents significant advantages for the study of cellular and molecular interactions underlying colon neoplastic progression.
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PMID:Oncogene-mediated transformation of fetal rat colon in vitro. 137 76

Interrelationships between neoplastic progression and the expression of intermediate filaments were examined in primary cultures, immortal lines, and Kirsten murine sarcoma virus (KiMSV) transformed lines of rat ovarian surface epithelial (ROSE) cells. Immunofluorescence microscopy revealed abundant keratin filaments in all cells of primary cultures. In immortal, nontumorigenic lines, keratin filaments were detected in fewer cells, in smaller numbers, and in microscopically altered forms. The percentage of keratin-positive cells ranged from 4 to 54%. Its expression was inversely proportional to cell density. Keratin expression was similar in the two immortal lines, although one had retained a monolayered epithelial growth pattern resembling primary cultures, while in the other the growth pattern of the cells was more atypical. The two KiMSV-transformed lines were previously shown to produce tumors in vivo that resemble human ovarian endometrioid stromal sarcomas. In spite of this histologic appearance, the proportion of keratin-positive cells in these cells was increased over the immortal lines. Keratin expression was unrelated to cell density, and keratin in most virally transformed cells was limited to few, fine filaments. In thymidine-labelled immortal and virus-transformed cultures stained for keratin, no correlation was found between keratin expression and proliferative activity. The keratin profiles of primary and immortal cultures were identical on Western blots, with subtypes ranging from 52 to 66 kDa. The two virally transformed lines lacked some of the subtypes. Vimentin networks were faint or absent in primary cultures. In the immortal and the virus-transformed lines, neoplastic progression was associated with increasing vimentin expression but with no changes in filament morphology and distribution. The results show that the abnormalities in intermediate filament expression that accompany immortalization do not preclude the retention of a normal epithelial morphology and growth pattern in this cell type. Furthermore, the number of intermediate filaments and their intracellular distribution appear to be altered at an earlier stage in neoplastic progression than those mechanisms that select for specific keratin subtypes, or those that respond to regulation by cell density. Finally, the presence of keratin in the KiMSV-transformed lines examined in this study supports the hypothesis that human ovarian stromal sarcomas can arise in the OSE.
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PMID:Intermediate filaments in rat ovarian surface epithelial cells: changes with neoplastic progression in culture. 137 15

The sensitivity of outbred SENCAR mice and inbred SENCAR (SSIN) mice to multistage carcinogenesis was studied. Tumors were induced using either 7,12-dimethylbenz[a]anthracene or N-methyl-N'-nitro-N-nitrosoguanidine as initiators and 12-O-tetradecanoylphorbol-13-acetate or benzoyl peroxide as promoting agents. Although the number of papillomas per mouse was higher in SSIN than in outbred SENCAR mice, the number of carcinomas observed in the SSIN strain was significantly lower regardless of the initiator or promoter used. It was also observed that the expression of markers of premalignant progression (i.e., dysplasia, expression of keratin K13, and loss of keratin K1 expression) was markedly suppressed in SSIN papillomas. After 50 wk of promotion with 12-O-tetradecanoylphorbol-13-acetate, the pattern of expression of K13 and K1 in SSIN mice was comparable to the pattern observed in outbred SENCAR mice after 10 to 20 wk of promotion with 12-O-tetradecanoylphorbol-13-acetate. It was also observed that 67% of the tumors induced in SSIN mice by initiation with 7,12-dimethylbenz[a]anthracene exhibited a mutation in codon 61 of the Ha-ras-1 gene. This latter finding suggests that the differences observed in tumor progression between the inbred strain and the outbred stock are not related to a genetic alteration in the Ha-ras-1 gene but rather to an independent event that we have postulated to involve a putative suppressor gene. The data reported here suggest that the putative gene(s) that confers susceptibility to tumor promotion was segregated from the gene(s) involved in tumor progression during selection and inbreeding of the SENCAR mouse stock.
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PMID:Dissociation of sensitivities to tumor promotion and progression in outbred and inbred SENCAR mice. 137 69

Rat keratin K5 and vimentin complementary DNAs have been isolated, identified, and used to study keratin and vimentin expression as markers for cell differentiation. Isologous rat neoplastic epithelial cell lines used were based on a clonal benign epithelial line (A5P/B10) and a clonal anaplastic malignant derivative line (T952/F7). Stable cytoplasmic mRNA was detected for keratin but not vimentin in the benign cells. The anaplastic derivative cells expressed vimentin but showed a 1000-fold reduction in the keratin message, which nuclear run-on assays identified as being due to posttranscriptional down-regulation. An identical pattern of posttranscriptional down-regulation was found in independent malignant somatic cell hybrids of the benign and anaplastic cells. trans-acting regulatory mechanisms implicated in posttranscriptional (pretranslational) keratin down-regulation in these anaplastic malignant cells may play a role in the apparent loss of differentiation evident in tumor progression.
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PMID:Loss of keratin expression in anaplastic carcinoma cells due to posttranscriptional down-regulation acting in trans. 138 67

The pathological and cytogenetic features of an extrarenal malignant rhabdoid tumor (MRT) arising from the paravertebral region in an infant were investigated. The patient died 4 months after diagnosis, due to aggressive tumor progression. The tumor was composed of medium-sized round cells with cytoplasm containing eosinophilic inclusions, which ultrastructurally were composed of densely packed whorled intermediate filaments. Flow-cytometric analysis of the tumor cells revealed a diploid pattern. Amplification of the N-myc oncogene was not identified. Immunohistologically, the inclusion bodies showed a positive reaction with antiserum against vimentin. The tumor cells were not reactive with antiserum against epithelial membrane antigen, anti-keratin (polyclonal) or cytokeratin (monoclonal, CK1), but did react with 5H10, an antiserum established from human sarcomatous Wilms' tumor. This case is discussed with reference to the literature on extrarenal MRT, placing stress on the histogenesis of this tumor.
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PMID:Cytogenetic characteristics of a malignant rhabdoid tumor arising from the paravertebral region. A case report. 150 7

The ovarian surface epithelium (OSE) is known to contribute to postovulatory repair of the ovarian cortex by proliferation and migration over the site of follicular rupture, and by deposition of a basement membrane. We examined the production of other extracellular matrix components in culture by OSE cells of the rat (ROSE), using immunofluorescence microscopy, electron microscopy, and proline incorporation. We compared recently explanted cells in low passage, the immortal line ROSE 239, whose growth pattern resembles low passage cultures, and the immortal line ROSE 199, which forms ridges and papillae. The epithelial nature of all three cell types was confirmed by the presence of keratin and laminin. All three cell types secreted collagen types I and III and at least one (ROSE 199) produced highly polymerized banded fibrils, which are characteristic for stromal or interstitial extracellular matrix. Simultaneous production of collagen types I and III, keratin, and laminin by cloned subpopulations ruled out an origin of the lines in mixed epithelial/fibroblast populations. The results demonstrate that OSE has the capacity to synthesize major components of connective tissue stroma. They suggest that this epithelium, in addition to its postulated proteolytic role, may also express synthetic activity in the remodelling of the ovarian cortical stroma. A capacity of OSE cells to produce stromal components autonomously might be an important factor in the formation of ovarian surface papillae and in neoplastic progression of OSE-derived ovarian carcinomas.
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PMID:Ovarian surface epithelium: autonomous production of connective tissue-type extracellular matrix. 171 May 11

The cell-cell adhesion molecule E-cadherin is specifically expressed in epithelia and is involved in the maintenance of the epithelial phenotype. Expression of E-cadherin is downregulated in many poorly differentiated carcinomas, which leads to higher motility and invasiveness of the cells. To examine the mechanisms that regulate tissue-specific expression, we have characterized the promoter of the E-cadherin gene. We found that an upstream fragment (positions -178 to +92) mediates strong expression of a chloramphenicol acetyltransferase reporter gene in epithelial cells (i.e., 60% of the level obtained with simian virus 40 promoter/enhancer constructs), whereas in nonepithelial cells this promoter was either inactive or much less active. By DNase I footprinting and gel retardation analysis as well as through functional dissection of the regulatory sequences, we identified two regions that contribute to tissue-specific activity of the promoter: (i) a G-C-rich region between -25 and -58 that generates basic epithelial promoter activity, most likely in combination with an "initiator" element present at the single transcription start site of the gene, and (ii) a palindromic sequence between -75 and -86 (named E-pal) that potentiates the activity of the proximal E-cadherin promoter and confers epithelial cell-specific activity on a simian virus 40 promoter. The E-pal sequence is homologous to cis regulatory elements active in keratin gene promoters and competes with these elements for nuclear factor binding. Interestingly, the activity of the E-cadherin promoter was reduced in dedifferentiated breast carcinoma cells, indicating that the identified elements are subject to negative regulation during tumor progression.
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PMID:The E-cadherin promoter: functional analysis of a G.C-rich region and an epithelial cell-specific palindromic regulatory element. 176 63

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

Three monoclonal anti-keratin antibodies, AE1, AE3, and AE4, were used to compare the expression of keratins in normal, preneoplastic, and malignant mouse mammary epithelial cells growing in primary culture. In indirect immunofluorescence, AE1 did not stain normal cells but did stain a minority of preneoplastic and carcinoma cells. AE3 reacted with a subpopulation of epithelial cells in both the normal and abnormal cultures, except for certain cultures from one type of tumor wherein all of the epithelial cells were reactive. AE4 decorated an elaborate keratin filament network in all cultured mammary epithelial cells, regardless of neoplastic state. In double-label immunofluorescence, a guinea pig anti-keratin antiserum, which reacts preferentially with myoepithelial cells, exhibited coincident staining with AE1 in the tumor cultures and AE3 in the normal and most tumor cultures, indicating that the cells recognized by the antibodies in these populations were myoepithelial. Immunoblot experiments with cytoskeletal polypeptides extracted from the normal and tumor cells demonstrated that the set of keratins recognized by each monoclonal antibody was essentially the same in all of the cells except for a Mr 40,000 component that was present in normal cells but either absent or diminished in the cancer cells. Thus, while normal cells had Mr 40,000 and 50,000 keratins recognized by AE1, the epitope detected by this antibody was apparently concealed or "masked" in situ. AE3 reacted in immunoblots with a major keratin group (Mr 54,000-55,000) and a minor keratin (Mr 57,000), while AE4 reacted only with the Mr 54,000-55,000 keratin species. Because immunofluorescence with AE4 showed that the Mr 54,000-55,000 keratin group was present in all mammary epithelial cells, the AE3-reactive epitope must be masked in the majority of normal and tumor cells. The data therefore showed that epitopes on three major keratins, the Mr 40,000, 50,000, and 54,000-55,000 group, were "masked" in normal cells, whereas in tumor cells "masking" involved primarily the Mr 54,000-55,000 keratin. Attempts to "unmask" the epitopes recognized by AE1 in normal cells or to increase the number of cells reactive with AE3 in the normal and tumor cultures failed. Thus, certain cultured preneoplastic and neoplastic mammary cells with a myoepithelial phenotype have an altered organization of keratins that is manifested by a keratin antigenic determinant which is visible by immunocytochemistry in the abnormal cells but not in normal mouse mammary cells. This is the first demonstration that the immunoreactivity of keratins can be modified during neoplastic progression of epithelial cells.
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PMID:A keratin epitope that is exposed in a subpopulation of preneoplastic and neoplastic mouse mammary epithelial cells but not in normal cells. 241 2

An in vitro system for studying the interaction between human papillomavirus (HPV) 16 and 18 recombinant DNA and normal human exocervical epithelial cells is described. Eight HPV-immortalized human exocervical epithelial cell lines were established; all the lines contained either integrated HPV16 or 18 sequences and expressed HPV mRNAs. Thus, integration and expression appear to be required for immortalization. Immortalized cells (greater than 200 population doublings to date) divided rapidly (doubling time of 30 to 46 h) and morphologically resembled primary cultures of normal human exocervical epithelial cells. They expressed a keratin pattern consistent with their origin from exocervical epithelium. When cultured at high density or in the presence of serum they terminally differentiated. Sublines resistant to terminal differentiation were selected by growth in serum-supplemented medium. Keratin pattern changes suggest they have some properties in common with cervical squamous carcinoma cells. However, HPV-immortalized cell lines were not tumorgenic in nude mice. Thus, HPV16/18 is not carcinogenic by itself. These cell lines represent an appropriate model for studying factors that regulate HPV gene expression in normal cervical epithelial cells and examining the influence of cocarcinogens on neoplastic progression.
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PMID:Characterization of normal human exocervical epithelial cells immortalized in vitro by papillomavirus types 16 and 18 DNA. 245 44


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