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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because of interest in mechanisms of carcinogenesis in human epithelial cells, quantitative procedures were developed for the mass culture of human epidermal keratinocytes in the absence of feeder cells. Several approaches were used to enhance proliferation since target cells are considered most susceptible to transformation if they are treated with carcinogenic agents during DNA synthesis. Mass cultures of enzymatically dispersed human foreskin were initiated in collagen-coated flasks containing medium NCTC 168 with 10% Chelex 100-treated horse serum. Under these conditions, human keratinocytes required a higher calcium ion concentration ([Ca2+]) than that reported for suspensions plated at low cell density. Neither the cohesiveness of the epidermal sheet nor continued proliferation was maintained by 0.15 mM Ca2+; 0.3 mM Ca2+ maintained these properties in primary culture only. A concentration of 1.0 mM Ca2+ provided the highest cell yield for prolonged growth as determined by the enumeration of cell nuclei isolated by citric acid. Reproducibility of successful initiation was achieved by inoculation of cells into a medium designed for clonal growth followed by culture in medium NCTC 168. Thus the balance of nutrients and electrolytes must be adjusted to satisfy the requirements of a dynamically expanding keratinocyte population.
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PMID:Approaches to enhance proliferation of human epidermal keratinocytes in mass culture. 657 29

Carcinogenesis is commonly considered to be a multi-step process, comprising "initiation" and "promotion" events. Skin fibroblasts from patients with hereditary retinoblastoma (RB) and familial polyposis coli (FPC) were chosen for study since their predisposition to the tumour may be due to an inherited "initiation" event which is present in every somatic cell. Thus, one might predict that skin fibroblasts from these patients might exhibit an increased susceptibility to in vitro transformation, by either tumour promoters alone or by the complete carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). In the case of skin fibroblasts from RB patients, transformation as measured by the ability of cells to grow in semi-solid medium and their migration in collagen gels, did not occur with either class of agent. However, experiments involving skin fibroblasts from FPC patients, showed these cells to grow in semi-solid medium following treatment with the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) alone, although their pattern of migration in collagen gels was unchanged and they were non-tumorigenic in nude mice. The clones which grew in semi-solid medium were also unaltered in terms of their migration in collagen gels and tumorigenicity in nude mice and were considered not to be completely transformed. These results are discussed in relation to theories that tumour promoters are only involved in cell selection and clonal expansion of initiated cells a second "mutational" event being required for complete transformation.
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PMID:In vitro studies of the possible mechanisms whereby tumour promoters mediate their responses. 668 Jul 26

The physiological state of pregnancy confers significant resistance to polycyclic aromatic hydrocarbon (PAH)-induced mammary tumorigenesis. We have tested the abilities of primary mammary cells from pregnant and virgin rats cultured on collagen-coated plates to metabolize PAHs and convert these carcinogens to mutagenic derivatives. Using a cell-mediated mutagenesis assay, we found that mammary epithelial cells from pregnant rats produced half the levels of mutagenic 7,12-dimethylbenz[a]anthracene (DMBA) metabolites formed by cells from virgin rats. Pregnant-derived mammary cells also showed consistently lower levels of metabolism of DMBA and benzo[a]pyrene (B[a]P) than cells from virgin rats. H.p.l.c. analysis of B[a]P metabolism by these cell populations indicated no significant qualitative differences in the extracellular and intracellular metabolites formed. We have previously shown that mammary cells from rat strains exhibiting significant differences in susceptibility to PAH-induced tumors have equivalent qualitative and quantitative abilities to metabolize PAH carcinogens. Our current data suggest that modifications in mammary tumor susceptibility found in various physiological states, unlike genetically determined differences, may be related in part to an altered ability to activate chemical carcinogens within the mammary gland.
Carcinogenesis 1984 Jan
PMID:Differences in mediated mutagenesis and polycyclic aromatic hydrocarbon metabolism in mammary cells from pregnant and virgin rats. 669 80

An assay for measuring chemically-induced DNA repair in primary cultures of rat tracheal epithelial (TE) cells has been developed and characterized. Chemical exposure may be either in vitro or in vivo. Epithelial cells were removed from the trachea by protease digestion, allowed to attach to collagen-coated glass slides, and incubated with [3H]-thymidine. DNA repair was assessed as unscheduled DNA synthesis by quantitative autoradiography. The direct acting genotoxicants methyl methanesulfonate (100 microM) and N-methyl-N'-nitro-N-nitrosoguanidine (10 microM) yielded a positive response in vitro. 1,6-Dinitropyrene (DNP) (0.05 microM) and dimethylnitrosamine (DMN) (1 mM) were also positive in vitro demonstrating that TE cells have the capacity to metabolically activate these compounds. 2-Acetylaminofluorene (AAF), aflatoxin B1 (AFB1), and benzo[a]pyrene (BP) were all negative in vitro, suggesting organ specific patterns of metabolic activation. DMN, which has been shown to induce DNA repair in TE cells following exposure by inhalation, was negative when administered by gavage. 1,6-DNP, BP and AAF did not induce DNA repair or alter the fraction of cells in S-phase when administered by gavage. Formaldehyde did not induce DNA repair or increase the fraction of cells in S-phase in TE cells following either in vivo exposure by inhalation (0.47, 2, 5.9 or 14.8 p.p.m. for 1, 3 or 5 days) or exposure of the cultured cells in vitro (100 microM). This assay provides the means to assess the genotoxic potential of environmental chemicals in the epithelial cells of the respiratory system.
Carcinogenesis 1984 Jun
PMID:Assessment of chemically-induced DNA repair in rat tracheal epithelial cells. 672 86

The genetic disease familial polyposis coli (hereditary adenomatosis of the colon and rectum) provides an excellent model for the study of tumour progression in the large bowel. We have isolated and characterized four epithelial cell lines from colorectal tumours from polyposis coli patients. These cell lines are grown on collagen-coated Petri dishes in the presence of mouse 3T3 feeder cells in medium containing 20% foetal bovine serum. Of these cell lines three were isolated from premalignant adenomas and one from an adenocarcinoma. All four lines have a characteristic cuboidal epithelial morphology, and their epithelial origin was confirmed by positive staining with a monoclonal antibody which reacts specifically with the keratin filaments of simple epithelia. The adenoma-derived lines display ultrastructural features characteristic of colonic epithelium including desmosomes, microvilli and mucin droplets. One of the adenoma-derived cell lines, designated PC/AA, has retained differentiated functions in culture, namely mucin production, after 21 in vitro passages. PC/AA has a karyotype of 46, XY with no detectable chromosome rearrangements. The adenoma-derived lines could be passaged from clumps of cells but not from single cells even in the presence of 3T3 feeder cells. The carcinoma-derived line, designated PC/JW, could however grow from single cells in the presence of a feeder layer. The one premalignant adenoma-derived line tested so far, PC/AA, did not produce tumours in athymic nude mice. In contrast, the carcinoma-derived line, PC/JW was tumorigenic in athymic nude mice. PC/JW produced moderately well-differentiated tumours which were histologically similar to the adenocarcinoma from which the cell line was isolated. PC/JW has a near-diploid chromosome number with an isochromosome (1q), an isochromosome (14q) and an (Xp; 17q) translocation. Unidentified marker chromosomes were present in a few cells. The features at present which distinguish the carcinoma-derived line from the adenoma-derived lines are tumorigenicity, growth from single cells and chromosomal abnormalities. The isolation and characterization of differentiating human epithelial cell lines at different stages in malignant transformation provide an opportunity to examine the cellular and molecular mechanisms controlling tumour progression in the large intestine, and to obtain an insight into the multistep process of human epithelial carcinogenesis.
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PMID:The isolation and characterization of colorectal epithelial cell lines at different stages in malignant transformation from familial polyposis coli patients. 674 17

The purpose of our studies was to determine whether specific differences in nutritional and/or substrate requirements exist between normal and carcinogen treated tracheal epithelial cells. Epithelial cells were collected from control tracheas or from tracheas exposed in vivo for 4 weeks to the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). This carcinogen exposure was shown in previous studies (18) to induce various types of transformed epithelial cell phenotypes. The cells were cultured under 7 different culture conditions, one of which was designed to provide optimum growth conditions for all cells (nonselective condition = SC0) and contained F12, conditioning factors from 3T3 fibroblasts, Dulbecco's minimal essential medium (DME), insulin, transferrin, hydrocortisone, fetal bovine serum (FBS) and bovine hypothalamus extract. By removing one or more factors from SC0 we hoped to design conditions selecting against normal and for "carcinogen altered" cells. It was found that normal cells require collagen and conditioning factors (CF) (produced from 3T3 fibroblasts grown in DME + 2% FBS) for growth in hormone supplemented medium. Increasing the serum concentration to 10% did not compensate for the collagen and CF requirements. In comparison, cells from carcinogen-exposed tracheas clearly had reduced nutritional and substrate requirements. Such cells grew for at least 30 days without collagen substratum as long as CF were present or without CF as long as collagen was present. High serum concentration replaced the requirement for both collagen and CF. Immortalization and anchorage independence of growth occurred in all cultures derived from DMBA-exposed tracheas except in those maintained in high serum but without DME, collagen and CF. These studies indicate that "carcinogen-altered" cells can be identified and selected for based on substrate and nutrient requirements. This should be useful in designing a quantitative epithelial transformation system.
Carcinogenesis 1982
PMID:Identification of early carcinogen-induced changes in nutritional and substrate requirements in cultured tracheal epithelial cells. 681 82

Primary cultures of rat tracheal epithelial cells were treated with the chemical carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) to quantitatively study the early events during neoplastic transformation. Epithelial cells were dissociated from tracheas of specific-pathogen-free Fischer-344 rats and were plated on collagen-coated tissue culture dishes. To determine cytotoxicity, cells were exposed on day 1 to various concentrations of MNNG for 3 h and colony forming efficiency (CFE) was determined on day 7. MNNG at a concentration of 0.1 microgram/ml did not decrease CFE as compared to the control cultures, whereas 1 microgram/ml reduced the CEF by 75%. For transformation studies, primary cell cultures received single exposures to MNNG (0.1-0.6 microgram/ml) or multiple exposures to 0.1 microgram/ml of MNNG for 3 h between days 1 and 17. In carcinogen-exposed cultures, morphologically altered foci appeared on day 18, recognizable by high cell density. Transformation frequencies between 1 and 8% were observed depending on MNNG concentration. Cultures containing altered foci continued to grow during the third and fourth week when control cultures had ceased to proliferate and exfoliated from the dish. Over 40% of the cultures which received multiple exposures to MNNG acquired cell line status and could be subcultured greater than or equal to 20 times. None of the 30 control cultures became cell lines. Seventy per cent of MNNG-exposed cell lines showed the anchorage independent growth phenotype at passage 20 as judged by growth in agarose. Four of 10 cultures exposed either 6 or 8 times to MNNG formed invasive squamous cell carcinomas at passage 20 upon inoculation into nude mice. Based on these and previous studies, we feel that unrestricted cell replication is an early key event in carcinogen-exposed epithelial cell populations, preceding neoplastic transformation.
Carcinogenesis 1983
PMID:Neoplastic transformation of primary tracheal epithelial cell cultures. 683 11

Defined culture conditions for routine clonal growth of normal human adult bronchial epithelial cells have been developed. Serum and feeder cell requirements were abrogated by: (a) optimizing the calcium concentration in nutrient medium, MCDB 151; (b) supplementing with purified factors (epidermal growth factor, 5 ng/ml; insulin, 5 micrograms/ml; transferrin, 10 microgram/ml; hydrocortisone, phosphoethanolamine and ethanolamine, each at 5 x 10(-7) M; and trace elements); and (c) coating the surface of the culture dish with a mixture of fibronectin, collagen, and bovine serum albumin. Endothelial cell growth supplement (100 micrograms/ml) and retinoic acid (3 x 10(-10) M) further enchanced growth, whereas cholera toxin was nonmitogenic and serum supplementation (greater than 2%) markedly reduced the growth rate. Using the defined system, dissociated cultures of bronchial epithelial cells, obtained from more than 15 donors, have been subcultured at clonal densities with a colony forming efficiency of 3 to 4%. In addition, high density cultures have been subcultured more than five times with four to six population doublings per passage. The features of this system permit pathobiologic investigations of bronchial epithelial cells, e.g., aging, differentiation, and carcinogenesis using conditions that isolate the results from the influence of serum, feeder cells, and other undefined factors.
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PMID:Clonal growth of normal adult human bronchial epithelial cells in a serum-free medium. 714 47

Analysis of invasive malignancy focuses on the particularly high growth rate of tumor cells, and on the aggressive mechanisms of histolysis favoring the infiltration of the malignant cells into the surrounding tissue. Specific significance is attributed to a certain enzyme directed against type IV collagen, and to the auto-locomotion of tumor cells, properties that may also explain the highly selective process of metastazation in at least three consecutive steps: Tumor cells invade a blood or lymph vessel, they are transported along blood or lymphatic pathways, and they eventually infiltrate foreign tissue after penetration and destruction of blood of lymph vessel walls. Among the factors involved in the process of metastazation, special interest is due to blood coagulation and to the coexistence of different tumor cell subpopulations within a primary. These features of malignant growth are based on the loss of functional differentiation as manifested e.g. in the loss of tissue-specific nuclear chromatin structures. Tumor development is triggered by the so-called primary factors which always affect the DNA, i.e. the cell genome. Chemical carcinogens, viruses, and shortwave or ionizing irradiation induce DNA defects which, however, will be reversed and mended by special repair mechanisms in most cases. Thus, the actual development and spread of malignancy is ultimately due to deficient reparation. Co-factors favorizing and promoting carcinogenesis may shorten the latency period, among other several specific chemicals and hormones. Based on current knowledge of tumor dormancy a new concept is proposed for the chronological and morphological sequence of carcinogenesis: Following the development of a primary tumor certain as yet undefined growth factors and especially immunological factors may be responsible for the development of a progressive tumor disease.
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PMID:[Mechanisms of malignant growth (author's transl)]. 728 41

Inhibition studies were carried out to study possible cross-reactivity between a peptide fragment of the Epstein-Barr virus nuclear antigen, EBNA-1, and keratin/collagen. The 20-amino acid peptide (pAG), derived from a glycine-alanine repeat region of EBNA-1, uniquely makes up about one-third of the viral protein and is a dominant IgA antigenic epitope in patients with nasopharyngeal carcinoma (NPC). A small percentage of normal human sera (NHS) also binds pAG and this reactivity is examined in this study. Ten percent (2/20) and 13.4% (2/15) of IgA-pAG-positive NPC sera and NHS, respectively, were significantly inhibited by keratin in a competitive ELISA system. Conversely, 31.6% (6/19) and 30.8% (4/13) of IgA-keratin-positive NPC sera and NHS, respectively, were significantly inhibited by pAG. This indicated minimum cross-reactivity between IgA serum antibodies to EBNA-1 and keratin. Using collagen as inhibitor, none of 18 and only 2/13 IgA-pAG-positive NPC sera and NHS, respectively, were inhibited. In the collagen ELISA system, only 2/19 (10.5%) and 4/25 (16%) of IgA-collagen-positive NPC sera and NHS, respectively, were inhibited with pAG. Therefore, cross-reactivity with collagen was also low. IgA-pAG-positive NHS may therefore not be a false positive phenomenon, but whether it may represent an early serological profile related to NPC carcinogenesis remains to be determined.
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PMID:Serum IgA cross-reactivity between glycine-alanine repeat sequence of EBNA-1 and keratin or collagen in nasopharyngeal carcinoma. 751 12


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