[Reverse transformation of neoplastic cells and phytoglycosides, with special reference to redifferentiation induction in cancer cells by ginsenosides].
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Cell Division↗
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Results for “Cell Transformation, Neoplastic”
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Amplification of the Ect2 proto-oncogene and over-expression of Ect2 mRNA and protein in nickel compound and methylcholanthrene-transformed 10T1/2 mouse fibroblast cell lines.
Occupational exposure of humans to mixtures of insoluble and soluble nickel (Ni) compounds correlates with increased incidences of lung, sinus, and pharyngeal tumors. Specific insoluble Ni compounds are carcinogenic to animals by inhalation and induce morphological and neoplastic transformation of cultured rodent cells. Our objectives were to (1) understand mechanisms of nickel ion-induced cell transformation, hence carcinogenesis and (2) develop biomarkers of nickel ion exposure and nickel ion-induced cell transformation. We isolated mRNAs from green nickel oxide (NiO), crystalline nickel monosulfide (NiS), and 3-methylcholanthrene (MCA) transformed C3H/10T1/2 Cl 8 cell lines, and determined by mRNA differential display that nine mRNA fragments were differentially expressed between Ni transformed and non-transformed 10T1/2 cell lines. Fragment R2-5 was expressed at higher steady-state levels in the transformed cell lines. R2-5 had 100% sequence identity to part of the coding region of Ect2, a mouse proto-oncogene encoding a GDP-GTP exchange factor. The 3.9-kb Ect2 transcript was expressed at 1.6- to 3.6-fold higher steady-state levels in four Ni transformed, and in two MCA-transformed, cell lines. Ect2 protein was expressed at 3.0- to 4.5-fold higher steady-state levels in Ni-transformed and in MCA-transformed cell lines. The Ect2 gene was amplified by 3.5- to 10-fold in Ni transformed, and by 2.5- to 3-fold in MCA transformed cell lines. Binding of nickel ions to enzymes of DNA synthesis likely caused amplification of the Ect2 gene. Ect2 gene amplification and over-expression of Ect2 mRNA and protein can cause microtubule disassembly and cytokinesis, contributing to induction and maintenance of morphological, anchorage-independent, and neoplastic transformation of these cell lines. Over-expression of Ect2 protein is a useful biomarker to detect exposure to nickel compounds and nickel ion-induced morphological and neoplastic cell transformation.
Animals↗
Human proteins sensitive to neoplastic transformation in cultured epithelial and fibroblast cells.
We resolved the [35S]methionine polypeptides synthesized by normal [lung fibroblasts (WI-38), amnion cells] and transformed [SV40 transformed WI-38, AMA (spontaneously transformed amnion cells)] cultured human cells, using two-dimensional gel electrophoresis under conditions in which about 1300 polypeptides could be reproducibly separated. These studies demonstrated important changes in the relative proportions of several polypeptides that are present both in normal and transformed cells. Of a total of 400 common polypeptides that we quantitated for each cell type, 53 (22 basic and 31 acidic) varied by 40% of more in both cell pairs. Among these, we have identified vimentin (IEF 26), cyclin (IEF 49), and a tropomyosin-related polypeptide (IEF 52). No new major polypeptide was detected in the transformed cells, at least at the level of resolution currently achieved by this technique. Similar but qualitative studies of [32P]orthophosphate-labeled proteins revealed that, of 250 analyzed, only seven common phosphoproteins, including phosphovimentin (IEF 26e), varied consistently in both cell pairs. These results strengthen our previous conclusion that transformation results in changes in the relative proportions of polypeptides synthesized in normal and transformed cells rather than in the appearance of new polypeptides in transformed cells.
Amnion↗
Carcinogen-induced phenotypic alterations in mammary epithelial cells accompanying the development of neoplastic transformation.
Epithelial cells isolated from the mammary glands of virgin Sprague-Dawley rats and treated with 7,12-dimethylbenz[a] anthracene (DMBA) acquire an indefinite life span and anchorage-independent (AI) growth and form carcinomas in athymic nu/nu mice. Epithelial cells separated from fibroblasts and lipocytes by density-gradient centrifugation after collagenase digestion of the fat pads are grown in a hormone-supplemented medium. Control mammary epithelial cells survived approximately 30 days. After 2 days in culture, the mammary epithelial cells were treated with DMBA (1 microM) for 24 hr allowing for maximum oxidative metabolism of the hydrocarbon. DMBA-treated cells acquired an extended life span and grew in AI medium; however, in most cases, they were nontumorigenic and eventually ceased dividing. A pool of mammary epithelial cells, ME 10CL1, treated with DMBA has grown indefinitely, exhibited AI growth, and after 195 days in culture formed adenocarcinomas when 5 X 10(6) cells were injected into athymic nu/nu mice. When the tumor promoter, 12-O-tetra-decanoylphorbol-13-acetate (100 ng/ml), was added to another pool (ME 11CL2) of DMBA-treated mammary epithelial cells which had been in culture for 110 days, an irreversible increase in cell growth rate and a significant morphological alteration resulted. The 12-O-tetradecanoylphorbol-13-acetate-treated cells also formed colonies in AI medium after 140 days and poorly differentiated carcinomas in athymic nu/nu mice. Inhibition of tumor cell proliferation by tamoxifen is consistent with the mammary origin of the epithelial cells and suggests the presence of a viable estrogen receptor. The results demonstrate in vitro neoplastic transformation of rat mammary epithelial cells by DMBA or promotion of DMBA-initiated cells by 12-O-tetradecanoylphorbol-13-acetate resulting in two different epithelial tumor cell lines.
9,10-Dimethyl-1,2-benzanthracene↗
Reduced temperature (22 degrees C) results in enhancement of cell killing and neoplastic transformation in noncycling HeLa x skin fibroblast human hybrid cells irradiated with low-dose-rate gamma radiation.
The effect of reduced temperature (22 degrees C) or serum deprivation during low-dose-rate (0.66 cGy/min) gamma irradiation on cell killing and neoplastic transformation has been examined using the HeLa x skin fibroblast human hybrid cell system. The reduced temperature stops progression of these cells through the cell cycle while serum deprivation slows down cell turnover markedly. The data demonstrate an enhancement in both of the end points when cells are held at 22 degrees C compared to parallel experiments done at 37 degrees C. In operational terms, the decreased survival and increased neoplastic transformation are consistent with our earlier hypothesis of a higher probability of misrepair at reduced temperature (Redpath et al., Radiat. Res. 137, 323-329, 1994). The interpretation that this damage enhancement was associated with the reduced temperature, and not the fact that the cells were noncycling, was supported by the results of experiments performed with cells cultured at 37 degrees C in serum-free medium for 35 h prior to and then during the 12.24 h low-dose-rate radiation exposure. Under these conditions, cell cycle progression, as shown by reduction in growth rate and dual-parameter flow cytometric analysis, was considerably inhibited (cell cycle time increased from 20 h to 40 h), and there was no significant enhancement of cell killing or neoplastic transformation.
Cell Cycle↗
Progressive state selection of cells in low serum promotes high density growth and neoplastic transformation in NIH 3T3 cells.
A subline of NIH 3T3 cells maintained by frequent passage (every 2 to 3 days) in 10% calf serum (CS) at low population density reached a low saturation density in 2% CS and produced no transformed foci on prolonged incubation at confluency in 2% CS. Within 3 frequent low density passages in 2% CS, the saturation density and focus-forming capacity in that serum concentration began an increase which was continued in subsequent passages. The saturation density and focus-forming capacities of the cells in both 2% and 1% CS were further enhanced by passage in 1% CS. The cells could then be passaged in 0.5% CS and then in 0.25% CS, which would support no multiplication of cells previously passaged only in 10% CS. The cells passaged in 0.25% CS gradually increased their saturation density and focus-forming capacity in that extremely low serum concentration during 24 low density passages, although their initial growth rate did not increase. They also attained a colony-forming efficiency in 0.25% CS of about 30%, as compared to less than 1% for cells passaged in 10% CS. Cells passaged, cloned, and passaged again in 2% CS yielded clonal populations which differed from one another in saturation density and focus-forming capacity in 2% CS. We conclude that NIH 3T3 cells diversify phenotypically at a high rate in their capacity to multiply and produce foci in limiting concentrations of serum, and we propose that progressive selection of these heterogeneous states accounts for the acquired capacity to function effectively in low concentrations of serum growth factors. Since lymph and presumably extracellular fluid in vivo contain low concentrations of growth factors which govern the multiplication of normal cells, the adaptation we observe in vitro may be related to tumor production in the animal.
Animals↗
[The possibility of viral etiology in cervical carcinogenesis].
Oncogenic potential of herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) which are both associated with occurrence of cervical cancer and the mechanism of oncogenesis by these viruses were investigated by transformation experiments in vitro. The results were obtained as follows. 1) HSV-2 induced neoplastic transformation of normal diploid cells is a multistep process. Cervical cancer associated antigen AG-4 is encoded within the specific region of HSV-2 DNA which converts immortalized cells to tumorigenic lines. 2) Tumor cells express cellular oncogene at a final stage of neoplastic transformation induced by HSV-2 and "hit and run" theory is applicable to oncogenesis of this virus. 3) Complete carcinogenesis can be mediated by HPV-16 or HPV-18 DNA under collaboration with other cofactors such as HSV-2. 4) It is suggested that neoplastic transformation induced by HPV-18 DNA is based on "hit and run" oncogenesis. 5) HPV-16 or HPV-18 DNA can immortalize primary diploid cells and convert them to fully tumorigenic phenotype by repeating cell passage. 6) It has been experimentally proved that the difference in transforming potential exists between HPV 6/11 and HPV 16/18. 7) Amplification and overexpression of c-myc oncogene was detected in transformed cells obtained by HPV-16 transfection. While overexpression of c-myc was detected in transformed cells induced by HPV-18 DNA, but no amplification was observed. On the other hand, detection of HPV, DNA and amplification or overexpression of protooncogenes was performed in cervical intraepithelial neoplasias (CIN) and invasive cervical carcinomas. The results were summarized as follows. 1) HPV DNA was detected in approximately 70% of a population with CIN by in situ hybridization. CIN II showed the highest incidence of positive HPV DNA (91%), and the positive ratio decreased in CIN III (56%). 2) Immunohistochemical study of paraffin-embedded specimens with monoclonal antibodies to oncogene products revealed that only some of cervical invasive carcinomas expressed c-myc protein, ras p21 or EGFR. 3) HPV DNA was detected in 46% of invasive cervical carcinomas by Southern blot hybridization. The percentage of patients with positive results for HPV 16/18 was 29%. However, it increased up to 58% by use of polymerase chain reaction (PCR), suggesting that there are many cervical cancer tissues in which a number of cells lack viral DNA. 4) Northern blot hybridization analysis revealed overexpression of c-myc mRNA in 30% of cervical invasive carcinomas although amplification of c-myc oncogene was detected in only one of invasive carcinomas.(ABSTRACT TRUNCATED AT 400 WORDS)
Cell Transformation, Neoplastic↗
[The role of stem and pluripotent cells in differentiation and the neoplastic transformation of pancreatic cells].
Certain differentiation-specific antigenic determinants are characteristic of pancreatic cells at each stage of embryonic development. Using immunohistochemical markers, we have demonstrated that the cells of several pancreatic tumors express some fetal proteins characteristic of embryonic cells of the pancreas. We propose that the presence of fetal antigens and proteins in the tumor is a sign of a lower tumor differentiation and a less favorable prognosis.
Cell Differentiation↗
Induction of ETS-1 and ETS-2 transcription factors is required for thyroid cell transformation.
The proteins of the Ets family are transcription factors involved in signal transduction, cell cycle progression, and differentiation. In this study, we report that thyroid cell neoplastic transformation is associated with a dramatic increase in ETS transcriptional activity, which is dependent on the accumulation of Ets-1, Ets-2, and other Ets-related proteins. Inhibition of ETS transactivation activity by the Ets-dominant negative construct (Ets-Z) induced programmed cell death in human thyroid carcinoma cell lines but not in normal thyroid cells. Apoptotic cell death induced by Ets-Z was dependent on the reduction of c-MYC protein levels, because it was prevented by overexpression of c-myc. Taken together, these data indicate that the induction of Ets-1 and Ets-2 transcription factors plays a pivotal role in thyroid cell neoplastic transformation.
Apoptosis↗
Alteration of cell cycle kinase complexes in human papillomavirus E6- and E7-expressing fibroblasts precedes neoplastic transformation.
Expression of viral oncoproteins results in the loss of cell cycle checkpoint control and the accumulation of chromosomal abnormalities. Expression of both human papillomavirus type 16 oncoproteins, E6 and E7, in normal human fibroblasts completely dissociates p21 and proliferating cell nuclear antigen from the quarternary cyclin-cyclin-dependent kinase (CDK) complexes present in normal cells, causes disruption of the cyclin D-CDK4 complex and replacement with a CDK4-p16 complex, and leaves binary complexes of cyclin B1-CDC2 and cyclin A-CDK2 intact. These results are identical to those observed in fully transformed cells. The expression of the individual oncoproteins dramatically affects the association of proliferating cell nuclear antigen into the complexes while leaving the total cellular levels unaltered. Expression of low-risk human papillomavirus has no effect on cyclin complexes. These findings provide evidence for the gross alteration of cyclin-CDK complexes in preneoplastic cells and links this alteration to the loss of genomic stability.
Carrier Proteins↗
Fibronectin distribution pattern and the three-dimensional growth behavior of mammalian cells under anchorage-independent conditions.
Several types of normal diploid cells, established "normal" cells, and transformed cells of human and rodent origin have been studied with reference to cell surface fibronectin distribution and their anchorage-independent growth behavior. All cell types that showed intercellular and fibrillar surface fibronectin were anchorage-dependent for growth. Lack of surface fibrillar fibronectin in spontaneously or virus-transformed cells and cells of neoplastic origin was accompanied by anchorage-independent growth potential. The degree of three-dimensional organization of cells under anchorage-independent growth conditions was dependent on the amount of intercellular fibronectin. The significance of these observations to in vivo tumor growth is discussed.
Animals↗
Correlation between the rates of aerobic glycolysis and glucose transport, unrelated to neoplastic transformation, in a series of BALB 3T3-derived cell lines.
The relationship between transformation, lactate production, and glucose transport was examined in a series of ten cell lines consisting of subclones of BALB 3T3 A31 cells and viral and chemical transformants of either the subclones or the original A31 line. Comparisons were made over a relatively narrow range of cell densities to minimize changes in the biochemical parameters during growth. A nitroquinoline oxide (NQT-3T3-714) and a temperature-sensitive Kirsten sarcoma virus (tsKi-3T3-714) transformant of subclone 714 exhibited transformed phenotypes with respect to morphology and growth properties, but their rates of lactate production and 2-[3H]deoxy-D-glucose (deoxyglucose) uptake were similar to those of the parent cells. 2- to 5-fold in these transformants, showing that there was no defect in the enzymes of this pathway. At a temperature nonpermissive for transformation of tsKi-3T3-714, lactate production by this line did not decrease relative to the rate of the parent cells. Another transformant, Ki-3T3-234, had a glycolytic rate which was 4 to 5 times greater than that of the low lactate producers while other transformants exhibited intermediate rates, and the rate of a third nontransformed 3T3 A31 subclone, K-1-1, was comparable to the rate of Ki-3T3-234. The rates of [3H]deoxyglucose uptake by this series of cells were closely proportional to their glycolytic rates rather than to their state of transformation. Increasing glycolysis by oligomycin or dinitrophenol treatment, however, did not cause a concomitant increase in sugar uptake. Neither glycolysis nor deoxyglucose uptake in the high-lactate producer (Ki-3T3-234) was inhibited by ouabain, suggesting that Na+-K+-adenosinetriphosphatase is not a regulatory of these functions in 3T3 cells. In 3T3-derived cells, it appears that the rates of glycolysis and glucose uptake may be regulated in tandem under some conditions and that neither process is an obligatory consequence of neoplastic transformation
4-Nitroquinoline-1-oxide↗
Neoplastic transformation of cells by soluble but not particulate forms of metals used in orthopaedic implants.
Recent developments in cell culture techniques have made it possible to study the cellular mechanisms involved in carcinogenesis and to apply these methods as screening tools in vitro. This study investigated and compared the ability of the metals most commonly used in orthopedic implants to induce toxicity and neoplastic transformation in the C3H10T1/2 mouse fibroblast cell line. Eight metals (cobalt, chromium, nickel, iron, molybdenum, aluminium, vanadium and titanium) and their alloys (stainless steel, cobalt-chrome alloy and titanium alloy) were tested, both as soluble salts and as solid particles. There were marked differences between the various metals in terms of both toxicity and transforming ability. Significant increases in the incidence of cell transformation were seen with soluble forms of cobalt, chromium, nickel and molybdenum but not with iron, aluminium, vanadium or titanium. For most of the metals. transforming ability was directly related to toxicity, although this correlation did not hold for either molybdenum or vanadium. The physical form of the metal was critically important in determining its effects, and transformation occurred only with soluble metal salts.
Alloys↗
Clonal chromosomal aberrations in simian virus 40-transfected human thyroid cells and in derived tumors developed after in vitro irradiation.
In vitro model cell systems are important tools for studying mechanisms of radiation-induced neoplastic transformation of human epithelial cells. In our study, the human thyroid epithelial cell line HTori-3 was analyzed cytogenetically following exposure to different doses of alpha- and gamma-irradiation and subsequent tumor formation in athymic nude mice. Combining results from G-banding, comparative genomic hybridization, and spectral karyotyping, chromosome abnormalities could be depicted in the parental line HTori-3 and in nine different HTori lines established from the developed tumors. A number of chromosomal aberrations were found to be characteristic for simian virus 40 immortalization and/or radiation-induced transformation of human thyroid epithelial cells. Common chromosomal changes in cell lines originating from different irradiation experiments were loss of 8q23 and 13cen-q21 as well as gain of 1q32-qter and 2q11.2-q14.1. By comparison of chromosomal aberrations in cell lines exhibiting a different tumorigenic behavior, cytogenetic markers important for the tumorigenic process were studied. It appeared that deletions on chromosomes 9q32-q34 and 7q21-q31 as well as an increased copy number of chromosome 20 were important for the tumorigenic phenotype. A comparative breakpoint analysis of the marker chromosomes found and those observed in radiation-induced childhood thyroid tumors from Belarus revealed a coincidence for a number of chromosome bands. Thus, the data support the usefulness of the established cell system as an in vitro model to study important steps during radiation-induced malignant transformation in human thyroid cells.
Animals↗
Neoplastic transformation of human cells in culture associated with deficient repair of light-induced chromosomal DNA damage.
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Caffeine↗
Quantitative neoplastic transformation in C3H/10T1/2 cells.
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Animals↗
Serum-induced chromosome damage and neoplastic transformation of mouse cells in vitro.
In previous studies, mouse cells grown in medium supplemented with horse serum (HS) developed more chromosomal aberrations and underwent malignant transformation earlier than cells from the same pool grown with fetal bovine serum (FBS) supplement. In the present study cells derived from C3Hf/HeN mouse embryos were grown in medium NCTC-135 supplemented with various combinations of large- and small-molecule fractions of HS and FBS in an effort to determine the effective components. The results indicate that the large-molecule fraction of HS (mare or stallion) produces alterations in chromosome number and structure. HS is also shown to cause chromatid breaks and exchanges at or near the centromere in contrast to fluorescent-light-induced breaks and exchange at or near the centromere in contrast to fluorescent-light-induced breaks which occur randomly along the chromatid. However, efforts to control completely chromosome stability and malignant transformation through the use of large- and small-molecule fractions of HS and FBS or combinations thereof were unsuccessful. In connection with this study, diagnosis of malignant transformation in vitro was made by a direct sampling method based on cytologic criteria previously described and documented. With one exception, the diagnoses of 11 different cell lines were consistent with results of in vivo assays.
Animals↗
Solubilization, cellular uptake, and activity of beta-carotene and other carotenoids as inhibitors of neoplastic transformation in cultured cells.
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Animals↗