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PubMed1989

Neoplastic cell transformation by high-LET radiation: molecular mechanisms.

Experimental data on molecular mechanisms are essential for understanding the bioeffects of radiation and for developing biophysical models, which can help in determining the shape of dose-response curves at very low doses, e.g., doses less than 1 cGy. Although it has been shown that ionizing radiation can cause neoplastic cell transformation directly, that high-LET heavy ions in general can be more effective than photons in transforming cells, and that the radiogenic cell transformation is a multi-step process [correction of processes], we know very little about the molecular nature of lesions important for cell transformation, the relationship between lethal and transformational damages, and the evolution of initial damages into final chromosomal aberrations which alter the growth control of cells. Using cultured mouse embryo cells (C3H10T1/2) as a model system, we have collected quantitative data on dose-response curves for heavy ions with various charges and energies. An analysis of these quantitative data suggested that two DNA breaks formed within 80 angstroms may cause cell transformation and that two DNA breaks formed within 20 angstroms may be lethal. Through studies with restriction enzymes which produce DNA damages at specific sites, we have found that DNA double strand breaks, including both blunt- and cohesive-ended breaks, can cause cell transformation in vitro. These results indicate that DNA double strand breaks can be important primary lesions for radiogenic cell transformation and that blunt-ended double strand breaks can form lethal as well as transformational damages due to misrepair or incomplete repair in the cell. The RBE-LET relationship is similar for HGPRT gene mutation, chromosomal deletion, and cell transformation, suggesting common lesions may be involved in these radiation effects. The high RBE of high-LET radiation for cell killing and neoplastic cell transformation is most likely related to its effectiveness in producing DNA double strand breaks in mammalian cells. At present the role of oncogenes in radiation cell transformation is unclear.

Animals↗
PubMed1986

Dose protraction studies with low- and high-LET radiations on neoplastic cell transformation in vitro.

A major objective of our heavy-ion research is to understand the potential carcinogenic effects of cosmic rays and the mechanisms of radiation-induced cell transformation. During the past several years, we have studied the relative biological effectiveness of heavy ions with various atomic numbers and linear energy transfer on neoplastic cell transformation and the repair of transformation lesions induced by heavy ions in mammalian cells. All of these studies, however, were done with a high dose rate. For risk assessment, it is extremely important to have data on the low-dose-rate effect of heavy ions. Recently, with confluent cultures of the C3H10T1/2 cell line, we have initiated some studies on the low-dose-rate effect of low- and high-LET radiation on cell transformation. For low-LET photons, there was a decrease in cell killing and cell transformation frequency when cells were irradiated with fractionated doses and at low dose rate. Cultured mammalian cells can repair both subtransformation and potential transformation lesions induced by X rays. The kinetics of potential transformation damage repair is a slow one. No sparing effect, however, was found for high-LET radiation. There was an enhancement of cell transformation for low-dose-rate argon (400 MeV/u; 120 keV/micrometer) and iron particles (600 MeV/u; 200 keV/micrometer). The molecular mechanisms for the enhancement effect is unknown at present.

Animals↗
PubMed1977

Antigenic distinctions of glycoproteins in plasma and mitochondrial membranes of lymphoid cells neoplastically transformed by simian virus 40.

Highly purified plasma membranes from hamster lymphocytes transformed by simian virus 40 (GD 248) were compared with the membranes of normal cells by crossed immune electrophoresis, crossed-line immune electrophoresis, and bidimensional isoelectric focusing-immune electrophoresis. Antiserum raised by inoculation of guinea pigs with GD 248 membranes was used as serologic reagent, either directly or after absorption with membranes from normal cells. Bidimensional immune electrophoresis reveals the presence in the plasma membranes of GD 248 cells of at least three antigens not detectable in the membranes from the normal cell population. At least two of these are also present in the mitochondrial membranes of GD 248 cells, but none could be detected in membranes of embryonic fibroblasts. Bidimensional isoelectric focusing-immune electrophoresis indicates that the distinctive antigens of the GD 248 membranes are glycoproteins.

Animals↗
PubMed1976

Membranes of normal hamster lymphocytes and lymphoid cells neoplastically transformed by simian virus 40. I. High-yield purification of plasma membrane fragments.

In this first paper of a series comparing the membranes of normal lymphocyte populations from male outbred Syrian hamsters with those of neoplastic transformants (GD 248) induced by simian virus 40, a method is described for the isolation of representative plasma membrane (PM) fragments from both cell types. Multiple criteria were used to monitor the purity and yield of PM material after cell disruption by nitrogen cavitation and after membrane fractionation by a combination of differential centrifugation and isopyknic ultracentrifugation in dextran density gradients. Lactoperoxidase-catalyzed radioiodination before cell disruption was used as an extrinsic surface marker; Na+,K+-activated ATPase, as well as alkaline phosphatase, was used as intrinsic functional PM markers. The distribution of nuclei, mitochondria, lysosomes, and endoplasmic reticulum (ER) during fractionation was monitored by the measurement of DNA, succinate dehydrogenase and monoamine oxidase, beta-glucuronidase and glucose-6-phosphatase, and NADH:lipoamide oxidoreductase, respectively. According to the three PM markers employed, a 15- to 20-fold purification (over homogenate) and a PM yield of about 65% were obtained for both cell categories, with negligible contamination by DNA, mitochondria, lysosomes, and er. The procedure also allowed recovery of 60% of the mitochondria free of other cell elements.

Adenosine Triphosphatases↗
PubMed1977

Differences between the structural dynamics of plasma membranes of normal hamster lymphocytes and lymphoid cells neoplastically transformed by simian virus 40 as revealed by laser Raman spectroscopy.

The Raman spectra of highly purified plasma membranes from SV40-transformed GD248 lymphocytes have been compared with the spectra of the membranes of normal cells over the spectral region 100 cm-1 to 3010 cm-1. Striking differences between the two membrane categories were observed in the thermal response of the CH-stretching and acoustical regions. Analysis of CH-stretching shows that the membranes of normal cells exhibit a thermal transition centered at 7 degrees and approximately 5 degrees wide. The membranes of GD248 cells, in contrast, show a lipid transition centered at -5 degrees and 12-18 degrees wide. Analysis of the acoustical region yields equivalent results. The membrane proteins of normal membranes undergo a large thermotropic transition, starting at 39 degrees (sample temperatures), whereas this transition begins at 23 degrees with GD248 plasma membranes. The results suggest the possibility that SV40-specific membrane proteins may modify the collective thermotropic behavior of both normal membrane proteins and membrane lipids.

Animals↗
PubMed1976

Membranes of normal hamster lymphocytes and lymphoid cells neoplastically transformed by simian virus 40. II. Plasma membrane proteins analyzed by dodecyl sulfate-polyacrylamide gel electrophoresis and two-dimensional immune electrophoresis.

The plasma membrane proteins of lymphocyte populations from normal outbred Syrian hamsters were compared with those of a neoplastic transformant line (GD 248) induced by simian virus 40. Both quantitative and qualitative differences were observed. Gradient dodecyl sulfate-polyacrylamide gel electrophoresis revealed 12 major protein components in the membranes of both cell populations. Both membrane categories also contained small amounts of immunoglobulin. Compared with the membranes of the reference cell population, GD 248 membranes showed a 60% decrease of approximately 210,000 daltons of glycoprotein; a 10% reduction of about a 48,000-dalton band and virtually complete loss of a 15,000-dalton component concomitant with a 57% increase in a 52,000-dalton band; fusion to two subcomponents (mol wt approximately 250,000 daltons); and emergence of approximately 120,000 and 30,000 daltons glycoproteins. In addition, the relative mobility of an approximately 95,000-dalton component increased by roughly 0.02 U. Crossed immune electrophoresis in Trition X-100 with heterologous antiserum against GD 248 microsomal membranes revealed both a new component with a high level of electrophoretic mobility and intensification and additional heterogeneity in a strongly antigenic component with a low level of electrophoretic mobility. Crossed-line immune electrophoresis indicated that at least two antigens in the membranes of GD 248 cells lacked the membranes of the reference cell population.

Animals↗
PubMed1996

Some characteristics of neoplastic cell transformation in transgenic mice.

The role of the expression of different cellular genes and viral oncogenes in malignant cell transformation is discussed. We pay special attention to the role of the genes for growth factors and their receptors and homeobox genes in oncogenesis. Based on both the literature and our own data, specific features of tumors developed in transgenic mice are discussed. All of these data are used to analyze current theories of multistep oncogenesis and the stochastic component in this process. We suggest that all known evidence about the mechanisms of oncogenesis be used in studying the problem at various structural and functional levels in an organism. The chapter shows that transgenic mice are a most suitable model for studying various aspects of malignant transformation from the molecular to the organismal and populational levels.

Animals↗
PubMed1983

Relationship of neoantigens induced by 3-methyl-cholanthrene treatment of Syrian hamster embryo cells to antigens expressed on fetal and 3-methyl-cholanthrene-transformed neoplastic cells.

Neoantigen(s) induced on Syrian hamster cells during chemical carcinogenesis are also found on fetal and neoplastic hamster cells. 46 neoplastic cell lines independently isolated from colonies of 3-methylcholanthrene (3-MCA) in vitro-transformed hamster cells growing in semi-solid agar medium were assayed for expression of neoantigens recognized by hamster antisera to primary cultured late-term (15 days) hamster embryo cells treated for 18 h with 10 micrograms 3-MCA/ml. Ratios of the binding of this sera compared to solvent control sera ranged from 0.7 to 2.1 in terms of cpm bound. Only four of the 46 neoplastic cell lines exhibited significant (P less than 0.05) neoantigen expression. No correlation existed between the concentration of 3-MCA used to establish the neoplastic cell line and expression of the neoantigen(s). Absorption of the sera with these four highly reactive neoplastic cell lines and mid-term (10 days) embryo cells indicated that the neoantigen(s) recognized were common to the four reactive neoplastic cell lines and the mid-gestation fetal cells. The occurrence of early persistent immunogenic cell-surface alterations during in vitro carcinogenesis provides an approach to isolation of preneoplastic populations and provides potential target structures for the inhibition of carcinogenesis.

Animals↗
PubMed1982

Neoplastic transformation of rabbit cells by murine sarcoma viruses.

Neoplastic transformation of rabbit cells by Kirsten murine sarcoma virus (Ki-MSV), the Ki-MSV pseudotype of baboon endogenous virus (Ki-MSV[BaEV]) and the Moloney-MSV pseudotype of feline leukemia virus (M-MSV[FeLV]) is reported. Rabbit cells can be readily transformed by Ki-MSV, Ki-MSV(BaEV) and M-MSV(FeLV). Rabbit cells transformed by Ki-MSV and M-MSV(FeLV) were found to be virus producers, whereas those transformed by Ki-MSV(BaEV) were nonproducers (NP). The NP cells were obtained by simply infection rabbit cells with Ki-MSV(BaEV) and subculturing the infected cells. Although the morphologically altered NP cells did not produce infectious virus or murine leukemia virus antigen, they did contain a rescuable MSV genome. All of the transformed cells formed colonies in soft agar, grew to high saturation densities and produced tumors when transplanted into nude mice. The Ki-MSV and M-MSV(FeLV)-transformed cells produced tumors in newborn WH/J rabbits, thus providing an important tool for studying tumor immunity in the rabbit.

Animals↗
PubMed1980

Plasminogen activator synthesis accompanying chemical carcinogen-induced in vitro transformation of Syrian hamster and guinea-pig fetal cells.

The production of the extracellular protease, plasminogen activator, in relationship to growth in semi-solid medium and tumorigenicity has been studied in Syrian hamster embryo and strain 2 guinea-pig embryo cell culture models of chemical carcinogenesis. Whereas normal hamster and guinea-pig embryo cells had negligible levels of plasminogen activator, neoplastically transformed cells derived from cultures exposed to chemical carcinogens had high levels of plasminogen activator and grew as progressively enlarging colonies in soft agar. The development of plasminogen activator secretion in relation to neoplastic transformation was further studied in the guinea-pig cells where the latent period between carcinogen exposure and neoplastic transformation ranged from 4 months to more than one year. The production of plasminogen activator in this system also exhibited a long latent period, and acquisition of extracellular plasminogen activator correlated temporally with growth in agar and tumorigenicity. Plasminogen activator and growth in semi-solid agar in concert are useful markers for identification of neoplastic cells transformed in culture following exposure to a chemical carcinogen.

Animals↗
PubMed1981

Responsiveness of fetal rat brain cells to glia maturation factor during neoplastic transformation in cell culture.

The effect of partially purified extracts from adult pig brains containing a glia maturation protein factor (BE) has been investigated on neural cells during carcinogenesis. Pregnant BD IX-rats were given a single transplacental dose of the carcinogen ethylnitrosourea (EtNU) on the 18th day of gestation. The brains of the treated fetuses were transferred to cell culture and underwent neoplastic transformation with a characteristic sequence of phenotypic alterations which could be divided into five different stages. During the first 40 days after explantation (stage I & II) BE induced morphological differentiation of epitheloid neural cells into astrocytes. This occurred in carcinogen treated cells as well as in untreated control cultures. At the same time cells with astrocyte morphology showed accumulation of glial fibrillary acidic protein (GFA) as tested by indirect immunofluorescence with monospecific antibodies against GFA. Thereafter, in the EtNU pre-treated cultures an increased number of cells with astrocyte morphology was seen, and BE further increased the number of cells with long cytoplasmic processes. Control cells were GFA negative, while some few strongly, as well as many weakly, positive cells were seen after treatment with BE (stage III). At the later stages of neoplastic transformation the effect of BE became gradually less, and in tumourigenic cells which occurred after about 200-300 days, only a slight morphological change took place in a few cell lines. No appreciable effect on GFA-content was seen any longer, although some few weakly GFA positive cells could be observed in all permanent cell lines. Fetal rat brain cells therefore seem to become less responsive to this differentiation inducer during neoplastic transformation in cell culture.

Animals↗
PubMed2006

Neoplastic transformation of a human hybrid cell line by alpha particles in relation to mammography X rays.

The hybrid cell line CGL1 is the only cell line which allows quantitation of neoplastic transformation in human cells. Hybrid cells were exposed to 3.4 MeV alpha particles or to mammography X rays (29 kV(p)) and both survival and neoplastic cell transformation were assayed. For comparison, previously published data obtained with 200 kV(p) X rays are also included. Alpha particles were significantly more efficient than 29 kV(p) X rays in cell killing. Surprisingly, the efficiency of mammography X rays for the induction of neoplastic cell transformation was close to that observed for alpha particles.

Alpha Particles↗
PubMed2000

Rat protein tyrosine phosphatase eta suppresses the neoplastic phenotype of retrovirally transformed thyroid cells through the stabilization of p27(Kip1).

The r-PTPeta gene encodes a rat receptor-type protein tyrosine phosphatase whose expression is negatively regulated by neoplastic cell transformation. Here we first demonstrate a dramatic reduction in DEP-1/HPTPeta (the human homolog of r-PTPeta) expression in a panel of human thyroid carcinomas. Subsequently, we show that the reexpression of the r-PTPeta gene in highly malignant rat thyroid cells transformed by retroviruses carrying the v-mos and v-ras-Ki oncogenes suppresses their malignant phenotype. Cell cycle analysis demonstrated that r-PTPeta caused G(1) growth arrest and increased the cyclin-dependent kinase inhibitor p27(Kip1) protein level by reducing the proteasome-dependent degradation rate. We propose that the r-PTPeta tumor suppressor activity is mediated by p27(Kip1) protein stabilization, because suppression of p27(Kip1) protein synthesis using p27-specific antisense oligonucleotides blocked the growth-inhibitory effect induced by r-PTPeta. Furthermore, we provide evidence that in v-mos- or v-ras-Ki-transformed thyroid cells, the p27(Kip1) protein level was regulated by the mitogen-activated protein (MAP) kinase pathway and that r-PTPeta regulated p27(Kip1) stability by preventing v-mos- or v-ras-Ki-induced MAP kinase activation.

Animals↗