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PubMed1994

A method for distinguishing human and mouse cells in solid tumors using in situ hybridization.

A common technique used in the study of human malignancies involves the inoculation of nude mice with human neoplastic cells. It is usually assumed that the tumor arising is composed predominantly of human cells with mouse tissue present only to provide minimal stromal support. Several reports, however, have shown evidence of host cell neoplastic transformation. Therefore, in order to effectively study and characterize such xenografts, it is important to establish the relative involvement of human and mouse cells. In the present study, a method for easily distinguishing human and mouse cells is described. The method involves in situ hybridization of formalin-fixed tissues using DIG-labeled oligomer probes which correspond to species-specific portions of Alu sequences. This method can be applied to archival material either as a means of confirming that the tissue taken from nude mice xenografts is predominantly human or as a vehicle for studying the mechanisms of host cell neoplastic transformation and their relevance to human malignant spread. The proposed technique may also serve as a basis for other in situ applications, particularly those involving formalin-fixed tissues and oligomer probes.

Animals↗
PubMed1980

Toward a model for the molecular genetics of carcinogenesis in rats.

Cultured rat embryo cells are resistant to neoplastic transformation by chemical carcinogens unless they are extensively subcultured or infected with a murine leukemia virus (MuLV) first. We found that, in normal cultured cells, MuLV activates expression of rat genes that are the progenitors of sarcoma virus genes, but not those of endogenous "leukemia" virus. Elevated levels of sarcoma virus-related RNA in normal cells infected with MuLV were indistinguishable from the levels in cells transformed spontaneously or by a carcinogen or a sarcoma virus. Because of previous reports that some carcinomas in rats also contain elevated levels of sarcoma virus-related RNA, we believe these events can be explained by a molecular genetic model which may be generally valid for initiation of carcinogenesis. The basic elements of the model are: transcriptional activation of all the multiple copies of normal rat progenitors of sarcoma virus genes is required before cellular transformation can be initiated, and initiation occurs when a spontaneous or induced mutation in any one active copy of these same genes generates a dominant transforming function.

Animals↗
PubMed1979

Overview and status of in vitro transformation.

The development of standardized assay procedures has permitted the exploitation of cell culture systems as bioassay tools for the detection of chemical carcinogens. These systems fall generally into 3 classes: diploid cell strains, Syrian hamster embryo cells; cell lines, mouse BALB/c-3T3 and mouse C3H-10T1/2; and cells+virus, Fischer rat cells infected with Rauscher leukemia virus and Syrian hamster embryo cells infected with adenovirus. The results accumulated to date show a good correlation between transformation response in cell culture and carcinogenicity of chemicals in whole animal studies. The major advantages of these systems are their relative brevity (10 days-6 weeks) and resultant low costs, their agreement with whole animal bioassays, and their direct biological relevance to the carcinogenic process. The present major disadvantages are the uncertain nature of the metabolic capabilities of the target cells and the lack of a metabolic activation system that is reliable and adaptable for routine bioassays. The development of epithelial cell systems such as breast, liver, lung, and skin may solve the problem of carcinogen metabolism as well as provide target cells that are representative of major organ sites for cancer in man. The rational use of cell culture bioassays for neoplastic transformation is a valuable component of the toxicological armamentarium to assess risk to humans from exposure to chemicals.

Adenoviridae↗
PubMed1988

Neoplastic transformation of mouse mammary epithelial cells by in vitro exposure to N-methyl-N-nitrosourea.

High-efficiency neoplastic transformation of mouse mammary epithelial cells in primary collagen gel culture was induced by N-methyl-N-nitrosourea (MNU). Mammary epithelial cells, isolated from virgin BALB/c mice, were embedded within collagen gels and grown in a serum-free medium containing prolactin, progesterone, and linoleic acid. The cells were then treated with MNU on day 3 of culture and subsequently at weekly intervals for up to 4 weeks. Eleven to 14 days after the final carcinogen treatment, the cells were removed from the collagen gels and injected into the cleared mammary fat pads of syngeneic hosts to assay for transformed cell populations. A single exposure or multiple exposures of these cells to MNU was effective in inducing tumorigenic cells that produced palpable tumors as early as 6 weeks after transplantation. Two treatments with MNU (100 micrograms/ml) were optimal for neoplastic transformation and produced tumors in 79% of the injected fat pads. All the tumors originated at the site of injection and had extensive central necroses. Histological examination indicated that the tumors were mammary carcinomas. Secondary transplantation of tumor pieces into intact mammary glands produced palpable carcinomas of the same histology within 1-8 weeks. Control cells cultured for the same periods of time as MNU-treated cells produced only ductal outgrowths that were morphologically similar to those found in the mammary glands of adult virgin hosts. This system provides a distinct means to study the mechanism of mammary neoplastic transformation at cellular and molecular levels.

Animals↗
PubMed1999

Uracil misincorporation, DNA strand breaks, and gene amplification are associated with tumorigenic cell transformation in folate deficient/repleted Chinese hamster ovary cells.

Clinical and experimental evidence has linked nutritional folic acid status to both anti- and procarcinogenic activity. Folate supplementation of normal cells appears to have a protective effect; however, folate supplementation of initiated cells may promote neoplastic progression. Given these considerations, the present series of experiments examines alterations in DNA metabolism and cumulative DNA lesions using an in vitro model of folate deprivation and repletion. DNA repair-deficient CHO-UV5 cells were cultured in Ham's F-12 medium or in custom-prepared Ham's F-12 medium lacking in folic acid, thymidine and hypoxanthine for a period of 18 days without cell passage. The results indicated that progressive folate and nucleotide depletion leads to a significant increase in the ratio of dUTP/dTTP and to the misincorporation of uracil into DNA. These alterations were accompanied by growth inhibition, DNA strand breaks, abasic sites and phenotypic abnormalities. After 14 days in culture, there was significant increase in gene amplification potential in the chronically folate-deficient cells, but no significant increase in anchorage-independent growth or in neoplastic transformation. Acute folate repletion of the deficient cells was used as a proliferative stimulus under conditions of dNTP pool imbalance and multiple lesions in DNA. A further increase in gene amplification was accompanied by anchorage-independent growth and neoplastic cell transformation as evidenced by aggressive tumor growth in Balb/c nu/nu mice. Using a sensitive in vitro model system, these results emphasize the essentiality of folic acid for de novo nucleotide synthesis and the integrity of the DNA. However, the in vivo relevance, especially in terms of tumorigenic potential, is not clear.

Animals↗
PubMed1987

Fate and expression of simian virus 40 DNA after introduction into murine cells under nonselective conditions.

When SV40 infects mouse cells, it does not replicate but instead causes neoplastic transformation of a small percentage of the cells. It is unknown, however, what happens to the virus in those cells that do not become transformed. We introduced SV40 into mouse cells by nonselective means, either by cotransfection of SV40 DNA with a selectable marker or by random cloning of SV40-infected cells. We analyzed the fate of viral DNA sequences, expression of T antigens, and transformation properties of these cells. We found that, upon infection, viral DNA integration occurs at a frequency that is at least 10-fold higher than the frequency of transformation. The majority of these cells are not transformed due to lack of expression of T antigen. One cell line which expresses a truncated T antigen is not transformed. We have mapped the viral sequences in the genome of these cells and find that integration in the large T intron is probably responsible for the defect. Lack of transformation can therefore be attributed to both cellular and viral factors, namely, introduction of viral DNA into cells that are resistant to transformation or integration of viral DNA in such a way that T antigen expression is prohibited.

Animals↗
PubMed1991

Neoplastic transformation of C3H/10T1/2 cells following exposure to 120-Hz modulated 2.45-GHz microwaves and phorbol ester tumor promoter.

Some recent epidemiological studies have shown a positive association between cancer incidence and exposure to electromagnetic (EM) fields. Evidence from in vitro studies indicates that this effect could be due to synergistic interaction between EM fields and tumor promoters. However, no dose-response data related directly to carcinogenesis have been published. In this study, actively growing cultures of C3H/10T1/2 cells were exposed for 24 h to 2.45-GHz microwaves pulse-modulated at 120 Hz. Conditions of EM-field exposure were designed to simulate low-field exposures (specific absorption rate 0.1, 1, or 4.4 W/kg; the corresponding peak amplitudes were electric field 18, 56, or 120 V/m, magnetic field 0.09, 0.27, or 0.56 muT, respectively). In separate experiments, a 24-h EM-field exposure at 4.4 W/kg was preceded or followed by X irradiation at 0.5, 1, or 1.5 Gy. Cells were assayed for cell survival and neoplastic transformation with or without post-treatment administration of 0.1 micrograms/ml of 12-O-tetradecanoylphorbol-13-acetate (TPA) for the duration of the assay. The EM fields alone had no effect on cell survival or induction of neoplastic transformation. However, enhancement of transformation due to EM fields plus TPA was highly significant and ranged up to a level equivalent to that produced by 1.5 Gy of X rays. The frequency of neoplastic transformation was dependent on the level of EM exposure and was additive with doses of X rays given as a cocarcinogen.

Animals↗
PubMed2003

Cerebral chemical dominance and neural regulation of cell division, cell proliferation, neoplastic transformation, and genomic function.

The study assessed the isoprenoid pathway, digoxin synthesis, and neurotransmitter patterns in individuals of differing hemispheric dominance, neurogenetic disorders, and neoplasms. The HMG CoA reductase activity, serum digoxin, magnesium, tryptophan catabolites, tyrosine catabolites, and RBC membrane Na+-K+ ATPase activity were measured in individuals of differing hemispheric dominance. The digoxin status, membrane Na+-K+ ATPase activity, and serum magnesium were assessed in Huntington's disease, trisomy 21, glioblastoma multiforme, and non-Hodgkin's lymphoma (high grade lymphoma). The results showed that right hemispheric, chemically dominant individuals had elevated digoxin synthesis, increased tryptophan catabolites, and reduced tyrosine catabolites, and membrane Na+-K+ ATPase with hypomagnesemia. Left hemispheric, chemically dominant individuals had the opposite patterns. In neurogenetic disorders and neo plasms also hyperdigoxinemia induced membrane Na+-K+ ATPase inhibition, and hypomagnesemia similar to right hemispheric chemical dominance could be demonstrated. The role of hemispheric chemical dominance and hypothalamic digoxin secretion play a key role in the regulation of cell differentiation/proliferation and genomic function. Ninety-five percent of the patients with neurogenetic disorders and neoplasms were right-handed/left hemispheric dominant by dichotic listening test. However, all of them had biochemical patterns similar to right hemispheric chemical dominance. Hemispheric chemical dominance has no correlation to cerebral dominance detected by handness/dichotic listening test.

Adult↗
PubMed1981

A cellular protein that associates with the transforming protein of Rous sarcoma virus is also a heat-shock protein.

A single viral protein (pp60src) mediates neoplastic transformation of cells infected with Rous sarcoma virus. Immunoprecipitation of pp60src has revealed two cellular proteins (Mr 50,000 and 89,000) that appear to associate with pp60src in a specific manner. Neither of the cellular proteins has been well characterized, but it is thought that both may participate in the function of pp60src. Treatment of avian cells with unphysiological temperature or certain chemical agents amplifies the production of several proteins in the manner of the "heat shock" response earlier described for Drosophila. We report here that one of these proteins, with a molecular weight of 89,000 is identical to the 89-kilodalton protein found associated with pp60src. The 89-kilodalton protein is a major constituent of both uninfected and infected cells, even in the absence of inducing agents, but only a small fraction of this protein appears to associate with pp60src in cells transformed by Rous sarcoma virus. The complex containing pp60src and the 89-kilodalton protein can be precipitated by an immune reaction involving pp60src alone. The complexed form of the 89-kilodalton protein did not react directly with antibodies but regained its reactivity subsequent to release from the complex. We conclude that the 89-kilodalton protein is bound to pp60src in a relatively stable complex. We suggest that the 89-kilodalton protein may have overlapping roles in viral oncogenesis and the heat shock response, and that evidence on the function of the protein in either setting may illuminate its function in the other. In addition, it may prove profitable to search for other overlaps between the cellular response to heat shock and the neoplastic transformation of cells by pp60src.

Animals↗
PubMed1987

Transforming growth factors and control of neoplastic cell growth.

Transforming growth factors (TGFs) are peptides that affect the growth and phenotype of cultured cells and bring about in nonmalignant fibroblastic cells phenotypic properties that resemble those of malignant cells. Two types of TGFs have been well characterized. One of these, TGF alpha, is related to epidermal growth factor (EGF) and binds to the EGF receptor, whereas the other, TGF beta, is not structurally or functionally related to TGF alpha or EGF and mediates its effects via distinct receptors. TGF beta is produced by a variety of normal and malignant cells. Depending upon the assay system employed, TGF beta has both growth-inhibitory and growth-stimulating properties. Many of the mitogenic effects of TGF beta are probably an indirect result of the activation of certain growth factor genes in the target cell. The ubiquitous nature of the TGF beta receptor and the production of TGF beta in a latent form by most cultured cells suggests that the differing cellular responses to TGF beta are regulated either by events involved in the activation of the factor or by postreceptor mechanisms. The combined effects of TGF beta with other growth factors or inhibitors evidently play a central role in the control of normal and malignant cellular growth as well as in cell differentiation and morphogenesis. Since transforming growth factor as a concept has partially proven misleading and insufficient, there is a need to find a new nomenclature for these regulators of cellular growth and differentiation.

Animals↗
PubMed1992

Adaptive evolution of degrees and kinds of neoplastic transformation in cell culture.

Human cancers undergo protracted complex development from benign to malignant states, as most thoroughly documented in the mole-to-melanoma sequence. The early stages of the sequence tend to redifferentiate into normal tissues; the later stages progress to ever increasing multiplication and malignancy. When placed under the growth constraint of either crowding or low serum concentrations, the NIH 3T3 line of mouse cells readily undergoes transformation, expressed in the development of foci of cells that continue to multiply at confluence when the rest of the population has stopped. If the nontransformed cells are maintained for 3 months by frequent low-density passages in high concentrations of calf serum, they gradually lose the capacity to undergo transformation when the constraints are applied. The same conditions of passage have been used to reverse the transformation, both processes resembling in principle the reversal of the early stages of the mole-to-melanoma sequence. When the frequent low-density passages are made in high concentrations of fetal bovine serum, which supports a slightly lower growth rate than an equal concentration of calf serum, the degree of transformation is gradually increased, so that the foci become more numerous, broader, and thicker, reaching a maximum in successive assays at about 3 months of passaging. A diversity of focal morphologies is sporadically generated in the calf serum passage by exposing the cells to various concentrations of calf serum for 14 days of growth and confluency before assaying them. The dependence of the number, density, and morphology of foci on the environment in which the cells had been grown before assay reinforces the evidence that the transformation is an epigenetic process. The fact that these effects develop in culture gradually over an extended period of time suggests parallels to the characteristically long-term early regression and later progression, as well as the diversity of the mole-to-melanoma sequence, and may also be representative of other cancers.

3T3 Cells↗
PubMed1979

Uninfected vertebrate cells contain a protein that is closely related to the product of the avian sarcoma virus transforming gene (src).

Neoplastic transformation of cell by avian sarcoma virus is mediated by a single viral gene (src), which encodes a phosphoprotein (pp60src) with the enzymatic activity of a protein kinase. The DNAs of vertebrate species contain a highly conserved homologue of src that is also represented in the polysomal RNA of uninfected cells and, hence, may specify a normal cellular protein. We have used antisera directed against pp60src to isolate a closely related phosphoprotein (denoted vertebrate pp60) from uninfected chicken, quail, rat, and human cells. Our data indicate that vertebrate pp60 is a homologue of pp60src, highly conserved both antigenically and chemically. Moreover, the cellular protein may possess protein kinase activity similar to that associated with pp60src. We conclude that the product of src is a slightly modified analogue of a normal cellular protein.

Alpharetrovirus↗