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PubMed1992

Differential c-jun expression in response to tumor promoters in JB6 cells sensitive or resistant to neoplastic transformation.

The activity of AP-1, a trans-acting transcription factor, is stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF) in promotion-sensitive (P+) but not in promotion-resistant (P-) JB6 mouse epidermal cell lines. TPA and EGF also promote neoplastic transformation only in P+ cells. Thus, it has been proposed that AP-1-dependent gene expression is involved in determining sensitivity to tumor promotion. This paper explores the possible basis for the differential inducibility of AP-1 activity in P+ and P- JB6 cells, focusing in particular on the regulation of expression of the components of the AP-1 complex at the mRNA level. The expression of jun and fos gene family members, which make up the AP-1 complex, can be stimulated by serum and a number of growth factors, including EGF, and by TPA. Therefore, the possibility that differential expression of one or more forms of jun or fos contributes to the differential AP-1 activity was considered. The data presented here demonstrate both similarities and differences in the basal and TPA- or EGF-induced levels of fos and jun family members between P+ and P- cells. The most striking observation was that the overall TPA- and EGF-induced levels of jun but not fos expression were higher in P+ cells. This suggests that tumor promoter-regulated c-jun expression may contribute to the differential AP-1 activation observed in these cells and may be important in determining sensitivity to promotion of neoplastic transformation.

Animals↗
PubMed1999

The adenovirus E4orf6 protein contributes to malignant transformation by antagonizing E1A-induced accumulation of the tumor suppressor protein p53.

The adenovirus type 5 (Ad5) E4orf6 protein promotes focus formation of primary baby rat kidney (BRK) cells in cooperation with Ad5 E1 proteins. This activity is most likely related to the ability of the E4orf6 protein to bind to p53 and modulate its tumor suppressor functions. In this study we report that transformed BRK cells that stably express E4orf6 in addition to E1A and E1B (ABS cells) displayed multiple additional properties commonly associated with a high grade of oncogenic transformation compared to cells expressing only E1A and E1B (AB cells). These properties included morphological alterations, markedly enhanced growth rates and growth to much higher saturation densities. Following injection into nude mice ABS-derived tumors exhibited accelerated growth and, based on histopathological criteria, proofed to be much more malignant compared to tumors generated by AB cells. Interestingly, these highly transformed properties of ABS cells correlated with a dramatic reduction of p53 steady-state levels which inversely correlated with E4orf6 expression. From these results we conclude that expression of the Ad5 E4orf6 protein (i) confers additional transformed in vitro properties to primary rat cells expressing the Ad5 E1 proteins, and (ii) increases the tumorigenic and malignant potential of these cells in vivo. Our data suggest that the Ad5 E4orf6 protein enhances the intrinsic ability of E1-transformed rat cells to grow in a neoplastic state by completely inactivating p53 tumor suppressor function in combination with the E1A and E1B proteins.

Adenovirus E1A Proteins↗
PubMed1994

Neoplastic transformation of C3H 10T1/2 cells: a study with fractionated doses of monoenergetic neutrons.

As most occupational and environmental exposures to ionizing radiation are at low dose rates or in small dose fractions, risk estimation requires that the effects of the temporal distribution of dose are taken into account. Previous in vitro studies of oncogenic transformation, as well as in vivo studies of carcinogenesis induced by high-LET radiation, yielded controversial results concerning the presence of an inverse dose-rate effect. The present study tested the influence of one scheme of dose fractionation of monoenergetic neutrons on neoplastic transformation of C3H 10T1/2 cells. Neutrons of 0.5, 1.0 and 6.0 MeV were used. Cells were exposed to doses of 0.25 and 0.5 Gy, given acutely or in five fractions at 2-h intervals. The acute and fractionated irradiations with each energy were done on the same day. No significant difference between the two irradiation modes was found for both cell inactivation and neoplastic transformation at all energies. These results are in agreement with our data for fractionated fission-spectrum neutrons from the RSV-TAPIRO reactor.

Animals↗
PubMed1988

Cooperation of V-oncogenes in human epithelial cell transformation.

The development of tissue culture systems for propagation of human epithelial cells has aided the investigation of events that lead epithelial cells to become neoplastic. In the present study, nontumorigenic human epidermal keratinocytes, immortalized by Ad12-SV40 virus or pSv3-neo, were transformed by a variety of retroviruses containing bas, H-ras, fes, fms, erbB and src oncogenes. Such transformants showed morphological alterations and induced carcinomas when transplanted into nude mice. These findings demonstrate the malignant transformation of human primary epithelial cells in culture by the combined action of Ad12-SV40 virus and retroviral oncogenes and support a multistep process for neoplastic conversion. This in vitro system may be useful in studying the interaction of a variety of retroviral oncogenes and human epithelial cells.

Adenoviridae↗
PubMed1985

Persistence of sister chromatid exchanges and in vitro morphological transformation of Syrian hamster fetal cells by chemical and physical carcinogens.

The induction of neoplastic cell transformation is closely associated with DNA alterations which occur shortly after carcinogen exposure. Sister chromatid exchange (SCE) formation is a sensitive indicator of carcinogen-DNA interaction and correlates with the induction of morphological cell transformation. The persistence of lesions generating SCE produced by chemical and physical carcinogens and its relevance to the induction of morphologic transformation was evaluated in coordinated experiments with cultured Syrian hamster fetal cells (HFC). Exponentially growing HFC were exposed for 1 h to benzo[a]pyrene (BP), methyl-methanesulfonate (MMS), cis-platinum (II) diaminedichloride (cis Pt II), N-methyl-N'-nitrosourea (MNU), mitomycin C (MMC), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), N-acetoxy-2-fluorenyl-acetamide (AcAAF) or u.v. light irradiated. Cells were incubated for 24 h with 5-bromodeoxyuridine (BrdUrd) required for SCE visualization at 1, 24 and 48 h after carcinogen exposure. The induction of morphological transformation was determined on the quantitative colony assay at 6 days after carcinogen treatment. SCE analysis demonstrates that for a period of 48 h after carcinogen exposure, during which time the cells undergo at least four replicative cycles, DNA damage generating SCE induced by all chemical carcinogens either persisted or was partially removed, whereas u.v.-induced lesions were completely removed. An elevated SCE frequency persisted after two additional cell cycles after treatment with BP, AcAAF or MMC without increased cell lethality as compared to other carcinogens whose lesions were completely eliminated during the same period. Although a correlation between the persistence of SCE and the induction of transformation was not observed for all carcinogens, this study illustrates that DNA damage generating SCE can persist over several replicative cycles, thus raising the possibility that lasting DNA alterations are important for the induction of neoplastic cell transformation.

Animals↗
PubMed1986

Changing responsiveness to all-trans retinoic acid of rat tracheal epithelial cells at different stages of neoplastic transformation.

Retinoic acid (RA) treatment of rat tracheal epithelial (RTE) cells, pre-exposed to the direct-acting carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), inhibited transformation in a dose-dependent manner. Treatment with RA at concentrations ranging from 3-33 nM reduced the MNNG-induced transformation frequencies by 13-81% and in some experiments by greater than 90%. RA treatment for only 3 days caused 65-75% inhibition of transformation; treatments of longer duration resulted in greater inhibition of transformation. Delaying the onset of RA treatment reduced its effectiveness, but even when RA treatment was delayed for 3 weeks following MNNG exposure, 60% inhibition still occurred. The inhibition of transformation appeared to be irreversible. The colony forming efficiency of cells isolated from transformed colonies 5 weeks after MNNG exposure was drastically reduced when the replated cells were treated with RA either 1 day or 4 days after plating, indicating that RA blocked cell replication. However, cells isolated from transformed colonies at later times after MNNG exposure were increasingly resistant to the antiproliferative effects of RA. The RA concentration causing 50% inhibition (RA-IC50) of colony formation was 0.1-0.3 nM for cells isolated from 3-5 week-old transformed colonies; it increased greater than 100-fold for cells isolated from 12-week-old transformants. Five established RTE cell lines also showed a much increased resistance to the antiproliferative effects of RA; two of these cell lines were even slightly stimulated in their colony forming ability by RA. The RA-IC50 of colony forming efficiency of normal RTE cells was also determined and compared to that of cells isolated from 5-week-old transformed colonies. Since the normal RTE cells require 3T3 feeder layers for clonal growth, both cell types were grown on feeders. For both cell types, the RA-IC50 was similar (150-300 nM); the requirement for relatively high RA concentrations was attributed in part to the rapid RA metabolism by the feeder cells. These experiments show that early RTE cell transformants are growth-inhibited by RA; however, they increasingly lose their sensitivity to the growth controlling effects of RA as they progress to a more advanced stage of transformation. The inhibition of tracheal cell transformation by RA is probably due to the antiproliferative effects of the retinoid.

Animals↗
PubMed1996

Overexpression of the AML1 proto-oncoprotein in NIH3T3 cells leads to neoplastic transformation depending on the DNA-binding and transactivational potencies.

The AML1 gene encodes DNA-binding proteins that contain the runt homology domain and is found at the breakpoints of t(8;21) and t(3;21) translocations associated with myelogenous leukemias. From the AML1 gene, two representative forms of proteins, AML1a and AML1b, are generated by alternative splicing. Both forms have the runt homology domain that possesses the DNA-binding ability but, unlike AML1b, AML1a lacks a putative transcriptional activation domain downstream of the runt homology domain. By using retroviral infection, we demonstrated that AML1b causes neoplastic transformation of NIH3T3 cells. AML1b-expressing cells form macroscopic colonies in soft agar and induce tumors in nude mice, indicating that AML1 can be a transforming gene when overexpressed in fibroblasts. Both the runt homology domain and the transactivational domain were required to transform NIH3T3 cells. By analysis of deletion mutants, it was shown that an element determining the transactivational potency exists between amino acids 288 and 396 within the region downstream of the runt homology domain. Furthermore, we demonstrated that this region was also required for fibroblast transformation, indicating that the transforming activity of AML1 is correlated with the transactivational potencies. These results suggest a role of AML1 in the regulation of cellular proliferation, as well as myeloid cell differentiation.

3T3 Cells↗
PubMed1985

The oncogene and its potential role in carcinogenesis.

Cellular onc genes are a group of evolutionarily conserved sequences which are homologous to the transforming genes (v-onc) of oncogenic retroviruses. Although their functions in normal cells are largely not known, the sequence homology between viral and cellular onc genes is consistent with the idea that neoplastic transformation may, in some cases, be due to abnormal levels of cellular onc gene expression. Several models can be proposed for such a mechanism, including the insertion nearby of a viral promoter, alteration of the physiological promoter by a mutagenic agent, gene amplification, relocation in a transcriptionally active region of the genome as a consequence of chromosomal rearrangements and point mutations induced by external factors. Examples of these different mechanisms of onc gene activation can be found in animal and human tumors. Finally, the detail description of one cellular onc gene (c-sis), its relation to the viral gene and to a known cellular growth factor and its possible mode of activation in neoplastic transformation is presented.

Animals↗
PubMed1978

High molecular weight, cell surface-associated glycoprotein (fibronectin) lost in malignant transformation.

Fibronectin is a polymorphic glycoprotein found in blood and tissues of vertebrates and in cultures of adherent vertebrate cells. There are several forms of fibronectin is composed of two high molecular weight subunits held together by forms found in tissues and on and around the surfaces of cultured cells. Soluble fibronectin is composed of two high molecular weight subunits held together by disulfide bonds. Insoluble fibronectin may be covalently cross-linked in larger complexes. Fibronectin has affinities for collagen, fibrin, heparin, and cell surfaces. In culture, fibronectin in growth medium may mediate attachment of cells to substratum, and fibronectin synthesized by cells may mediate adhesion to substratum. The widespread occurrence of fibronectin in basal lamina indicates that may different cell types in vivo abut against a fibronectin-containing matrix. Cultured transformed cells usually lack cell-surface fibronectin, also called large, external transformation-sensitive (LETS) protein. The failure of transformed cells to synthesize or bind fibronectin is paralleled (at least in some systems) by failures to synthesize or bind collagen and proteoglycans. Abnormal synthesis of fibronectin and other matrix components and abnormal interactions with the tissue matrix may account for several phenotypic characteristics of transformed cultured cells and for some of the malignant behavior of neoplastic cells in vivo.

Amino Acids↗
PubMed1992

Role of DNA repair in malignant neoplastic transformation of human mammary epithelial cells in culture.

Epithelial cells derived from normal human mammary tissue were examined for capacity to repair radiation-induced chromatin DNA damage. Repair capacity was estimated by quantifying chromatid aberrations in metaphase cells arrested 0.5-1.5 h after X-irradiation during G2. The parental cells at passage 12 had 19 chromatid breaks and 16 gaps per 100 metaphase cells, representing efficient repair. Of two continuous cell lines, derived after benzo[a]pyrene treatment, A1 maintained the efficient repair phenotype through passage 50, while a subline of A1 developed the repair-deficient phenotype characterized by a 3- to 5-fold higher frequency of chromatid breaks or gaps. This line was transformed to tumorigenic cells by HaMSV and SV40 T antigen. The second continuous line B5 and derivatives had 102-165 chromatid breaks and 87-134 gaps per 100 metaphases (deficient repair phenotype). This line was transformed to tumorigenic cells by KiMSV. As reported previously for human epidermal keratinocytes, acquisition of this repair-deficient phenotype appears to be an early requisite step in the malignant neoplastic transformation of human cells in culture.

Adult↗
PubMed1992

Cellular and molecular mechanisms of renal carcinogenesis induced by avian erythroblastosis virus.

Besides erythroleukemias and sarcomas, avian erythroblastosis virus strain ES4 (AEV-ES4) induces renal adenocarcinomas (RCas) in chickens. To search for the cells of origin and the mechanism of the development of RCas, we investigated the RCas produced by td359AEV, a mutant of AEV-ES4 which lacks a leukemogenic effect, but which is sarcomagenic. Spindle cell sarcomas in various organs and RCas developed in a high number of chickens inoculated with td359AEV. RCas were tubulo-cystopapillary structures of basophilic cells and originated only from differentiated principal cells (PCs) of the renal collecting duct system. The origin of tumors from PCs was indicated by connections of tumor epithelium to segments of the collecting duct system, including connecting tubules and cortical and medullary collecting ducts. Tumor cells showed typical mucopolysaccharide-containing vacuoles which are characteristic of chicken PCs. Viral particles were observed throughout the kidney. Moreover, the highest numbers of particles as well as budding-images of them were seen (apart from tumor cells) in podocytes and distal tubule cells which did not undergo neoplastic change. The susceptibility of PCs to undergo neoplastic transformation could not be related to a particular activation state of the erbB gene, in view of the fact that cerbB expression was detected by in situ hybridization in the epithelium lining the Bowmann's capsule and the entire renal tubule system. From data of Northern blot and in situ hybridization techniques, it was suggested that the neoplastic transformation of PCs was elicited by overexpression of the v-erbB oncogene, a feature of tumor cells already detected in renal tubules lined by basophilic proliferating cells, the first stages of renal carcinogenesis induced by td359AEV. According to Southern blot analysis, td359AEV proviruses were randomly inserted in tumor DNAs and the RCas were polyclonal in nature.

Alpharetrovirus↗
PubMed1979

Conditions for inhibiting and enhancing effects of the protease inhibitor antipain on x-ray-induced neoplastic transformation in hamster and mouse cells.

Using cultured normal hamster embryo cells and the heterploid mouse C3H cell line 10T1/2, clone 8, we have studied the effect of the protease inhibitor antipain on x-ray-induced neoplastic transformation. We found in both cell systems that, while there was no effect on cell survival as compared to irradiated controls, the addition of antipain at a concentration of 6 microgram/ml to the cultures 24 hr prior to irradiation resulted in enhanced transformation as compared to the frequency in cultures exposed to radiation alone. Yet the addition of antipain to cultures 10 min after irradiation resulted in a decreased transformation rate. This decrease was not found when antipain was added to the mouse cells 24 hr after irradiation or to the hamster cells 48 hr after irradiation. These results suggest that the protease inhibitor antipain has more than one mechanism of action in modulating the fixation and expression of transformation by x-irradiation, possibly by the modification of DNA repair.

Animals↗
PubMed1999

Dr. Josef Steiner Cancer Research Prize Lecture: the role of physiological cell death in neoplastic transformation and in anti-cancer therapy.

Cell death is a physiological process which is required for normal development and existence of multi-cellular organisms. Physiological cell death, or apoptosis, is controlled by an evolutionarily conserved mechanism. Abnormalities in this process are implicated as a cause or contributing factor in a variety of diseases. Inhibition of apoptosis can promote neoplastic transformation, particularly in combination with dysregulated cell-cycle control, and can influence the response of tumour cells to anti-cancer therapy. Molecular biological and biochemical approaches are used to find missing cell-death regulators and to define signalling cascades, while experiments in genetically modified mice will identify the essential function of these molecules. Discoveries from cell death research should provide clues for designing therapies for a variety of diseases, including degenerative disorders, auto-immunity and cancer.

Animals↗
PubMed1980

Different lymphoid cell targets by transformation by replication-competent Moloney and Rauscher mouse leukemia viruses.

Mouse leukemia viruses (MuLV) have been reported to induce tumors involving cells within the T lymphocyte lineage. In the present study, striking differences were demonstrated in the target cells for in vivo transformation by two clonal replication-competent type C viruses, Moloney- and Rauscher-MuLV. Moloney-MuLV-induced tumors and lymphoma cell lines exhibited Thy.1 antigen in the absence of detectable Fc or C3 receptors, indicating their T cell origin. Rauscher-MuLV primary tumors and lymphoma cell lines of the same mouse strain, however, invariably exhibited Fc receptors in the absence of Thy.1 antigen, suggesting that these tumors were of the B lymphoid lineage. The pattern of immunoglobulin synthesis by individual Rauscher-MuLV tumor cell lines was determined by both biosynthetic and radioimmunologic techniques. Rauscher-MuLV lymphoma lines invariably expressed immunoglobulin heavy (mu) chain in the absence of detectable light (kappa or lambda) chains. These findings establish that the target of neoplastic transformation in response to Rauscher-MuLV is an immature cell within the B lymphoid lineage. The demonstration of different target cells for transformation by well characterized clonal strains of mouse leukemia virus should aid in elucidating the mechanisms by which these viruses induce malignancy.

Animals↗
PubMed1998

Thymosin beta-10 gene overexpression correlated with the highly malignant neoplastic phenotype of transformed thyroid cells in vivo and in vitro.

A subtractive thyroid cDNA library was constructed from two human thyroid carcinoma cell lines originating from an anaplastic carcinoma and a papillary thyroid carcinoma. The library was used to identify genes correlated with the progression to a highly malignant phenotype. The thymosin beta-10 gene was isolated and found to be expressed at much higher levels in the anaplastic cell line than in the papillary cells. The thymosin beta-10 gene was overexpressed in five carcinoma cell lines compared with normal thyroid tissue and normal thyroid primary culture cells. The highest expression occurred in the most malignant cell lines. Thymosin beta-10 gene expression was also increased in surgically removed human thyroid carcinomas and was highest in the anaplastic carcinomas. Thymosin beta-10 gene expression was correlated with the degree of the malignant phenotype also in rat thyroid cells transfected with cellular and viral oncogenes of different tumorigenicity. These results show that thymosin beta-10 overexpression is a general event of thyroid cell neoplastic transformation and suggest that the gene is involved in the progression of thyroid carcinogenesis. Finally, the thymosin beta-10 gene was located on chromosome 2q37 by fluorescence in situ hybridization analysis.

Animals↗
PubMed2001

The role of Epstein-Barr virus in neoplastic transformation.

In this review, we focus on new data from basic, translational and clinical research relating to the Epstein-Barr virus (EBV). Beside its well-known tropism for B lymphocytes and epithelial cells, EBV also infects T lymphocytes, monocytes and granulocytes. After primary infection, EBV persists throughout the life span in resting memory B cells, from where it is reactivated upon breakdown of cellular immunity. In the process of neoplastic transformation, the EBV-encoded latent membrane protein 1 (LMP1) oncogene represents the major driving force. LMP1 acts like a constitutively activated receptor of the tumor necrosis factor receptor family and allows the amplification or bypassing of physiological regulatory signals through direct and indirect interactions with proteins of the tumor necrosis factor receptor-associated factor (TRAF) family. TRAF2-mediated NF-kappaB activation, AP-1 induction and JAK3/STAT activation may result in sustained proliferation leading to lymphoma. The ability of LMP1 to suppress germinal center formation and its capacity to mediate its own transcriptional activation shed new light on the pathogenesis of EBV-associated latency type II lymphoproliferations like Hodgkin's disease and angioimmunoblastic lymphadenopathy. The carboxy terminus of LMP1 is also a reliable marker for individual EBV strain identification and thus offers new possibilities in tracing the molecular events leading to posttransplant lymphoproliferative disorders (PTLDs). Cytotoxic T lymphocytes directed against well-characterized epitopes of EBV latency genes represent an already successful and promising therapeutic approach to EBV-associated lymphomas, in particular PTLDs.

Apoptosis↗