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PubMed1999

Altered influence of CCK-B/gastrin receptors on HDC expression in ECL cells after neoplastic transformation.

Gastrin is one of the main factors controlling enterochromaffin-like (ECL) cell endocrine function and growth. Long-standing hypergastrinemia may give rise to ECL cell carcinoids in the gastric corpus in man and in experimental models. We have analysed the expression and function of CCK-B/gastrin receptors in normal ECL cells and in ECL cell tumours (gastric carcinoids) of the African rodent Mastomys natalensis. Hypergastrinemia induced by short-term (5 days) histamine2-receptor blockade (loxtidine) resulted in increased histidine decarboxylase (HDC) mRNA expression in the gastric oxyntic mucosa. This increase was significantly and dose-dependently reversed by selective CCK-B/gastrin receptor blockade (YM022). Long-term (12 months) hypergastrinemia, induced by histamine2-receptor blockade, gave rise to ECL cell carcinoids in the gastric oxyntic mucosa. CCK-B/gastrin receptor mRNA was only slightly elevated while HDC mRNA expression was eight-fold elevated in ECL cell carcinoids and was not influenced by CCK-B/gastrin receptor blockade. Thus CCK-B/gastrin receptor blockade of hypergastrinemic animals reduces the HDC mRNA expression in normal mucosa but not in ECL cell carcinoids. These results demonstrate that HDC mRNA expression in neoplastic ECL cells is not controlled by CCK-B/gastrin receptors.

Animals↗
PubMed1980

Effects of theophylline on the cell growth of normal and malignant human cells transformed in culture.

Proliferation of normal human diploid cell strains was inhibited to a greater extent by treatment with theophylline than the proliferation of neoplastic human cell lines transformed in culture with Co-60 gamma rays (WI-38 CT-1) or SV40 (WI-38 VA-13). Theophylline was added to cultures at final concentrations of 1 to 3 mM. Morphologically, normal fibroblasts became slender and small when grown in theophylline-containing medium, while little morphological change was observed in neoplastically transformed cells. Growth inhibition of theophylline was cytostatic rather than cytotoxic. No significant difference was detected in the uptake of theophylline between the normal and the transformed cells. Incorporation of 3H-thymidine into acid-insoluble fractions of cells began to decrease in the normal cells about 4 hr after adding theophylline to the culture medium. The intracellular contents of adenosine 3',5'-cyclic monophosphate increased linearly in the normal human cells with the time of treatment with theophylline, but no increase was observed in the transformed cells. The present results suggest that the use of theophylline might be useful for quantitative experiments on neoplastic transformation in cultures of normal human cells.

Cell Division↗
PubMed1978

Neoplastic transformation of hamster brain cells in vitro by polyoma virus.

The transformation of cultivated hamster brain cells by polyoma virus is reported. The transformed cell line contained polyoma virus-specific nuclear, surface and transplantation antigens. Subcutaneous and intracranial inoculations revealed high tumorigenicity of the cells. Brain-specific S 100 protein was found in these tumors with immuno-peroxidase staining, suggesting that they were of a nervous nature. Both in vivo and in vitro, the cells had glial features as studied by phase contrast, light and electron microscopy. Type-H virus-like particles were found in the tumor cells and might have played a role in the viral transformation.

Animals↗
PubMed1997

Rel/NF-kappa B and I kappa B factors in oncogenesis.

Rel/NF-kappa B transcription factors play fundamental roles in the immune system. These structurally-related proteins share common pathways of activation that involve their release from inhibitory I kappa B factors in response to stimuli. Accumulating evidence also points to a role for Rel and I kappa B proteins in cellular growth control and oncogenesis. The rearrangement and amplification of genes encoding Rel/NF-kappa B and I kappa B proteins in several human cancers, together with the acute oncogenicity of the retroviral v-rel oncogene in birds and mammals, suggests a correlation between their effects on gene expression and their role in malignancy. This review focuses on the current status of the association of Rel/NF-kappa B and I kappa B proteins with neoplastic cell transformation in vitro and in vivo.

Cell Transformation, Neoplastic↗
PubMed1991

Characterization of bovine papillomavirus E1 region deletion mutants associated with neoplastic transformation in a murine cell line.

Spontaneous focus formation in the contact-inhibited C127 cell line, cl.2, harbouring multiple copies of a bovine papillomavirus type 1 deletion mutant, was associated with the evolution of further viral genomic deletions in addition to an amplification of the viral genome copy number. Three simple frameshift deletions of 308, 605 and 1291 bp, associated with separate transformation events, were mapped within the E1 open reading frame, implying a common mechanism of spontaneous transformation in this cell line. Furthermore, each transformed cell line also retained multiple copies of the intact E1 gene, suggesting that these novel deletion mutants might function by a dominant-negative mechanism to disrupt the normal control of viral DNA replication or viral transcription. These mutants had the potential to encode truncated E1 polypeptides with a common N-terminal region encoded by the 5' end of E1, i.e. overlapping the previously described E1 modulator gene. A possible role for these mutants in diverting a lethal type of virus-cell interaction is discussed.

Animals↗
PubMed1984

[Proliferative activity of cultures of embryonic mouse fibroblasts, infected by CA7(C8) adenovirus in a non-serum medium].

Primary monolayer cultures of mouse fetal cells were grown in serum-depleted medium. Cell proliferation parameters were measured by scanning cytophotometry and 3H-thymidine autoradiography. Both 1 h and 24 h thymidine labelling indices (LI) were extremely low in cultures growing without serum for 1 day indicating only residual proliferative activity. The number of cytophotometrically detected S-phase cells was slightly higher than the corresponding LI values. This suggests either the arrest of the cells in S-phase or failure to utilize exogenous thymidine without serum. 24 h after infection by oncogenic adenovirus SA7 (C8) a burst of proliferative activity was revealed in serum-depleted cultures with a dramatic increase of both LI values and the amount of S-cells detected by cytophotometry. These data are discussed in terms of possible virus-induced neoplastic cell transformation.

Adenoviridae↗
PubMed1981

Cellular differentiation and neoplasia: characterization of subpopulations of cells that have neoplasia-related growth properties in Syrian hamster embryo cell cultures.

Cellular subpopulations having two of the growth properties of neoplastically transformed cells--lack of postconfluence inhibition of cell division (CI-) and anchorage independence of growth (AD-)--were found in cell cultures established from 10- to 13-day-old Syrian hamster embryos. The subpopulations having these properties decrease with increasing gestation period of the embryo as well as with continuing passage in vitro. The decrease in these subpopulations was also observed when they were cultured on a lethally irradiated confluent monolayer of contact-inhibited cells (cell mat), a selection condition for CI- cells. Therefore, negative selection cannot be the explanation for the loss of CI- cells in the population, leaving two other possibilities: either the loss of proliferative capacity of the CI- cells or the acquisition of sensitivity to postconfluence inhibition of cell division (CI+) of this subpopulation on in vitro culture or in vivo growth. The CI- subpopulations were isolated clonally from cell mats and were cultured continuously on both cell mats or plastic dishes. The results indicate that these cells did not lose proliferative capacity but acquired the contact-inhibited phenotype. This result, together with the fact that embryonic development in vivo also decreases CI/AD-subpopulations, suggests that the disappearance of these subpopulations is due to cellular differentiation of the CI-/AD- cells to become CI+/AD+ cells.

Age Factors↗
PubMed2001

Activated ras oncogene collaborates with HBx gene of hepatitis B virus to transform cells by suppressing HBx-mediated apoptosis.

The hepatitis B virus HBx protein is a promiscuous transactivator implicated in the development of hepatocellular carcinoma. The ectopic expression of HBx fails to transform both primary and immortalized rodent cells, but rather induces apoptosis. Furthermore, most transgenic mice harboring HBx do not develop liver tumors. Thus, it remains unclear whether and how HBx contributes to oncogenesis. Here, we show that HBx collaborates with activated H-ras to transform immortalized rodent cells. Indeed, REF52 cells transfected by both HBx and activated H-ras were morphologically transformed and were able to grow in soft agar. Remarkably, nude mice injected with REF52 cells transfected by both HBx and activated H-ras developed tumors, whereas the mice injected with REF52 cells transfected by either gene alone did not. Thus, we concluded that HBx could contribute to neoplastic transformation of cells in collaboration with other oncogenes, such as H-ras, that renders cells to overcome the HBx-mediated apoptosis. Further, we found that HBx mediated apoptosis was suppressed by activated H-ras through activation of the phosphatidylinositol-3 kinase and Akt pathway. Data presented here firmly established the oncogenic potential of HBx during multistage carcinogenesis. Oncogene (2001) 20, 16 - 23.

3T3 Cells↗
PubMed1996

Sensitivity of C3H 10T1/2 cells to radiation-induced killing and neoplastic transformation as a function of cell cycle.

Cell-age sensitivity to both cell killing and neoplastic transformation induced by radiation was investigated using synchronized populations of C3H10T1/2 cells. Mitotic-cell suspensions, collected using a mitotic shake-off procedure, were irradiated with 4Gy 250 kVp X-rays or 0.5 Gy fission neutrons from the RSV-TAPIRO reactor at CR-Casaccia. For study of cell killing the mitotic-cell suspensions were either irradiated immediately after collection, or plated for subsequent irradiation, which was performed every hour, covering an interval of 17 h. The response pattern observed was similar after X-rays and neutron irradiation, but the magnitude of the variation through the cell cycle was smaller in the case of neutrons (1.3- compared with 5-fold). For study of neoplastic transformation induction the irradiation was performed immediately after collection, i.e. in M phase, or at later times corresponding to mid-G1, G1/S and G2 phases. The sensitivity of the G2/M phase was examined by irradiating the cells with 4Gy X-rays while still attached to the flask bottom, and dislodging them after 25 min. SimilarLy to cell survival, the transformation frequency showed a small variation after neutron irradiation (1.4- compared with 3.1-fold) for the phases examined.

Animals↗
PubMed2001

Production of delayed death and neoplastic transformation in CGL1 cells by radiation-induced bystander effects.

Other investigators have demonstrated by transfer of medium from irradiated cells and by irradiation with low-fluence alpha particles or microbeams that cells do not have to be directly exposed to ionizing radiation to be detrimentally affected, i.e. bystander effects. In this study, we demonstrate by transfer of medium from X-irradiated human CGL1 hybrid cells that the killing of bystander cells reduces the plating efficiency of the nonirradiated CGL1 cells by 33 +/- 6%. In addition, we show that the amount of cell death induced by bystander effects is not dependent on X-ray dose, and that the induction of apoptosis does not appear to be responsible for the cell death. Furthermore, we found that the reduction in plating efficiency in bystander cells is evident for over 18 days, or 22 cell population doublings, after medium transfer, despite repeated refeeding of the cell cultures. Finally, we report the novel observation that bystander effects induced by the transfer of medium from irradiated cells can induce neoplastic transformation. Exposing unirradiated CGL1 cells to medium from cells irradiated with 5 or 7 Gy increased the frequency of neoplastic transformation significantly from 6.3 x 10(-6) in unirradiated controls to 2.3 x 10(-5) (a factor of nearly four). We conclude that the bystander effect induces persistent, long-term, transmissible changes in the progeny of CGL1 cells that result in delayed death and neoplastic transformation. The data suggest that neoplastic transformation in bystander cells may play a significant role in radiation-induced neoplastic transformation at lower doses of X rays.

Apoptosis↗
PubMed1989

Viral DNA synthesis in nonpermissive rat F-111 cells and its role in neoplastic transformation by polyomavirus.

We have investigated the occurrence and role of polyomavirus DNA synthesis in neoplastic transformation by this virus. We show that after infection of Fischer rat F-111 cells at 37 degrees C, there is two- to threefold increase in the level of viral DNA as compared with the input signal, with a peak observed between 5 and 7 days postinfection. Viral DNA synthesis is about 10 times higher at 33 degrees C and increases up to 15 days postinfection. Most of the viral DNA produced is supercoiled (form I DNA). On the basis of in situ hybridization, it appears that viral replication is restricted to a small fraction of the population. At the lower temperature, more cells are permissive for viral DNA synthesis and the level of synthesis per permissive cell is higher. The DNA synthesis observed is large T-antigen dependent, and the increase in viral DNA synthesis at 33 degrees C is paralleled by an increase in the expression of this viral protein. When large T antigen is inactivated, the half-life of de novo-synthesized viral DNA is less than 12 h, suggesting that large T antigen may be responsible for the stability of the viral genomes as well as their synthesis. Surprisingly, at early times postinfection (0 to 48 h), when the essential function of large T antigen in transformation is expressed (as demonstrated in shift-up experiments with tsa mutants), the level of large T antigen is below the detection level and is at least 10-fold lower than the levels observed in permissive infections at the start of viral DNA synthesis. The difference in viral DNA at 37 and 33 degrees C allowed us to study its effect on transformation. Although an increase in transformation frequency is observed in wild-type A2 infections carried at 33 degrees C (frequencies two to three times higher than at 37 degrees C), this increase appears to be unrelated to the increase in viral DNA synthesis. Furthermore, the overall level of viral DNA and large T antigen in F-111 cells may not affect the integration of the viral genome, since the patterns of integration in cells transformed by wild-type A2 at 33 and 37 degrees C appear similar. The results are compatible with a role for large T antigen in integration-transformation which is not simply to amplify the viral genome to enhance the probability of its integration.

Animals↗
PubMed1982

Role of viruses in the induction of primary intracranial tumors.

The role of viruses in the induction of primary intracranial tumors is reviewed. Papovaviruses of the simian virus 40 (SV40) group are used as a representative model, and a distillation of the literature on virus induction of intracranial tumors in laboratory animals and neoplastic transformation of cells in culture is presented. The molecular sequence of events during tumor induction and neoplastic cell transformation is also discussed. Recent evidence that the papovaviruses play a role in the formation of human brain tumors is summarized.

Animals↗
PubMed1992

Changes in surface relief of suspended cells are morphological signs of the initial stage of neoplastic transformation in fibroblastic monolayer cultures.

The percentages of cells with different types of cell surface relief were determined in cell suspensions derived from monolayer cultures. Primary cultures of rat embryo fibroblasts (REF) and cell lines REF (LT) and REF-1, immortalized cells of which preserved normal phenotypic characteristics of the initial primary culture REF, as well as morphologically transformed tumorigenic lines REF (LT) ras and REF-2EJ were studied. In REF suspensions the cells with the blebbed type of surface relief were shown to be predominant as compared with those with microvillus relief whereas cell suspensions derived from both immortalized and fully transformed cultures display the reverse ratio of cells with those types of surface relief. Therefore, the pattern of cell surface relief in cell suspensions derived from fibroblastic monolayer cultures may serve as a morphological marker of the initial stage of neoplastic transformation-immortalization when typical morphological signs of cell transformation are not yet manifested in monolayer cultures.

Adenoviridae↗
PubMed1993

[Effects of extract solution of Aspergillus versicolor on human fetal gastric cells in vitro].

To detect the carcinogenicity of sterigmatocystin for human stomach, the human fetal gastric cells, cultured in vitro, were treated with extract solution of Aspergillus versicolor culture (0.117mg sterigmatocystin per Kg culture of Aspergillus versicolor). The cells showed random arrangement, loss of contact inhibition and cell polarity. Some transformed foci were present in different numbers and times according to the dosages of the extract solution. The cells with such changes were analysed with a flow cytometer and the results showed that the cell number in S phase of cell cycle distribution was greatly increased. The above changes were similar to those of the cells treated with MNNG, but no such changes were noted in the control group. These results indicated that sterigmatocystin could induce some characteristics of neoplastic transformed cells and that sterigmatocystin may be a carcinogen for human gastric cancer.

Aspergillus↗
PubMed1980

Cell culture tumor promotion experiments with saccharin, phorbol myristate acetate and several common food materials.

The BALB/c-3T3 cell neoplastic transformation system was modified to examine the tumor promoting activity of a set of substances. Following initiation of the target cells with 3-methylcholanthrene, treatment of the cultures with phorbol myristate acetate (0.01 microgram/ml; 1.5 X 10(-8) M) during the remainder of the 4-week assay interval resulted in a marked increase in both spontaneous and initiated Type III transformed foci. In contrast, a similar treatment with saccharin at 20, 100 or 500 microgram/ml (0.08, 0.4 or 2.1 X 10(-3) M) did not influence the occurrence of Type III transformed foci and did not result in a promoting response. Sodium ascorbate (2.53 X 10(-3) M) and L-tryptophan (2.45 X 10(-3) M) almost completely inhibited both spontaneous and initiated Type III transformed foci. Calcium pantothenate (2.10 X 10(-3) M) exhibited a marginal promoting effect. Under the conditions of this study in which the classical tumor promoter phorbol myristate acetate was highly active in promoting Type III transformed foci, saccharin was not active as either a direct transforming or promoting agent at doses up to 5 orders of magnitude higher.

Animals↗
PubMed1988

Neoplastic transformation of a human bronchial epithelial cell line by a recombinant retrovirus encoding viral Harvey ras.

Activated ras oncogenes have previously been implicated in the pathogenesis of human lung carcinomas. A v-Ha-ras-containing retrovirus, Zip-ras, was generated by inserting the coding region of the v-Ha-ras oncogene into the Zip-NeoSV(X) [Cepko et al., Cell 37:1053-1062, 1984] retroviral vector. Amphotrophic Zip-ras retrovirus was used to infect an SV40 large T antigen-positive immortalized cell line, BEAS-2B, derived from normal bronchial epithelial cells, the predominant progenitor cells of human lung carcinomas. Zip-ras-infected BEAS-2B cells selected for G418 resistance formed anaplastic carcinomas in 12 of 15 athymic nude mice (latency 3 wk), whereas Zip-NeoSV(X)-infected BEAS-2B control cultures inoculated into 12 nude mice formed no tumors after a minimum of 7 mo. Tumor cell lines were established and demonstrated to be of human epithelial origin and to express v-Ha-ras p21 protein. A common feature of the tumor cell lines was an increase in ploidy. The increased efficiency of neoplastic transformation by v-Ha-ras of cell lines as compared with our previous results with normal bronchial epithelial cells [Yoakum et al., Science 227:1174-1179, 1985] is consistent with the hypothesis that the "immortalization" step is rate-limiting in in vitro human epithelial cell carcinogenesis.

Animals↗
PubMedDate not supplied

Spontaneous neoplastic regression: the significance of apoptosis.

In mammalian cells, neoplastic transformation has a direct relationship with the expression of oncogenes, the production of certain growth factors and with the mutation, loss or simple inactivation of the function of tumor suppressor genes. Genes for suppression of the development of the malignant immunophenotype, as well as inhibitory growth factors have regulatory functions within the normal processes of cell division and differentiation. Telomerase (a ribonucleoprotein polymerase) activation is frequently observed in various types of neoplastic cell transformation. Telomerase activation is regarded as essential for cell immortalization and its inhibition may result in spontaneous regression (SR) of neoplasms. SR of neoplasms occurs when the malignant tumor mass partially or completely disappears without any treatment or as a result of a therapy considered inadequate to influence systemic neoplastic disease. This definition makes it clear that the term SR applies to neoplasms in which the malignant disease is not necessarily cured, and to cases where the regression may not be complete or permanent. A number of possible mechanisms of SR are reviewed, with the understanding that no single mechanism can completely account for this phenomenon. The application of the newest immunological, molecular biological and genetic insights for more individualized anticancer immunotherapy (biotherapy) is also discussed. In conclusion, of all the possible mechanisms of SR of neoplasms, programmed cell death (PCD) or apoptosis is involved in each. The immunological mechanism is probably the main effector mechanism of SR in human neoplasms with its trigger being apoptosis. The treatments of the tumor, such as with various anti-neoplastic drugs or radiation or immunotherapy, all include the basic mechanism of programmed cell death or apoptosis. Without apoptosis, there is practically no tumor regression, none of any kind.

Adult↗