Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ultraviolet irradiation triggers a response in mammalian cells known as the UV response. Part of the UV response forms the enhanced synthesis of various extracellular proteins able to transmit the response to non-irradiated cells. Because several cancer-prone syndromes with enhanced genetic instability also have an enhanced synthesis of the same set of proteins without prior stimulation it is possible that induction of these stress responsive proteins may be involved in the process of carcinogenesis and genetic instability. To test this hypothesis mouse T lymphoma cells, GRSL13, were treated with the conditioned medium of UV-induced cells under various experimental conditions. Overall the mutation rate is enhanced 1.8-fold (P < 0.01). However, the degree of enhancement is strongly influenced by culture conditions. UV-induced factors only lead to an enhanced mutation rate when cells, both for the production and response to those factors, originate from a similar cell density. In addition, it was found that fresh medium interferes with this response. To eliminate the hindrance of these factors on the effect of the conditioned medium on the mutation rate, serum-starved cells at high density were treated with serum-free medium derived from high-density UV-irradiated cultures. Using these conditions a 2.8-fold (P < 0.002) enhancement of the mutation rate was found. Fluctuation analysis indicated that the enhancement is 10-fold during the first five generations after treatment. UV-induced factors have also been found to induce cell growth, and the degree of induction was linearly correlated with the enhancement in mutation rate. These experiments are in agreement with the hypothesis that induction of stress responses leads to genetic instability.
Carcinogenesis 1992 Dec
PMID:A possible factor in genetic instability of cancer cells: stress-induced secreted proteins lead to decrease in replication fidelity. 147 51

The hypothesis that activation of the signal transduction pathways by environmental stress may lead to genetic instability was tested. Mouse T-lymphoma cells, GRSL13, were treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). The induction of transcription of c-fos, fosB, c-jun, junB and collagenase was studied as well as the mutation rate in the progeny of treated cells. It was found that mRNA levels of fosB, junB and collagenase, all known to be involved in the growth factor signal transduction pathway, were enhanced. No transcription of c-fos and c-jun was observed in control and TPA-treated cells. These results suggest that transcription of c-fos is not a prerequisite for the induction of transcription of collagenase. The degree of induction of the signal transduction pathway was dependent on culture conditions of the treated cells, growing cells having less response than stationary cells. The mutation rate was significantly enhanced in the progeny of TPA-treated cells from 4.2 X 10(-7) to 9.8 X 10(-7)/cell/generation. Fluctuation analysis showed that TPA leads to a temporary enhancement of the mutation rate up to the eighth generation after treatment. The enhancement of the mutation rate is less apparent in growing cells than in stationary cells (1.8- and 2.9-fold respectively) which, because the signal transduction pathways are less induced in growing cells than in stationary cells, is in agreement with the hypothesis that induction of the signal transduction pathway leads to genetic instability.
Carcinogenesis 1991 Mar
PMID:Concomitant induction of signal transduction pathways and genetic instability by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. 200 94

Metabolic carcinogenesis may be viewed as a process in which a chronic disturbance of metabolic homeostasis leads to malignancy. Fluctuation in the CO2 tension in tissues is accompanied by changes in the intracellular pH. This prompted investigations into the long-term clinical effects of high CO2 tensions on various normal tissues in mice by two different methods. The first consisted of exposing different tissues in vitro to a high CO2% in air before transplantation into syngeneic or autologous hosts. The second method consisted of exposing intraperitoneal tissues in vivo to CO2-infusion, thus avoiding graft-host interactions. This is a report of the most significant findings in the series of investigations analyzed, 1. High incidences of malignant lymphoma in strains of mice with a low or zero spontaneous incidence followed: (a) syngeneic transplantation, (b) autologous transplantation, (c) in vivo exposure to CO2-infusion. 2. Syngeneic graft recipients developed similar high lymphoma incidences, irrespective of the tissue grafted or the pretransplantation treatment of the graft. 3. In the autologous system, however, the clinical results reflect the differences in the pretransplantation treatment, in contrast to those in the syngeneic system. 4. Whereas intraperitoneal CO2-infusion induced lymphoma, air-infusion did not. 5. Non-lymphoid grafts exposed in vitro to elevated CO2 induced only lymphoid malignancies. But non-lymphoid tissues exposed in vivo to elevated CO2 developed tumors of other tissues, such as lung tumor, in addition to lymphoid malignancies. 6. The same morphological lymphoid abnormalities occurred in all lymphoma-developing animals in these three experimental models. Hyperplasia in the splenic T-cell areas appeared most frequently. 7. The presence of immune-associated lesions in experimental animals (amyloidosis, interstitial nephritis and myocarditis) points to the activation of immune mechanisms in this lymphoma development. The evidence as a whole suggests the possibility that chronic immunological stimulation of host lymphoid tissue may be involved in the development of lymphoid malignancies in these animal models.
 ...
PMID:Metabolic carcinogenesis--induction of murine lymphoma by CO2-treatment in vivo and in vitro. 677 34

Analysis of the role of gene mutations in the multistep process of neoplastic transformation requires that the discrete steps in carcinogenesis first be dissected. Toward this end, we have isolated and characterized preneoplastic Syrian hamster cells which exhibit in vitro a trait highly correlated with neoplastic conversion in vivo. Previous findings (J. C. Barrett, Cancer Res. 40:91-94, 1980) indicate that spontaneous neoplastic transformation of Syrian hamster cells occurs in at least two steps. An intermediate stage, characterized by an aneuploid established cell line which has a propensity to become neoplastic spontaneously upon further growth in vitro, has been described. These preneoplastic cells differ from diploid early-passage Syrian hamster cells in becoming capable of anchorage-independent growth in semisolid agar, as well as becoming neoplastic in vivo when attached to a solid substrate. Evidence presented here demonstrates that anchorage-independent conversion in vitro is a reliable marker for neoplastic conversion in this cell system. Fluctuation analyses, patterned after those described by Luria and Delbruck for microbial genetics, demonstrate that anchorage-independent variants are generated randomly from clonally derived preneoplastic cells at the rate of 10(-8) to 10(-7) variants per cell per generation. These results establish a multistep stochastic process for transformation in vitro and indicate that conversion to anchorage independence may be necessary for Syrian hamster cells to become tumorigenic. The possible role of gene mutation in this step during neoplastic progression is discussed.
 ...
PMID:Neoplastic conversion of preneoplastic Syrian hamster cells: rate estimation by fluctuation analysis. 686 45

Fluctuation assays are widely used for estimating mutation rates in microbes growing in liquid environments. Many cultures are each inoculated with a few thousand cells, each sensitive to a selective marker that can be assayed phenotypically. These parallel cultures grow for many generations in the absence of the phenotypic marker. A subset of cultures is used to estimate the total number of cells at risk of mutations (i.e., the population size at the end of the growth period, or Nt). The remaining cultures are plated onto the selective agar. The distribution of observed resistant mutants among parallel cultures is then used to estimate the expected number of mutational events, m, using a mathematical model. Dividing m by Nt gives the estimate of the mutation rate per locus per generation. The assay has three critical aspects: the chosen phenotypic marker, the chosen volume of parallel cultures, and ensuring that the surface on the selective agar is completely dry before the incubation. The assay is relatively inexpensive and only needs standard laboratory equipment. It is also less laborious than alternative approaches, such as mutation accumulation and single-cell assays. The assay works on organisms that go through many generations rapidly and it depends on assumptions about the fitness effects of markers and cell death. However, recently developed tools and theoretical studies mean these issues can now be addressed analytically. The assay allows mutation rate estimation of different phenotypic markers in cells with different genotypes growing in isolation or in a community. By conducting multiple assays in parallel, assays can be used to study how an organism's environmental context affects spontaneous mutation rate, which is crucial for understanding antimicrobial resistance, carcinogenesis, aging, and evolution.
 ...
PMID:Measuring Microbial Mutation Rates with the Fluctuation Assay. 3184 Jun 62