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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For the assessment of radiation risk at low doses, it is presumed that the shape of the low-dose-response curve in humans for cancer induction is linear. Epidemiological data alone are unlikely to ever have the statistical power needed to confirm this assumption. Another approach is to use oncogenic transformation in vitro as a surrogate for carcinogenesis in vivo. In mid-1990, six European laboratories initiated such an approach using C3H 10T1/2 mouse cells. Rigid standardisation procedures were established followed by collaborative measurements of transformation down to absorbed doses of 0.25 Gy of x-radiation resulting in a total of 759 transformed foci. The results clearly support a linear dose-response relationship for cell transformation in vitro with no evidence for a threshold dose or for an enhanced, supralinear response at doses approximately 200-300 mGy. For radiological protection this represents a large dose, and the limitations of this approach are apparent. Only by understanding the fundamental mechanisms involved in radiation carcinogenesis will further knowledge concerning the effects of low doses become available. These results will, however, help validate new biologically based models of radiation cancer risk thus providing increased confidence in the estimation of cancer risk at low doses.
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PMID:Transformation of C3H 10T1/2 cells by low doses of ionising radiation: a collaborative study by six European laboratories strongly supporting a linear dose-response relationship. 1040 Jan 55

Research on radiation carcinogenesis during the past 2 decades has focused on cellular and molecular mechanisms for the effects of radiation in mammalian cells. This paper will review several of these areas of research, as they may relate specifically to the induction of cancer by ionizing radiation. Knowledge of the critical DNA damage of biologic importance, and how this damage is repaired, will be discussed in relation to its role in the induction of mutations by radiation. The search for the initiating event in radiation carcinogenesis, as well as other genetic events that may be involved, is discussed in terms of the possible role of the activation of oncogenes or tumor suppressor genes and the loss of cell-cycle checkpoints. Finally, evidence will be described indicating that important genetic consequences of radiation may arise in cells that in themselves receive no direct nuclear irradiation. It has been shown that radiation can, by itself, induce a type of genomic instability in cells, which enhances the rate at which mutations and other genetic changes arise in the descendants of the irradiated cell after many generations of replication. Preliminary evidence has been presented that irradiation targeted to the cytoplasm yields a significant increase in the frequency of mutations. Finally, genetic events including the induction of mutations and changes in gene expression may occur in neighboring cells that receive no direct radiation exposure at all. This 'bystander effect' involves gap junction mediated cell-cell communication, and activation of the p53 damage response pathway. The possible role of these phenomena in radiation carcinogenesis is discussed.
Carcinogenesis 2000 Mar
PMID:Radiation carcinogenesis. 1068 60

Radiation carcinogenesis is one of the major biological effects considered important in the risk assessment for space travel. Various biological model systems, including both cultured cells and animals, have been found useful for studying the carcinogenic effects of space radiations, which consist of energetic electrons, protons and heavy ions. The development of techniques for studying neoplastic cell transformation in culture has made it possible to examine the cellular and molecular mechanisms of radiation carcinogenesis. Cultured cell systems are thus complementary to animal models. Many investigators have determined the oncogenic effects of ionizing and nonionizing radiation in cultured mammalian cells. One of the cell systems used most often for radiation transformation studies is mouse embryonic cells (C3H10T1/2), which are easy to culture and give good quantitative dose-response curves. Relative biological effectiveness (RBE) for heavy ions with various energies and linear energy transfer (LET) have been obtained with this cell system. Similar RBE and LET relationship was observed by investigators for other cell systems. In addition to RBE measurements, fundamental questions on repair of sub- and potential oncogenic lesions, direct and indirect effect, primary target and lesion, the importance of cell-cell interaction and the role of oncogenes and tumor suppressor genes in radiogenic carcinogenesis have been studied, and interesting results have been found. Recently several human epithelial cell systems have been developed, and ionizing radiation have been shown to transform these cells. Oncogenic transformation of these cells, however, requires a long expression time and/or multiple radiation exposures. Limited experimental data indicate high-LET heavy ions can be more effective than low-LET radiation in inducing cell transformation. Cytogenetic and molecular analyses can be performed with cloned transformants to provide insights into basic genetic mechanism(s) of radiogenic transformation of human epithelial cells.
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PMID:Radiogenic cell transformation and carcinogenesis. 1153 46

Genomic instability is a hallmark of cancer cells, and is thought to be involved in the process of carcinogenesis. Indeed, a number of rare genetic disorders associated with a predisposition to cancer are characterised by genomic instability occurring in somatic cells. Of particular interest is the observation that transmissible instability can be induced in somatic cells from normal individuals by exposure to ionising radiation, leading to a persistent enhancement in the rate at which mutations and chromosomal aberrations arise in the progeny of the irradiated cells after many generations of replication. If such induced instability is involved in radiation carcinogenesis, it would imply that the initial carcinogenic event may not be a rare mutation occurring in a specific gene or set of genes. Rather, radiation may induce a process of instability in many cells in a population, enhancing the rate at which the multiple gene mutations necessary for the development of cancer may arise in a given cell lineage. Furthermore, radiation could act at any stage in the development of cancer by facilitating the accumulation of the remaining genetic events required to produce a fully malignant tumour. The experimental evidence for such induced instability is reviewed.
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PMID:Genomic instability and radiation. 1287 49

Implications for carcinogenesis of radiation-induced bystander effects are both mechanistic and practical. They include induction of second cancers, perturbations to tissue social control and induction of genomic instability and delayed or immediate mutations in areas not receiving a direct deposition of energy. Bystander effects have consequences for DNA damage-mutation-cancer initiation paradigms of radiation carcinogenesis that provide the mechanistic justification for low-dose risk estimates. If carcinogenesis does not result from directly induced DNA mutations, then the carcinogenic initiation process may not simply relate to radiation dose. Modification of the preclonal state through genetic and epigenetic mechanisms may occur. To deal with the complexity of these interactions, a 'chaotic' or 'bifurcation' model invoking autopoietic theory is proposed that could accommodate both beneficial (hormetic) and harmful effects of radiation at comparable doses. Carcinogenesis may then be thought of as the result of a disturbance of the genetic/epigenetic balance occurring within the organ. Ultimate clonality may reflect domination due to selection processes rather than the initiating damage.
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PMID:Radiation-induced bystander effects, carcinogenesis and models. 1455 7

It is generally thought that reactive oxygen species (ROS) play an important role in carcinogenesis. However, direct evidence supporting this idea is still lacking. In the present study, we measured ROS in thymocytes at the thymic prelymphoma stage in C57BL/6 mice. Mice (n = 20) were irradiated at 1.6 Gy/week for 4 consecutive weeks and the levels of ROS were measured 8 to 11 weeks later by dehydrorhodamine 123, which accumulated in mitochondria and became fluorescent dye upon oxidation. Unirradiated littermates (n = 17) served as controls. Thymic prelymphoma cells were diagnosed by the aberrant CD4/CD8 staining profile and monoclonal or oligoclonal T-cell receptor gene rearrangement. A significant fraction of mice (11/13) bearing thymic prelymphoma cells exhibited elevated levels of ROS in thymocytes (P < 0.001). The result is consistent with the hypothesis that ROS may play an important role in radiation carcinogenesis.
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PMID:An association between oxidative stress and radiation-induced lymphomagenesis. 1516 56

The study of radiation-induced transformation in vitro has long been an experimental approach to examine mechanisms underlying radiation carcinogenesis. Even though the major concern of exposure to radiation is the risk of cancer induction at low radiation doses, most laboratory mechanistic studies have focused on high dose effects. This, coupled with the fact that epidemiologic data are rarely powerful enough to accurately discriminate this risk at doses <5 cGy, has led in recent years to an increased effort to study low dose effects using the endpoint of neoplastic transformation in vitro. Since transformation frequencies at low doses are typically low (< 10(-4)), such studies are, by necessity, large and labor intensive. However, they have yielded quantitative dose-response data, as well as insights into underlying cellular and molecular mechanisms. An interesting, and potentially important, finding is that low doses of low LET radiation can suppress neoplastic transformation in vitro to levels below that seen spontaneously. Mechanistic studies have revealed that multiple mechanisms are likely to be involved, and these include both the death of a subpopulation of cells prone to spontaneous neoplastic transformation and the induction of DNA repair. The relative contribution of these mechanisms appears to be dose-dependent. The relevance of in vitro studies to carcinogenesis in vivo is discussed.
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PMID:Radiation-induced neoplastic transformation in vitro: evidence for a protective effect at low doses of low LET radiation. 1519 33

Ionizing radiation is a known "universal carcinogen" for a wide variety of tumors in man. Human populations are exposed to radiation coming from natural and industrial environment, and from medical sources. However, these are radiotherapy patients who receive the highest doses. Radiation both mutates and sterilizes cells (lethal effect). The risk of cancer induction from cells that have received very high doses of radiation (therapeutic dose about 2 Gy) is lower then from the cells with low doses, since the majority of them will have been sterilized. The epidemiological studies based on the population of atomic bomb survivors have indicated that the most acceptable model of carcinogenesis is the linear non-threshold model. The evaluation of clinical risk related to a wide range of radiation doses, which range from 0.01 Gy to 2 Gy, is connected with many methodological problems such as: differences in treatment factors (dose range, irradiated volume, anatomical site), unknown epidemiological data (smoking abuse, comorbidity), shortening of the follow-up (short lifespan, migration), evaluation of small groups of patients. The most important difficulty is lack of the sufficient knowledge of genetic background which is probably most significant in carcinogenesis process. The introduction into clinical practice of a new sophisticated method of irradiation such as the three-dimensional conformal radiotherapy (3D CRT) or intensity modulated radiotherapy (IMRT) leads to the increase of low irradiation dose for very large volume of normal tissue. Thus, the evaluation of these new methods in the context of carcinogenesis is a very important objective in the future. Today, we can only introduce the most important questions concerned with the risk of carcinogenesis induction which await answers: what is the risk of induction of cancer due to the implementation of these new methods of treatment, and how important is this risk for clinical practice, especially in the case of combined radiochemotherapy? Despite a large body of experimental and clinical studies, radiation carcinogenesis is not fully understood yet. Additional problems related to the impact of irradiation of low dose on carcinogenesis are not resolved. For example, the bystander effect, the low dose hypersensitivity and the adaptive response could modulate the total response after irradiation, but the impact on the carciongenesis is unknown.
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PMID:[Risk of postirradiation induction of cancer of the modern methods of radiotherapy (3D CRT and IMRT) head and neck cancer]. 1573 71

Given the complexity of the carcinogenic process and the lack of any mechanistic understanding of how ionizing radiation at low-level exposures affects the multistage, multimechanism processes of carcinogenesis, it is imperative that concepts and paradigms be reexamined when extrapolating from high dose to low dose. Any health effect directly linked to low-dose radiation exposure must have molecular/biochemical and biological bases. On the other hand, demonstrating some molecular/biochemical or cellular effect, using surrogate systems for the human being, does not necessarily imply a corresponding health effect. Given the general acceptance of an extrapolated LNT model, our current understanding of carcinogenesis cries out for a resolution of a real problem. How can a low-level acute, or even a chronic, exposure of ionizing radiation bring about all the different mechanisms (mutagenic, cytotoxic, and epigenetic) and genotypic/phenotypic changes needed to convert normal cells to an invasive, malignant cell, given all the protective, repair, and suppressive systems known to exist in the human body? Until recently, the prevailing paradigm that ionizing radiation brings about cancer primarily by DNA damage and its conversion to gene and chromosomal mutations, drove our interpretation of radiation carcinogenesis. Today, our knowledge includes the facts both that epigenetic events play a major role in carcinogenesis and that low-dose radiation can also induce epigenetic events in and between cells in tissues. This challenges any simple extrapolation of the LNT model. Although a recent delineation of "hallmarks" of the cancer process has helped to focus on how ionizing radiation might contribute to the induction of cancers, several other hallmarks, previously ignored--namely, the stem cells in tissues as targets for carcinogenesis and the role of cell-cell communication processes in modulating the radiation effects on the target cell--must be considered, particularly for the adaptive response, bystander effects, and genomic instability phenomena.
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PMID:Low-dose ionizing radiation: induction of differential intracellular signalling possibly affecting intercellular communication. 1582 25

By modulating the microenvironment of malignant or premalignant cells, inhibitory or stimulatory signals from nearby cells can play a key role in carcinogenesis. However, current commonly used quantitative models for induction of cancers by ionizing radiation focus on single cells and their progeny. Intercellular interactions are neglected or assumed to be confined to unidirectional radiation bystander effect signals from cells of the same tissue type. We here formulate a parsimoniously parameterized two-stage logistic (TSL) carcinogenesis model that incorporates some effects of intercellular interactions during the growth of premalignant cells. We show that for baseline tumor rates, involving no radiation apart from background radiation, this TSL model gives acceptable fits to a number of data sets. Specifically, it gives the same baseline hazard function, using the same number of adjustable parameters, as does the commonly used two-stage clonal expansion (TSCE) model, so it is automatically applicable to the many data sets on baseline cancer that have been analyzed using the TSCE model. For perturbations of baseline rates due to radiation, the models differ. We argue from epidemiological and laboratory evidence, especially results for the atomic bomb survivors, that for radiation carcinogenesis the TSL model gives results at least as realistic as the TSCE or similar models, despite involving fewer adjustable parameters in many cases.
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PMID:Modeling intercellular interactions during carcinogenesis. 1613 6


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