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PubMed2002

A new perspective of carcinogenesis from protracted high-LET radiation arises from the two-stage clonal expansion model.

When applied to the Colorado Plateau miner population, the two-stage clonal expansion (TSCE) model of radiation carcinogenesis predicts that radiation-induced promotion dominates radiation-induced initiation. Thus, according to the model, at least for alpha-particle radiation from inhaled radon daughters, lung cancer induction over long periods of protracted irradiation appears to be dominated by radiation-induced modification of the proliferation kinetics of already-initiated cells rather than by direct radiation-induced initiation (i.e., mutation) of normal cells. We explore the possible consequences of this result for radiation exposures to space travelers on long missions. Still unknown is the LET dependence of this effect. Speculations of the cause of this phenomenon include the suggestion that modification of cell kinetics is caused by a "bystander" effect, i.e., the traversal of normal cells by alpha particles, followed by the signaling of these cells to nearby initiated cells which then modify their proliferation kinetics.

Alpha Particles↗
PubMed2006

The GOD of hematopoietic stem cells: a clonal diversity model of the stem cell compartment.

Hematopoietic stem cells (HSC) show heterogeneous behavior even when isolated as phenotypically homogeneous populations. The cellular and molecular mechanisms that control the generation of diversity (GOD) in the HSC compartment are not well understood, but have been the focus of much debate. There is increasing evidence that the most important HSC functions, self-renewal and differentiation, are epigenetically preprogrammed and therefore predictable. Indeed, recent data show that the adult HSC compartment consists of a limited number of functionally distinct subsets of HSC. This contradicts older models of HSC behavior, which postulated a single type of HSC that can be continuously molded into different subtypes of HSC. We propose a clonal diversity model where the adult HSC compartment consists of a fixed number of different types of HSC, each with epigenetically preprogrammed behavior. Aging or disease may change the overall function of the HSC population. The model predicts that these changes reflect the relative composition of the HSC subsets, rather than changes in individual HSC. This view has implications for using HSC in experimental and clinical settings. Selection for the appropriate subsets of HSC, rather than attempts to force HSC to adjust, should improve their utility in transplantation and gene transfer applications.

Animals↗
PubMed2001

Interaction between two carcinogens in the two-stage clonal expansion model of carcinogenesis.

BACKGROUND: Exposure to two or more carcinogens may result in interactive effects in which the joint effect may be greater or less than that expected to arise as the sum of the effects of the two agents alone. In this article, we investigate the joint effects of exposure to two carcinogens within the context of the two-stage clonal expansion model of carcinogenesis. METHODS: Different measures of interaction are considered based on the notions of response and dose additivity, and an index of synergy S due to Thomas (1982) used to broadly characterise the effects of joint exposure. RESULTS: Interactive effects based on the index S were found to be qualitatively similar, regardless of whether cancer risk was defined in terms of age-specific relative risk, or the cumulative probability of cancer occurrence at the same age. For joint exposure to two initiators or to two completers (affecting the first or second mutation rate in the two-mutation model, respectively), S assumed values near zero, reflecting an additive relative-risk relationship. For joint exposure to two promoters (which increase the rate of proliferation of initiated cells that have sustained the first mutation), the relative-risk relationship was found to range from supramultiplicative (S > 1) in younger age groups, to subadditive (S < 0) in older ages. Other combinations of carcinogens involving promotion also displayed a broad range of interaction effects. CONCLUSIONS: These results differ markedly from those reported previously by Kodell et al. (1991) for an approximate form of the two-stage model, which predicts much higher values of the index of synergy S than the exact form of the model when promotion is involved.

Carcinogens↗
PubMed2004

Comparing regression methods for the two-stage clonal expansion model of carcinogenesis.

In the statistical analysis of cohort data with risk estimation models, both Poisson and individual likelihood regressions are widely used methods of parameter estimation. In this paper, their performance has been tested with the biologically motivated two-stage clonal expansion (TSCE) model of carcinogenesis. To exclude inevitable uncertainties of existing data, cohorts with simple individual exposure history have been created by Monte Carlo simulation. To generate some similar properties of atomic bomb survivors and radon-exposed mine workers, both acute and protracted exposure patterns have been generated. Then the capacity of the two regression methods has been compared to retrieve a priori known model parameters from the simulated cohort data. For simple models with smooth hazard functions, the parameter estimates from both methods come close to their true values. However, for models with strongly discontinuous functions which are generated by the cell mutation process of transformation, the Poisson regression method fails to produce reliable estimates. This behaviour is explained by the construction of class averages during data stratification. Thereby, some indispensable information on the individual exposure history was destroyed. It could not be repaired by countermeasures such as the refinement of Poisson classes or a more adequate choice of Poisson groups. Although this choice might still exist we were unable to discover it. In contrast to this, the individual likelihood regression technique was found to work reliably for all considered versions of the TSCE model.

Adult↗
PubMed1987

Cellular aging (the Hayflick limit) and species longevity: a unification model based on clonal succession.

A model is presented which proposes a specific cause-and-effect relationship between a limited cell division potential and the maximum lifespan of humans and other mammals. It is based on the clonal succession hypothesis of Kay which states that continually replicating cell beds (e.g. bone marrow, intestinal crypts, epidermis) could be composed of cells with short, well-defined division potentials. In this model, the cells of these beds are proposed to exist in an ordered hierarchy which establishes a specific sequence for cell divisions throughout the organism's lifespan. The depletion of division potential at all hierarchical levels leads to a loss of bed function and sets an intrinsic limit to species longevity. A specific hierarchy for cell proliferation is defined which allows the calculation of time to bed depletion and, ultimately, to organism mortality. The model allows the existence of a small number (n) of critical cell beds within the organism and defines organism death as the inability of any one of these beds to produce cells. The model is consistent with all major observations related to cellular and organismic aging. In particular, it links the PDLs (population doubling limit) observed for various species to their mean lifespan; it explains the slow decline in PDL as a function of age of the donor; it establishes a thermodynamically stable maximum lifespan for a disease-free population; and it can explain why tissue transplants outlive donors or hosts.

Aging↗
PubMed2005

Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics.

To delineate multiple myeloma (MM) subgroups and their clonal evolution, we analyzed 81 newly diagnosed patients by interphase fluorescence in situ hybridization using a comprehensive probe set for 10 chromosomes and two IGH rearrangements. A median of 5 probes per patient displayed aberrant signal numbers (range, 1-10). Additional copies most frequently found were for 15q22, 19q13, 9q34, 11q23, and 1q21. Losses commonly observed were of 13q14.3, 17p13, and 22q11. Predominance of gain or loss was quantified by a copy number score (CS) for each patient. Two peaks (CS = +3 and CS = 0) were found by plotting patient copy number scores over CS values corresponding to hyperdiploid and nonhyperdiploid MM. Cluster analysis revealed four major branches: (i) gain of 9q, 15q, 19q, and/or 11q; (ii) deletion of 13q and t(4;14); (iii) t(11;14); and (iv) gain of 1q. Statistical modeling of an oncogenetic tree indicated that early independent events were gain of 15q/9q and/or 11q, t(11;14); deletion of 13q followed by t(4;14); and gain of 1q. Aberrations of 17p13, 22q11, 8p12, and 6q21 were found as subsequent events. MM with gain of 1q was delineated as a subentity with significantly higher beta-2-microglobulin and lower hemoglobin levels, indicating a poor prognosis. From our results, we propose a model of MM for clonal evolution.

Evolution, Molecular↗
PubMed1976

[Demonstration by the analysis of principal components of the of the equivalence of two models of clonal survival].

The principal component analysis of 21 chlorella cell survival curves, adjusted by one-hit and two-hit target models, lead to quite similar projections on the principal plan: the homologous parameters of these models are linearly correlated; the reason for the statistical equivalence of these two models, in the present state of experimental inaccuracy, is revealed.

Chlorella↗
PubMed2004

PC-3 cells with enhanced androgen receptor signaling: a model for clonal selection in prostate cancer.

BACKGROUND: Two sublines of the human prostate cancer cell line, PC-3, which is widely used as a model of prostate cancer progression, have been reported: PC-3(AR-) that do not express androgen receptor (AR), and PC-3AR+ that have measurable AR RNA but little protein. METHODS: We assayed the geneotype, karyotype, AR expression, and physical characteristics of the two PC-3 sublines, and compared their ability to elicit a transactivation response from ectopic AR in the presence and absence of specific AR coregulators. RESULTS: PC-3(AR-) and PC-3AR+ cells are genotypically and karyotypically similar, but exhibit salient differences in their morphology, growth rate, and expression of AR RNA. Whereas endogenous AR expression in PC-3AR+ cells does not result in sufficient protein to confer androgen responsiveness in culture, ectopic AR consistently elicited a much greater transactivation response in PC-3AR+ than in PC-3(AR-) cells, without altered sensitivity to activation by native ligand or AR coregulators including GRIP1, BRCA1, and Zac1. Moreover, phenotypic differences of AR variants implicated in prostate cancer susceptibility and progression were only observed in PC-3AR+ cells. Higher levels of known AR coregulator proteins detected in PC-3AR+ compared with PC-3(AR-) cells likely contribute to these differences. CONCLUSIONS: These studies provide new evidence that the androgen-signaling axis can be sensitized in prostate cancer cells, and have important implications for the analysis and interpretation of AR structure and function in in vitro cell systems.

Cell Division↗
PubMed2001

A clonal growth model: time-course simulations of liver foci growth following penta- or hexachlorobenzene treatment in a medium-term bioassay.

A combination of experimental and simulation approaches were used to analyze the clonal growth of preneoplastic, enzyme-altered foci during liver carcinogenesis in an initiation-promotion regimen. Male Fisher 344 rats, 8 weeks of age, were initiated with a single dose (200 mg/kg, i.p.) of diethylnitrosamine (DEN). Beginning 2 weeks later, animals were exposed to daily gavage consisting of 0.1 mmol/kg pentachlorobenzene (PECB) or hexachlorobenzene (HCB) in corn oil vehicle for 6 weeks. Partial hepatectomy was performed 3 weeks after initiation. Experimental data including liver weight, hepatocyte density (number of hepatocytes/unit volume), 5-bromo-2'-deoxyuridine-labeling index for analysis of cell division rate, and number and volume of glutathione-S-transferase pi-positive foci were collected 23, 26, 28, 47, or 56 days after initiation. Model parameters describing liver growth were obtained directly from the experimental data. The probability of mutation/division of normal cells and the growth rate of initiated cells were inferred by a comparison of model outcomes with the observed time courses of foci development. To describe the time-dependent increases in foci volume and the concomitant reduction of foci number observed in all treatment groups, the calibrated model for the DEN controls incorporated the hypothesis of two initiated cell populations (referred to as A and B cells) within the framework of the two-stage model. The B cells are initiated cells that have a selective growth advantage under conditions that inhibit the growth of A cells and normal hepatocytes. The parameter values defined in the DEN controls were used to evaluate experiments involving the administration of PECB or HCB. Both PECB and HCB caused a significant increase in foci volume compared with the DEN controls. HCB treatments resulted in increased proliferation of normal hepatocytes, which was not observed for PECB under the same treatment regimen. The best description of the data resulted from the model incorporating the hypothesis that PECB and HCB promoted the growth of foci via increased net growth rates of B cells. We present here a biologically based clonal growth simulation platform to describe the growth of preneoplastic foci under experimental manipulations of initiation-promotion studies. This simulation work is an example of quantitative approaches that could be useful for the analysis of other initiation-promotion studies.

Animals↗
PubMed1986

An in vitro model for clonal anergy in continuously growing antigen-specific B-cell lines.

Two continuously growing nonmalignant B-cell lines specific for the hapten DNP have been used to study tolerance in developing B cells. These cell lines have previously been shown to consist of small cells without sIgM but with cytoplasmic mu chains, and mature sIgM- and sIgD-bearing cells. When the sIgM-negative cells are placed in culture, mature DNP-specific B cells begin to appear. The studies reported here have shown that when these cell lines were propagated in the presence of either 200 micrograms/ml or 1 mg/ml of the tolerogen DNP-MGG there was no inhibition of cell line growth as measured by thymidine incorporation, and no inhibition of receptor expression by maturing B cells. The cell line lymphocytes propagated in the presence of 200 micrograms/ml DNP-MGG for 7, 30, 45, or 60 days became tolerant and the tolerance persisted for at least 6 days after removal of DNP-MGG. However, tolerance was lost between 6 and 10 days after removal of DNP-MGG. Propagation of the cell lines for 30 days in either DNP-KLH or DNP-Ficoll produced the same results. Limiting dilution cultures of cell line lymphocytes made tolerant by growing them for 30 days in the presence of DNP-MGG demonstrated that there was a marked decrease in precursor frequency compared to controls. However, cell line lymphocytes made tolerant by a 48-hr incubation with DNP-MGG did not have a significant decrease in precursor frequency. These data suggest that tolerance induced by growing these cell lines in the presence of DNP-MGG is a valid in vitro model of tolerance in developing antigen-specific B cells. Tolerance induced in this model is consistent with the clonal anergy hypothesis, but requires the continued presence of DNP-MGG to maintain unresponsiveness. This suggests that clonal anergy can occur in B cells but may not be the sole mechanism of self tolerance for those antigens which are sequestered from the immune system.

Animals↗
PubMed1989

Model for clonal elimination in the thymus.

A thymic stromal cell clone, MRL104.8a, expresses class I as well as class II H-2k antigens after exposure to gamma-interferon. This clone also produces thymic stroma-derived T-cell growth factor (TSTGF), which is distinct from other known interleukins and is capable of promoting the growth of various antigen-specific helper T cell (Th) clones without requiring a specific antigen or interleukin 2. When the keyhole limpet hemocyanin (KLH)-specific, I-Ek-restricted Th clone 9-16 was cultured on an Ia (I-Ak and I-Ek)-expressing MRL104.8a monolayer, potent proliferation of the 9-16 cells was induced by TSTGF produced by the monolayer. In contrast, the addition of KLH resulted in lethal growth inhibition of Th clone 9-16 cells. Another Th clone that is KLH-specific but I-Ab-restricted was capable of proliferating on the Iak-expressing MRL104.8a monolayer whether or not KLH was present. More importantly, death of Th clone 9-16 cells cultured on a MRL104.8a monolayer in the presence of KLH was almost completely prevented by the addition of anti-I-Ek or anti-CD3 monoclonal antibodies, which are capable of blocking antigen recognition by the T-cell receptor. However, when Th clone 9-16 cells were cultured in the presence of KLH but on a monolayer of MRL28.8a cells, another thymic stromal clone that expresses a comparable amount of I-Ek antigen but produces a marginal amount of TSTGF, cells did not die; a lethal effect was induced by adding TSTGF. These results indicate that the TSTGF-producing and Ia-expressing thymic stromal cells induce the continuous proliferation or selective elimination of each T-cell clone, depending on whether the T-cell receptor is stimulated by the relevant antigen associated with Ia molecules expressed on the stromal cell surface.

Animals↗
PubMed1976

A generalization of the clonal survival models: equations for the families of curves obtained with fractionated irradiation.

The survival curves obtained when cellular recovery follows various first radiation dose deliveries DI seem, when semi-logarithmically plotted, to be translated from the part of the curve corresponding to an unfractionated irradiation beyond a dose DR. A possible assumption consistent with such experimental observations is proposed which allows the generalization of any survival model S = f (D). The derived equation S = f (DR + D - DI) f (DI)/f (DR) is convenient for the whole family of experimental survival curves involving cellular damage repairs when the first radiation doses vary. All the parameters of the family equation can be simultaneously fitted so that their reliability is increased. The generalized equations are given for the four following models: two-hits targets, Chadwick and Leenhouts, Green and Burki, Wideröe. As an example, the Chadwick and Leenhouts generalized model parameters are fitted to a family of experimental survival curves concerning Chlorella cells exposed to fractionated and continuous gamma irradiation. The fittings are presented with their confidence limits and are briefly discussed.

Cell Survival↗