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Results for “clonal modeling”

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PubMed2004

Intratumoral patterns of clonal evolution in meningiomas as defined by multicolor interphase fluorescence in situ hybridization (FISH): is there a relationship between histopathologically benign and atypical/anaplastic lesions?

Meningiomas are cytogenetically heterogeneous tumors in which chromosome gains and losses frequently occur. Based on the intertumoral cytogenetic heterogeneity of meningiomas, hypothetical models of clonal evolution have been proposed in these tumors which have never been confirmed at the intratumoral cell level. The aim of this study was to establish the intratumoral patterns of clonal evolution associated with chromosomal instability in individual patients as a way to establish tumor progression pathways in meningiomas and their relationship with tumor histopathology and behavior. A total of 125 meningioma patients were analyzed at diagnosis. In all cases, multicolor interphase fluorescence in situ hybridization (iFISH) studies were performed on fresh tumor samples for the detection of quantitative abnormalities for 11 different chromosomes. In addition, overall tumor cell DNA content was measured in parallel by flow cytometry. iFISH studies were also performed in parallel on tissue sections in a subset of 30 patients. FISH studies showed that 56 (45%) of the 125 cases analyzed had a single tumor cell clone, all these cases corresponding to histologically benign grade I tumors. In the remaining cases (55%) more than one tumor cell clone was identified: two in 45 cases (36%), three in 19 (15%), and four or more clones in five cases (4%). Overall, flow cytometric analysis of cell DNA contents showed the presence of DNA aneuploidy in 44 of these cases (35%), 30% corresponding to DNA hyperdiploid and 5% to hypodiploid cases; from the DNA aneuploid cases, 35 (28%) showed two clones and 9 (7%) had three or more clones. A high degree of correlation (r >/= 0.89; P < 0.001) was found between FISH and flow cytometry as regards the overall quantitative DNA changes detected with both techniques, the former being more sensitive. Among the cases with chromosome abnormalities, the earliest tumor cell clone observed was frequently characterized by the loss of one or more chromosomes (64% of all meningiomas); loss of either a single chromosome 22 or, less frequently, of a sex chromosome (X or Y) and del (1p) was commonly found as the single initial cytogenetic aberration (30%, 5%, and 5% of the cases, respectively). Interestingly, an isolated loss of chromosome 22 was only found as the initial abnormality in one out of 14 atypical/anaplastic meningiomas, while the same cytogenetic pattern was present in the ancestral tumor cell clone of 32% of the benign tumors. Cytogenetic patterns based on chromosome gains were found in the ancestral tumor cell clone in 4% of the patients, 2% corresponding to tetraploid tumors. Overall, cytogenetic evolution of the earliest tumor cell clones was frequently associated with tetraploidization (31%). Our results show that meningiomas are genetically heterogeneous tumors that display different patterns of numerical chromosome changes, with the presence of more than one tumor cell clone detected in almost half of the cases including all atypical/anaplastic cases. Interestingly, the pathways of intratumoral clonal evolution observed in the benign tumors were different from those observed in atypical/anaplastic meningiomas, suggesting that the latter tumors might not always represent a more advanced stage of histologically benign meningiomas.

Adolescent↗

PubMed1977

Paroxysmal nocturnal hemoglobinuria (PNH) as a clonal disorder.

1. Clonal theories of disease, particularly progressive clonal growth and selection in tumorogenesis, were briefly cited. 2. Evidence for the clonal nature of PNH was presented. Correlation of red cell hemolysis with (a) G-6-PD type in two female G-6-PD mosaics with PNH and with (b) erythrocyte acetylcholinesterase deficiency, provides strong evidence for the clonal theory of PNH. 3. Possible pitfalls in defining "hidden PNH clones" in other diseases by the use of PNH hemolytic tests were discussed. 4. The potential of PNH as a study model for clonal evolution in human disease was emphasized.

Acetylcholinesterase↗

PubMed1989

Immunological tolerance then and now: was the Medawar school right?

As perhaps the staunchest advocates of repertoire purging as the central mechanism of immunological tolerance, we note with satisfaction a spate of recent, elegant papers which suggest an intrathymic clonal abortion model as the explanation for at least some examples of T-cell tolerance. This view agrees with the classical formulation of the Billingham-Brent-Medawar school of tolerance as a specific, central failure of immune responsiveness. Repertoire purging within the B-lymphocyte compartment remains much more controversial. There is no doubt that experimental models exist where the B cell is the reversible target of tolerance induction. The question is, in view of the ease of inducing autoantibody formation both in vivo and in vitro, just how relevant are such clonal anergy mechanisms to authentic self-tolerance? Arguments are presented that there must be two windows of tolerance susceptibility in the ontogeny of the B cell; one while it is maturing in the bone marrow, to prevent autoreactivity of high affinity to important accessible self-antigens; and a second soon after activation of pre-memory cells by exogenous antigen, to prevent fortuitous mutations towards high-affinity anti-self-reactivity establishing a forbidden clone.

Animals↗

PubMed2001

A mechanistic approach to modelling the risk of liver tumours in mice exposed to fumonisin B1 in the diet.

Data from the National Toxicology Program's carcinogenesis study of fumonisin B1 in B6C3F1 mice, conducted at the National Center for Toxicological Research, were used to fit the Moolgavkar-Venzon-Knudson (MVK) two-stage, clonal-expansion model of carcinogenesis. In addition to tumour data from the conventional 2-year bioassay, the study included data on tissue weights, cell proliferation, cell death, and sphingolipid metabolism in primary target organs. The model was used to predict 2-year liver tumour rates in female and male mice based on differences among dose groups in the effect of fumonisin B1 on the growth of normal tissue and on the proliferation of preneoplastic cells as a compensatory response to sphinganine-induced cell death. Fumonisin B1 was assumed to be non-genotoxic, i.e. the model did not include any effect of fumonisin B1 on either of the two mutation rates of the MVK model. The model was able to reproduce reasonably well the observed tumour rates in both female and male mice, predicting substantially increased rates above background only at the highest doses of fumonisin B1 in females.

Animals↗

PubMed1999

Control of replicative life span in human cells: barriers to clonal expansion intermediate between M1 senescence and M2 crisis.

The accumulation of genetic abnormalities in a developing tumor is driven, at least in part, by the need to overcome inherent restraints on the replicative life span of human cells, two of which-senescence (M1) and crisis (M2)-have been well characterized. Here we describe additional barriers to clonal expansion (Mint) intermediate between M1 and M2, revealed by abrogation of tumor-suppressor gene (TSG) pathways by individual human papillomavirus type 16 (HPV16) proteins. In human fibroblasts, abrogation of p53 function by HPVE6 allowed escape from M1, followed up to 20 population doublings (PD) later by a second viable proliferation arrest state, MintE6, closely resembling M1. This occurred despite abrogation of p21(WAF1) induction but was associated with and potentially mediated by a further approximately 3-fold increase in p16(INK4a) expression compared to its level at M1. Expression of HPVE7, which targets pRb (and p21(WAF1)), also permitted clonal expansion, but this was limited predominantly by increasing cell death, resulting in a MintE7 phenotype similar to M2 but occurring after fewer PD. This was associated with, and at least partly due to, an increase in nuclear p53 content and activity, not seen in younger cells expressing E7. In a different cell type, thyroid epithelium, E7 also allowed clonal expansion terminating in a similar state to MintE7 in fibroblasts. In contrast, however, there was no evidence for a p53-regulated pathway; E6 was without effect, and the increases in p21(WAF1) expression at M1 and MintE7 were p53 independent. These data provide a model for clonal evolution by successive TSG inactivation and suggest that cell type diversity in life span regulation may determine the pattern of gene mutation in the corresponding tumors.

Cell Compartmentation↗

PubMed2004

Radon-induced lung cancer in French and Czech miner cohorts described with a two-mutation cancer model.

A two-mutation carcinogenesis model with clonal expansion of pre-malignant cells is used to describe lung cancer mortality data from studies on French and Czech miners with relatively low exposures to radon. The aim was to derive radon-induced lung cancer risk estimates applicable to different populations using a model description consistent with both cellular dose-response relationships, and previous model analyses of animal and human epidemiological data. The significantly different baseline lung cancer risks for the two cohorts that include the effects from the unknown smoking habits, are described with different background model parameters. A uniform description of the effect of radon for both miner cohorts is achieved by applying the same multiplicative effect for radon on the background mutation rates in the model. Incorporating the effects of decreased cellular proliferation at very advanced age improves the description of the baseline lung cancer risk, but does not lead to significant changes in the estimated radiation parameters. Here, a multi-stage model demonstrates the possibility of transferring radon-induced lung cancer risks across populations. The inherent age-time dose-rate relationships in the model allow for extrapolation to lifelong exposures to residential radon concentrations. The resulting cumulated (lifetime) risks from continuous exposure to low-level radon concentrations were found to agree with the results of the BEIR VI models.

Algorithms↗

PubMed2026

Sequential gene loss promotes expansion of monophasic Salmonella Typhimurium ST34.

Understanding the genetic factors facilitating emergence of infectious diseases is critical, however, mechanisms underlying expansion of pathogenic bacterial variants remain unclear. Here we performed a large-scale genomic analysis of 44,597 Salmonella Typhimurium genomes and observe that sequential gene loss in monophasic Salmonella Typhimurium (mSTM) ST34 explains its clonal expansion as an increasingly prevalent zoonotic lineage. Functional and in vivo competition experiments show that a frameshift mutation in dinB, a polymerase for translesion DNA synthesis, leads to transcriptional changes affecting flagellin gene expression and subsequent loss of the flagellin-encoding fljB, altering the requirements for gut infection. Temporal evolutionary modelling supports a role for gene loss events in a specific chronological order for mSTM ST34 expansion. Our findings reveal a stepwise pathoadaptation model underpinning clonal global spread, providing mechanistic insights relevant to forecasting future pandemics.

Journal Article↗

PubMed1998

The avian embryo as a model in developmental studies: chimeras and in vitro clonal analysis.

The avian embryo is a model in which techniques of experimental embryology and cellular and molecular biology can converge to address fundamental questions of development biology. The first part of the chapter describes two examples of transplantation and cell labeling experiments performed in ovo. Thanks to the distinctive histologic and immunocytochemical characteristics of quail and chick cells, the migration and development of definite cells are followed in suitably constructed chimeric quail-chick embryos. Isotopic transplantations of neural tube portions between quail and chick, combined with in situ hybridization with a nucleic probe specific for a quail oligodendrocyte marker, allowed study of the origin and migration of oligodendroblasts in the spinal cord. Heterotopic transplantations of rhombomeres were performed to establish the degree of plasticity of these segments of the hindbrain regarding Hox gene expression, which was revealed by labeling with chick-specific nucleic probes. The second part describes in vitro cell cloning experiments devised to investigate cell lineage segregation and diversification during development of the NC. An original cloning procedure and optimal culture conditions permitted analysis of the developmental potentials of individual NC cells taken at definite migration stages. The results revealed a striking heterogeneity of the crest cell population, which appeared to be composed of precursors at different states of determination. Clonal cultures also provide a means to identify subsets of cells that are the target of environmental factors and to understand how extrinsic signals influence the development of responsive cells.

Animals↗

PubMed2002

Increased radioresistance, modelling of carcinogenesis and low-dose risk estimation.

Increased radioresistance for exposures to low-LET radiation with doses exceeding a few hundred milligray is a well established fact for cell inactivation in vitro and in vivo. Cell inactivation and the subsequent replacement by intermediate cells is a possible mechanism for a radiation-induced increase of the number of intermediate cells in carcinogenesis in an irradiated organ. In the present work this mechanism has been implemented in the two-step clonal expansion model for carcinogenesis in the lung in addition to the conventionally assumed radiation-induced initiation. Compared with the original TSCE model, the new model has the same number of parameters and fits the lung cancer incidence data for the atomic bomb survivors slightly better. The resulting estimate of the lung cancer risk after low-dose exposures of persons with an age of 20 or 40 years is similar in the two models; however, it is higher by about an order of magnitude in the new model for an age-at-exposure of 60 years. Age-at-exposure dependence and risk estimates at low dose turn out to be closer to best estimates obtained with a constant-excess-relative-risk model for different age-at-exposure subgroups.

Animals↗

PubMed2006

Plant population growth and competition in a light gradient: a mathematical model of canopy partitioning.

Can a difference in the heights at which plants place their leaves, a pattern we call canopy partitioning, make it possible for two competing plant species to coexist? To find out, we examine a model of clonal plants living in a nonseasonal environment that relates the dynamical behavior and competitive abilities of plant populations to the structural and functional features of the plants that form them. This examination emphasizes whole plant performance in the vertical light gradient caused by self-shading. This first of three related papers formulates a prototype single species Canopy Structure Model from biological first principles and shows how all plant properties work together to determine population persistence and equilibrium abundance. Population persistence is favored, and equilibrium abundance is increased, by high irradiance, high maximum photosynthesis rate, rapid saturation of the photosynthetic response to increased irradiance, low tissue respiration rate, small amounts of stem and root tissue necessary to support the needs of leaves, and low density of leaf, stem, and root tissues. In particular, equilibrium abundance decreases as mean leaf height increases because of the increased cost of manufacturing and maintaining stem tissue. All conclusions arise from this formulation by straightforward analysis. The argument concludes by stating this formulation's straightforward extension, called a Canopy Partitioning Model, to two competing species.

Ecosystem↗

PubMed2005

Inferring a tumor progression model for neuroblastoma from genomic data.

PURPOSE: The knowledge of the key genomic events that are causal to cancer development and progression not only is invaluable for our understanding of cancer biology but also may have a direct clinical impact. The task of deciphering a model of tumor progression by requiring that it explains (or at least does not contradict) known clinical and molecular evidence can be very demanding, particularly for cancers with complex patterns of clinical and molecular evidence. MATERIALS AND METHODS: We formalize the process of model inference and show how a progression model for neuroblastoma (NB) can be inferred from genomic data. The core idea of our method is to translate the model of clonal cancer evolution to mathematical testable rules of inheritance. Seventy-eight NB samples in stages 1, 4S, and 4 were analyzed with array-based comparative genomic hybridization. RESULTS: The pattern of recurrent genomic alterations in NB is strongly stage dependent and it is possible to identify traces of tumor progression in this type of data. CONCLUSION: A tumor progression model for neuroblastoma is inferred, which is in agreement with clinical evidence, explains part of the heterogeneity of the clinical behavior observed for NB, and is compatible with existing empirical models of NB progression.

Child↗

PubMed1997

Polyclonal structure of intestinal adenomas in ApcMin/+ mice with concomitant loss of Apc+ from all tumor lineages.

When tumors form in intestinal epithelia, it is important to know whether they involve single initiated somatic clones. Advanced carcinomas in humans and mice are known to be monoclonal. However, earlier stages of tumorigenesis may instead involve an interaction between cells that belong to separate somatic clones within the epithelium. The clonality of early tumors has been investigated in mice with an inherited predisposition to intestinal tumors. Analysis of Min (multiple intestinal neoplasia) mice chimeric for a ubiquitously expressed cell lineage marker revealed that normal intestinal crypts are monoclonal, but intestinal adenomas frequently have a polyclonal structure, presenting even when very small as single, focal adenomas composed of at least two somatic lineages. Furthermore, within these polyclonal adenomas, all tumor lineages frequently lose the wild-type Apc allele. These observations can be interpreted by several models for clonal interaction within the epithelium, ranging from passive fusion within regions of high neoplastic potential to a requirement for active clonal cooperation.

Adenomatous Polyposis Coli↗

PubMed1999

Threshold dose response for tumor induction by genotoxic carcinogens modeled via cell-cycle delay.

Dose-response relationships for tumor induction in animal bioassays for carcinogenicity are often postulated to include thresholds, particularly for nongenotoxic chemicals that increase the rate of cell proliferation at high doses. In this report, thresholds are postulated also for genotoxic carcinogens. The hypothesis is based on the idea of a delay of the cell cycle induced by low-level DNA damage and an acceleration at cytotoxic dose levels, thus resulting in a J-shaped (or U-shaped) dose response for cell turnover. Calculations were based on the 2-stage clonal expansion model of carcinogenesis. The background values chosen for the model parameters resulted in a 10.5% "spontaneous" 2-year cumulative tumor incidence. Using this as a starting point, a decrease by 3, 10, and 30% in the rates of cell turnover resulted in a decrease in the spontaneous tumor incidence to 9.4, 7.1 and 3.0%, respectively. Dose-responses with J-shaped curves for the rates of cell birth and death were modeled by shifted quadratic functions reaching the minimum at dose 1. Combinations with linearly increasing mutation rates also generated, under certain conditions, J-shaped dose-response curves for tumor incidence. As an example, for a 30% increase in mutation rates and a 10% decrease in cell turnover rates (both at dose 1), the dose-response curve showed an initial decrease of tumor incidence below the spontaneous rate, a reversion to the background value at 0.8 dose units, and an increase thereafter. The 0.8 dose could be considered to represent the "threshold dose." The approach presented might reconcile opposing views on thresholds on a biologically plausible mechanistic basis, and show a way for the quantitative estimation of threshold doses.

Animals↗

PubMed1991

Clonal anergy blocks the response to IL-4, as well as the production of IL-2, in dual-producing T helper cell clones.

In this report we extend the in vitro clonal anergy model to examine the regulation of proliferation in T cells that secrete both IL-2 and IL-4. Newly cloned Ag-specific murine T cells are shown to depend on both IL-2 and IL-4 synthesis for maximal proliferation. Whereas IL-2 responsiveness is constitutive in these cells, IL-4 responsiveness develops only after Ag and APC stimulation. Remarkably, proliferation of these cells to Ag is sensitive to inhibition by clonal anergy, even though IL-4 synthesis remains inducible. Anergy in these cells is associated with an inability to respond to IL-4, in addition to the development of an IL-2 production defect. The results suggest that anergy induction may be capable of preventing the clonal expansion of autoreactive T cells producing both IL-2 and IL-4 in vivo.

Animals↗

PubMed2000

Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model.

Bone marrow stromal cells can give rise to several mesenchymal lineages. The existence of a common stem/progenitor cell, the mesenchymal stem cell, has been proposed, but which developmental stages follow this mesenchymal multipotent progenitor is not known. Based on experimental evidence, a model of mesenchymal stem cell differentiation has been proposed in which individual lineages branch directly from the same progenitor. We have verified this model by using clonal cultures of bone marrow derived stromal fibroblasts. We have analyzed the ability of 185 non-immortalized human bone marrow stromal cell clones to differentiate into the three main lineages: osteo-, chondro- and adipogenic. All clones but one differentiated into the osteogenic lineage. About one third of the clones differentiated into all three lineages analyzed. Most clones (60-80%) displayed an osteo-chondrogenic potential. We have never observed clones with a differentiation potential limited to the osteo-adipo- or to the chondro-adipogenic phenotype, nor pure chondrogenic and adipogenic clones. How long the differentiation potential of a number of clones was maintained was assessed throughout their life span. Clones progressively lost their adipogenic and chondrogenic differentiation potential at increasing cell doublings. Our data suggest a possible model of predetermined bone marrow stromal cells differentiation where the tripotent cells can be considered as early mesenchymal progenitors that display a sequential loss of lineage potentials, generating osteochondrogenic progenitors which, in turn, give rise to osteogenic precursors.

Adolescent↗

PubMed1999

Loss of heterozygosity, differentiation, and clonality in microdissected male germ cell tumours.

Testicular germ cell tumours (TGCTs) are heterogeneous neoplasms with different histological patterns and malignant potential. The aim of this study was to determine whether the main TGCT subtypes (seminoma, embryonal carcinoma, yolk sac tumour, choriocarcinoma, and mature teratoma) are distinguished by their loss of heterozygosity (LOH) patterns and whether LOH typing can help to distinguish between clonal and multifocal development of different components in mixed TGCTs. In 76 tumours analysed for allelic losses at 25 chromosomal loci, different LOH patterns were found in distinct histological subtypes. A region around D18S543 frequently lost in yolk sac tumours could harbour one or more tumour suppressor genes. In 20 microdissected mixed tumours, losses of identical alleles in different histological components in 11 of 20 cases (over 50 per cent) were found, which is in favour of current histogenetic models of clonal TGCT development. Clonal losses were most often found at D13S317 (6 of 20 tumours). Two classes of allelic losses may therefore occur during TGCT development: clonal losses which are involved in early transformational events and others related to TGCT differentiation along different lines.

Adult↗

PubMed1985

Limiting dilution analysis of induced unresponsiveness to trinitrophenyl: increased suppression of cytotoxic T precursor cells at unchanged frequencies.

In this paper we address the problem of tolerance in the immune system. We are discussing results of experiments that we designed to distinguish between the two major alternative hypotheses that have been invoked for immunological tolerance: clonal deletion/anergy versus suppression. These alternative hypotheses make essentially different predictions with respect to the frequencies of lymphocytes that react with antigens to which the immune system is tolerant: clonal deletion models predict reduced frequencies, whereas in suppression models precursors of effector cells are postulated to occur at frequencies similar to the nontolerant situation. We investigate these questions by limiting dilution analyses of cytotoxic T cell precursors (CTLP), using two different ways to activate them into functional cytotoxic cells (CTL): polyclonally by Concanavalin A (ConA) and specifically by antigen. Tolerance should be apparent in either protocol since neither antigen nor ConA usually activates self-reactive cytotoxic cells. Moreover, in addition to providing information on precursor frequencies, the multihit results usually obtained in limiting dilution experiments of ConA activated T cells allow the determination of quantitative and qualitative parameters of suppression. In addition, clonal anergy situations could be expected to become apparent by a differential sensitivity of precursors to activation with ConA and with antigen. As experimental system we chose the induced unresponsiveness of mice to trinitrophenyl (TNP) achieved by intravenous injection of reactive trinitrobenzenesulfonic acid (TNBS) and measured in a primary cytotoxic response to TNP-coupled syngeneic cells (TNP-SC). An equally specific but perhaps not identical form of unresponsiveness is induced by coupling the responder cell population with TNBS in vitro. Although we do not propose that this model ideally reflects all aspects of self tolerance, we think that in this particular system of induced unresponsiveness the antigen becomes associated with the surfaces of a large proportion of the cells of the body. Therefore, tolerance to widely expressed cell surface determinants might be quite adequately "simulated" by this experimental unresponsiveness. In our limiting dilution experiments we can distinguish between frequent and infrequent cytotoxic precursors which correspond to virgin and memory cells, respectively. For the frequent CTLP the situation is quite clear: they occur at essentially equal frequencies in normal and tolerant mice, as demonstrated by their reactivity to antigen at low cell densities. However, they are under the influence of a suppressive activity which is strongly increased when compared to that of normal mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2004

ACAM2000 clonal Vero cell culture vaccinia virus (New York City Board of Health strain)--a second-generation smallpox vaccine for biological defense.

The threat of smallpox as a biological weapon has spurred efforts to create stockpiles of vaccine for emergency preparedness. In lieu of preparing vaccine in animal skin (the original method), we cloned vaccinia virus (New York City Board of Health strain, Dryvax by plaque purification and amplified the clone in cell culture. The overarching goal was to produce a modern vaccine that was equivalent to the currently licensed Dryvax in its preclinical and clinical properties, and could thus reliably protect humans against smallpox. A variety of clones were evaluated, and many were unacceptably virulent in animal models. One clonal virus (ACAM1000) was selected and produced at clinical grade in MRC-5 human diploid cells. ACAM1000 was comparable to Dryvax in immunogenicity and protective activity but was less neurovirulent for mice and nonhuman primates. To meet requirements for large quantities of vaccine after the events of September 11th 2001, the ACAM1000 master virus seed was used to prepare vaccine (designated ACAM2000) at large scale in Vero cells under serum-free conditions. The genomes of ACAM1000 and ACAM2000 had identical nucleotide sequences, and the vaccines had comparable biological phenotypes. ACAM1000 and ACAM2000 were evaluated in three Phase 1 clinical trials. The vaccines produced major cutaneous reactions and evoked neutralizing antibody and cell-mediated immune responses in the vast majority of subjects and had a reactogenicity profile similar to that of Dryvax.

Animals↗