Cell proliferation kinetics of normal and tumour tissue <i>in vitro</i>: quiescent reproductive cells and the cycling reproductive fraction

Baker, Fraser L.; Sanger, L.; Rodgers, Roger W.; Jabboury, K.; Mangini, O.

doi:10.1111/j.1365-2184.1995.tb00035.x

Cited by 22 publications

(22 citation statements)

References 29 publications

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“…T is varied in this paper from 170 for tissues with a low-cycling fraction (15,25,26) to 5,000 for highly proliferative tissues, such as colonic epithelium (27).…”

Section: Key Parameters and Their Valuesmentioning

confidence: 99%

Efficiency of carcinogenesis with and without a mutator mutation

Beckman¹,

Loeb

2006

Proc. Natl. Acad. Sci. U.S.A.

104

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Carcinogenesis involves the acquisition of multiple genetic changes altering various cellular phenotypes. These changes occur within the fixed time period of a human lifespan, and mechanisms that accelerate this process are more likely to result in clinical cancers. Mutator mutations decrease genome stability and, hence, accelerate the accumulation of random mutations, including those in oncogenes and tumor suppressor genes. However, if the mutator mutation is not in itself oncogenic, acquiring that mutation would add an extra, potentially time-consuming step in carcinogenesis. We present a deterministic mathematical model that allows quantitative prediction of the efficiency of carcinogenesis with and without a mutator mutation occurring at any time point in the process. By focusing on the ratio of probabilities of pathways with and without mutator mutations within cell lineages, we can define the frequency or importance of mutator mutations in populations independently of absolute rates and circumvent the question of whether mutator mutations are ''necessary'' for cancers to evolve within a human lifetime. We analyze key parameters that predict the relative contribution of mutator mutants in carcinogenesis. Mechanisms of carcinogenesis involving mutator mutations are more likely if they occur early. Involvement of mutator mutations in carcinogenesis is favored by an increased initial mutation rate, by greater fold-increase in mutation rate due to the mutator mutation, by increased required steps in carcinogenesis, and by increased number of cell generations to the development of cancer.cancer ͉ mathematical model ͉ mutator hypothesis T he development of a cancer requires multiple steps as suggested by epidemiologic data and animal models (1-5). At least some of these steps are believed to involve oncogenic mutations or other genetic changes.The mutator hypothesis originally stated that mutations in DNA polymerases and DNA repair enzymes would play a critical role in carcinogenesis by accelerating the acquisition of oncogenic mutations (6). This concept has been broadened to include a variety of mutator mutations that create genetic instability by mechanisms including microsatellite instability, chromosomal instability, and aberrations of checkpoint control (7-10).An alternative hypothesis is that enhanced rates of genetic instability are not necessary for carcinogenesis and that cancer arises from mutations occurring at the normal rate followed by multiple rounds of lineage selection and expansion (11)(12)(13)(14).These two hypotheses are not mutually exclusive. Indeed it is likely that carcinogenic pathways corresponding to both hypotheses contribute concurrently. For example, carcinogenesis could involve a mutator mutation and subsequent mutations augmented by lineage selection and expansion.The common outcome of a malignant lineage is likely approachable by numerous pathways, and we postulate that these pathways will be seen in clinical cancers in proportion to their relative efficiencies, irrespective of w...

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“…T is varied in this paper from 170 for tissues with a low-cycling fraction (15,25,26) to 5,000 for highly proliferative tissues, such as colonic epithelium (27).…”

Section: Key Parameters and Their Valuesmentioning

confidence: 99%

Efficiency of carcinogenesis with and without a mutator mutation

Beckman¹,

Loeb

2006

Proc. Natl. Acad. Sci. U.S.A.

104

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“…A 36-hr generation time allows for 17,000 cell generations in a 70-year human lifetime. However, normal cells of reproductive potential are generally quiescent, cycling ,1% of the time as measured by incorporation of bromodeoxyuridine (BrdUrd) with a 24-hr pulse as well as observation of cell growth kinetics for a 2-week period (Baker et al 1995). Thus, as few as 170 cell generations may be available in some tissues for generation of a cancer.…”

Section: The Modelmentioning

confidence: 99%

Negative Clonal Selection in Tumor Evolution

Beckman¹,

Loeb

2005

Genetics

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Development of cancer requires the acquisition of multiple oncogenic mutations and selection of the malignant clone. Cancer evolves within a finite host lifetime and mechanisms of carcinogenesis that accelerate this process may be more likely to contribute to the development of clinical cancers. Mutator mutations are mutations that affect genome stability and accelerate the acquisition of oncogenic mutations. However, mutator mutations will also accelerate the accumulation of mutations that decrease cell proliferation, increase apoptosis, or affect other key fitness parameters. These ''reduced-fitness'' mutations may mediate ''negative clonal selection,'' i.e., selective elimination of premalignant mutator clones. Target reduced-fitness loci may be ''recessive'' (both copies must be mutated to reduce fitness) or ''dominant'' (single-copy mutation reduces fitness). A direct mathematical analysis is applied to negative clonal selection, leading to the conclusion that negative clonal selection against mutator clones is unlikely to be a significant effect under realistic conditions. In addition, the relative importance of dominant and recessive reduced-fitness mutations is quantitatively defined. The relative predominance of mutator mutations in clinical cancers will depend on several variables, including the tolerance of the genome for reduced-fitness mutations, particularly the number and potency of dominant reduced-fitness loci.

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“…While asynchronous exponential growth often is used to model cell population dynamics, few cell populations behave in this way in vitro [14][15][16][17] or in vivo [18,19]. Even tumorigenic cells behave nonexponentially [20][21][22][23].…”

Section: ® Original Articlementioning

confidence: 99%

Modeling Stem Cell Population Growth: Incorporating Terms for Proliferative Heterogeneity

et al. 2003

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Expansion of the undifferentiated stem cell phenotype is one of the most challenging aspects in stem cell research. Clinical protocols for stem cell therapeutics will require standardization of defined culture conditions. A first step in the development of predictable and reproducible, scalable bioreactor processes is the development of mathematical growth models. This paper provides practical models for describing cell growth in general, which are particularly well suited for examining stem cell populations. The nonexponential kinetics of stem cells derive from proliferative heterogeneity, which is biologically recognized as mitosis, quiescence, senescence, differentiation, or death. Here, we examined the assumptions of the Sherley model, which describes heterogeneous expansion in the absence of cell loss. We next incorporated terms into the model to account for A) cell loss or apoptosis and B) cell differentiation. We conclude that the basic assumptions of the model are valid and a high correlation between the modified equations and experimental data obtained using muscle-derived stem cells was observed. Finally, we demonstrate an improved estimation of the kinetic parameters. This study contributes to both the biological and mathematical understanding of stem cell dynamics. Further, it is expected that the models will prove useful in establishing standardization of cell culture conditions and scalable systems and will be required to develop clinical protocols for stem cell therapeutics.

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Cell proliferation kinetics of normal and tumour tissue in vitro: quiescent reproductive cells and the cycling reproductive fraction

Cited by 22 publications

References 29 publications

Efficiency of carcinogenesis with and without a mutator mutation

Efficiency of carcinogenesis with and without a mutator mutation

Negative Clonal Selection in Tumor Evolution

Modeling Stem Cell Population Growth: Incorporating Terms for Proliferative Heterogeneity

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