scholarly journals A compartment size dependent selective threshold limits mutation accumulation in hierarchical tissues

2019 ◽  
Author(s):  
Daniel Grajzel ◽  
Imre Derenyi ◽  
Gergely J Szollosi
Keyword(s):  
Selective Advantage ◽  
Cell Number ◽  
Significant Determinant ◽  
Size Dependent ◽  
Somatic Evolution ◽  
Tissue Organization ◽  
Tissue Size ◽  
Risk Of Cancer ◽  
Proliferative Advantage ◽  
Fundamental Mechanism

Cancer is a genetic disease fueled by somatic evolution. Hierarchical tissue organization can slow somatic evolution by two qualitatively different mechanisms: by cell differentiation along the hierarchy "washing out" harmful mutations (Nowak et al. 2003, Werner et al. 2013) and by limiting the number of cell divisions required to maintain a tissue (Derenyi and Szollosi 2017). Here we explore the effects of compartment size on somatic evolution in hierarchical tissues by considering cell number regulation that acts on cell division rates such that the number of cells in the tissue has the tendency to return to its desired homeostatic value. Introducing mutants with a proliferative advantage we demonstrate the existence of a third fundamental mechanism by which hierarchically organized tissues are able to slow down somatic evolution. We show that tissue size regulation leads to the emergence of a threshold proliferative advantage, below which mutants cannot persist. We find that the most significant determinant of the threshold selective advantage is compartment size, with the threshold being higher the smaller the compartment. Our results demonstrate that in sufficiently small compartments even mutations that confer substantial proliferative advantage cannot persist, but are expelled from the tissue by differentiation along the hierarchy. The resulting selective barrier can significantly slow down somatic evolution and reduce the risk of cancer by limiting the accumulation of mutations that increase the proliferation of cells.

scholarly journals A compartment size-dependent selective threshold limits mutation accumulation in hierarchical tissues

2020 ◽  
Vol 117 (3) ◽  
pp. 1606-1611 ◽  
Author(s):  
Dániel Grajzel ◽  
Imre Derényi ◽  
Gergely J. Szöllősi
Keyword(s):  
Selective Advantage ◽  
Cell Number ◽  
Significant Determinant ◽  
Size Dependent ◽  
Somatic Evolution ◽  
Tissue Organization ◽  
Tissue Size ◽  
Risk Of Cancer ◽  
Proliferative Advantage ◽  
Fundamental Mechanism

Cancer is a genetic disease fueled by somatic evolution. Hierarchical tissue organization can slow somatic evolution by two qualitatively different mechanisms: by cell differentiation along the hierarchy “washing out” harmful mutations and by limiting the number of cell divisions required to maintain a tissue. Here we explore the effects of compartment size on somatic evolution in hierarchical tissues by considering cell number regulation that acts on cell division rates such that the number of cells in the tissue has the tendency to return to its desired homeostatic value. Introducing mutants with a proliferative advantage, we demonstrate the existence of a third fundamental mechanism by which hierarchically organized tissues are able to slow down somatic evolution. We show that tissue size regulation leads to the emergence of a threshold proliferative advantage, below which mutants cannot persist. We find that the most significant determinant of the threshold selective advantage is compartment size, with the threshold being higher the smaller the compartment. Our results demonstrate that, in sufficiently small compartments, even mutations that confer substantial proliferative advantage cannot persist, but are expelled from the tissue by differentiation along the hierarchy. The resulting selective barrier can significantly slow down somatic evolution and reduce the risk of cancer by limiting the accumulation of mutations that increase the proliferation of cells.

scholarly journals Trade-off between reducing mutational load and increasing commitment to differentiation determines tissue organization

2020 ◽  
Author(s):  
Márton Demeter ◽  
Imre Derényi ◽  
Gergely J. Szöllősi
Keyword(s):  
Tumor Suppressor Genes ◽  
Mutation Accumulation ◽  
Specific Level ◽  
Trade Off ◽  
Somatic Evolution ◽  
Tissue Organization ◽  
Copy Numbers ◽  
Magnitude Variation ◽  
Species Specific ◽  
Risk Of Cancer

AbstractSpecies-specific differences control cancer risk across orders of magnitude variation in body size and lifespan, e.g., by varying the copy numbers of tumor suppressor genes. It is unclear, however, how different tissues within an organism can control somatic evolution despite being subject to markedly different constraints but sharing the same genome. Hierarchical differentiation, characteristic of self-renewing tissues, can restrain somatic evolution both by limiting divisional load, thereby reducing mutation accumulation, and by increasing the cells’ commitment to differentiation, which can “wash out” mutants. Here, we explore the organization of hierarchical tissues that have evolved to limit their lifetime risk of cancer to a tissue-specific level. Analytically estimating the likelihood of cancer, we demonstrate that a trade-off exists between mutation accumulation and the strength of washing out. This result explains the differences in the organization of widely different hierarchically differentiating tissues, such as the colon and the blood.

scholarly journals Eiger/TNFα-mediated Dilp8 and ROS production coordinate intra-organ growth inDrosophila

2019 ◽  
Author(s):  
Juan A. Sanchez ◽  
Duarte Mesquita ◽  
María C. Ingaramo ◽  
Federico Ariel ◽  
Marco Milán ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Cell Number ◽  
Cell Populations ◽  
Adjacent Cell ◽  
Oxygen Species ◽  
Organ Growth ◽  
Animal Development ◽  
Tissue Size ◽  
Different Parts

ABSTRACTCoordinated intra- and inter-organ growth is essential during animal development to generate individuals of proper size and shape. TheDrosophilawing has been a valuable model system to reveal the existence of a stress response mechanism mediated by Drosophila p53 (Dmp53) and involved in the coordination of tissue growth between adjacent cell populations upon targeted reduction of growth rates. Here we present evidence that a two-step molecular mechanism is being used by Dmp53 to reduce in a non-autonomous manner growth and proliferation in adjacent cell populations. First, Dmp53-mediated transcriptional induction ofDrosophilaTNFα ligand Eiger leads to cell autonomous activation of JNK. Second, two different signaling events downstream of the Eiger/JNK axis are induced in the growth depleted territory in order to independently regulate tissue size and cell number in adjacent cell populations. Whereas expression of the systemic hormone dILP8 coordinates intra-organ growth and final tissue size, induction of Reactive Oxygen Species downstream of Eiger/JNK and, as a consequence of apoptosis induction, acts non-cell-autonomously to regulate proliferation rates of adjacent epithelial cells. Our results unravel how local and systemic signals can act concertedly to coordinate growth and proliferation within an organ in order to generate well-proportioned organs and functionally integrated adults.Author SummaryCoordination of growth between the different parts of a given developing organ is an absolute requirement for the generation of functionally integrated structures during animal development. Although this question has fascinated biologists for centuries, the responsible molecular mechanisms have remained so far unknown. In this work, we have used the developing wing primordium of Drosophila to identify the molecular mechanisms and signaling molecules mediating communication between adjacent cell populations upon targeted reduction in growth rates. We first present evidence that activation of Drosophila p53 in the growth-depleted territory induces expression of the fly TNF ligand Eiger which cell autonomously activates the JNK stress signaling pathway. While JNK-dependent expression of the systemic hormone dILP8 reduces growth and final size of the adjacent territories, production of Reactive Oxygen Species downstream of JNK and the apoptotic machinery act locally to regulate proliferation rates in adjacent epithelial cells. Our data reveal how signals acting locally or systemically can regulate cell proliferation and growth independently to accomplish coordination in tissue size and cell number among different parts of an organ in order to give rise to well-proportioned adult structures.HIGHLIGHTS✓ Dmp53-dependent Eiger expression is required to coordinate intra-organ growth✓ Eiger acts through its receptor Grindelwald and JNK signaling to reduce growth and proliferation rates in a non-cell-autonomous manner✓ Eiger/JNK-dependent Dilp8 expression coordinates intra-organ growth but not proliferation✓ Eiger/JNK activation triggers ROS production✓ ROS act non-cell-autonomously to regulate proliferation of adjacent epithelial cells.

Tissue size and cell number in the olive (Olea europaea) ovary determine tissue growth and partitioning in the fruit

2012 ◽  
Vol 39 (7) ◽  
pp. 580 ◽  
Author(s):  
Adolfo Rosati ◽  
Silvia Caporali ◽  
Sofiene B. M. Hammami ◽  
Inmaculada Moreno-Alías ◽  
Andrea Paoletti ◽  
...  
Keyword(s):  
Olea Europaea ◽  
Cell Number ◽  
Tissue Growth ◽  
Tissue Cell ◽  
Tissue Mass ◽  
Relative Growth ◽  
Tissue Size ◽  
The Relationship ◽  
Single Regression ◽  
Olea Europaéa

The relationship between tissue size and cell number in the ovary and tissue size in the fruit, was studied in eight olive (Olea europaea L.) cultivars with different fruit and ovary size. All tissues in the ovary increased in size with increasing ovary size. Tissue size in the fruits correlated with tissue size in the ovary for both mesocarp and endocarp, but with different correlations: the mesocarp grew about twice as much per unit of initial volume in the ovary. Tissue size in the fruit also correlated with tissue cell number in the ovary. In this case, a single regression fitted all data pooled for both endocarp and mesocarp, implying that a similar tissue mass was obtained in the fruit per initial cell in the ovary, independent of tissues and cultivars. Tissue relative growth from bloom to harvest (i.e. the ratio between final and initial tissue size) differed among cultivars and tissues, but correlated with tissue cell size at bloom, across cultivars and tissues. These results suggest that in olive, tissue growth and partitioning in the fruit is largely determined by the characteristics of the ovary tissues at bloom, providing important information for plant breeding and crop management.

scholarly journals Size matters: height, cell number and a person's risk of cancer

2018 ◽  
Vol 285 (1889) ◽  
pp. 20181743 ◽  
Author(s):  
Leonard Nunney
Keyword(s):  
Cancer Risk ◽  
Large Scale ◽  
Strong Relationship ◽  
Cell Number ◽  
Mammal Species ◽  
Division Rate ◽  
Multistage Model ◽  
Number Variation ◽  
Cancer Suppression ◽  
Risk Of Cancer

The multistage model of carcinogenesis predicts cancer risk will increase with tissue size, since more cells provide more targets for oncogenic somatic mutation. However, this increase is not seen among mammal species of different sizes (Peto's paradox), a paradox argued to be due to larger species evolving added cancer suppression. If this explanation is correct, the cell number effect is still expected within species. Consistent with this, the hazard ratio for overall cancer risk per 10 cm increase in human height (HR 10 ) is about 1.1, indicating a 10% increase in cancer risk per 10 cm; however, an alternative explanation invokes an indirect effect of height, with factors that increase cancer risk independently increasing adult height. The data from four large-scale surveillance projects on 23 cancer categories were tested against quantitative predictions of the cell-number hypothesis, predictions that were accurately supported. For overall cancer risk the HR 10 predicted versus observed was 1.13 versus 1.12 for women and 1.11 versus 1.09 for men, suggesting that cell number variation provides a null hypothesis for assessing height effects. Melanoma showed an unexpectedly strong relationship to height, indicating an additional effect, perhaps due to an increasing cell division rate mediated through increasing IGF-I with height. Similarly, only about one-third of the higher incidence of non-reproductive cancers in men versus women can be explained by cell number. The cancer risks of obesity are not correlated with effects of height, consistent with different primary causation. The direct effect of height on cancer risk suggests caution in identifying height-related SNPs as cancer causing.

scholarly journals An examination of adaptive reversion in Saccharomyces cerevisiae.

Genetics ◽  
1992 ◽  
Vol 132 (1) ◽  
pp. 9-21 ◽  
Author(s):  
D F Steele ◽  
S Jinks-Robertson
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Frameshift Mutation ◽  
Selective Advantage ◽  
Cell Number ◽  
Time Dependent ◽  
Complete Medium ◽  
Dependent Manner ◽  
Adaptive Mutations ◽  
Synthetic Complete ◽  
Selective Plating

Abstract Reversion to Lys+ prototrophy in a haploid yeast strain containing a defined lys2 frameshift mutation has been examined. When cells were plated on synthetic complete medium lacking only lysine, the numbers of Lys+ revertant colonies accumulated in a time-dependent manner in the absence of any detectable increase in cell number. An examination of the distribution of the numbers of early appearing Lys+ colonies from independent cultures suggests that the mutations to prototrophy occurred randomly during nonselective growth. In contrast, an examination of the distribution of late appearing Lys+ colonies indicates that the underlying reversion events occurred after selective plating. No accumulation of Lys+ revertants occurred when cells were starved for tryptophan, leucine or both lysine and tryptophan prior to plating selectively for Lys+ revertants. These results indicate that mutations accumulate more frequently when they confer a selective advantage, and are thus consistent with the occurrence of adaptive mutations in yeast.

The effects of Streptomyces hyaluronidase on tissue organization and cell cycle time in rat embryos

Development ◽  
1986 ◽  
Vol 98 (1) ◽  
pp. 59-70 ◽  
Author(s):  
Gillian M. Morriss-Kay ◽  
Fiona Tuckett ◽  
Michael Solursh
Keyword(s):  
Cell Cycle ◽  
Extracellular Matrix ◽  
Cycle Time ◽  
Cell Number ◽  
Considerable Reduction ◽  
Blue Staining ◽  
Neuroepithelial Cell ◽  
Cell Cycle Time ◽  
Rat Embryos ◽  
Tissue Organization

Day 9 rat embryos (late presomite stage with cranial neural plate or very early neural folds) were cultured for various periods of time from 6–48 h in medium containing 20 TRU ml−1Streptomyces hyaluronidase. Exposure to the enzyme resulted in considerable reduction of mesenchymal extracellular matrix. Access of the enzyme to the embryo was confirmed by alcian blue staining which indicated considerable reduction of extracellular and cell surface hyaluronate. Cranial neurulation was retarded, but not inhibited, and migration of both neural crest and primary mesenchyme cells occurred. In general, morphology was normal at 48 h. The major effect was on growth: embryos were smaller, with slightly reduced neuroepithelial cell number and greatly reduced mesenchymal cell number. Neuroepithelial cell cycle time was slightly prolonged, and that of the mesenchyme more than doubled. This differential effect on the growth rates of these two tissues reflects the normal distribution of hyaluronate, which is particularly abundant in the mesenchymal extracellular matrix.

The mechanism of the training of Bact. lactis aerogenes to D-arabinose

1951 ◽  
Vol 139 (894) ◽  
pp. 58-73 ◽  
Keyword(s):  
Experimental Studies ◽  
Selective Advantage ◽  
Cell Number ◽  
Lag Phase ◽  
Normal Cells ◽  
Metabolic Route ◽  
Statistical Variations ◽  
Sterile Filtrate ◽  
Mutant Cells ◽  
Bacterial Mass

Further experimental studies of the training of Bact. lactis aerogenes to utilize the pentose D-arabinose yield evidence against the presence in unadapted or partially adapted strains of the two distinct classes of normal and mutant cells. It has been found that the lag preceding colony formation by an unadapted strain on a solid medium is never less than the lag observed under comparable conditions in a liquid culture, but decreases continuously with the time of previous exposure to D-arabinose; that the presence of untrained cells does not inhibit the multiplication of rained cells; that the growth curve is not that characteristic of a simple mixture of normal cells and mutants; that at the end of the long lag phase the bacterial mass increases considerably before any detectable increase in cell number occurs, and that in favourable cases every cell present can become adapted. During the earliest stages of growth on D-arabinose no stably trained cells can be detected, all undergoing rapid reversion when grown in the presence of glucose under conditions where the selection of reverse mutants or of untrained cells could not be important. In mixtures of fully trained and normal cells there is no selective advantage in favour of the latter when prolonged subculture is made in glucose. The absence of reversion with fully trained cells cannot, therefore, be explained in this way (a matter relevant to a previous study). Co-operative effects result in a variation in lag according to the conditions of culture, and show themselves in the influence of sterile filtrate from grown cultures. The statistical variations in the length of the lag phase have been examined. It is concluded that no simple theory of mutation and selection will account for the observations, which, on the other hand, are adequately explained by a hypothesis of direct adaptation, i. e. the development on growth of an alternative metabolic route in the normal cell.

The mechanism of the training of Bact. lactis aerogenes to D-arabinose

1951 ◽  
Vol 210 (1100) ◽  
pp. 142-142
Keyword(s):  
Experimental Studies ◽  
Selective Advantage ◽  
Cell Number ◽  
Lag Phase ◽  
Normal Cells ◽  
Metabolic Route ◽  
Statistical Variations ◽  
Sterile Filtrate ◽  
Mutant Cells ◽  
Bacterial Mass

Further experimental studies of the training of Bact. lactis aerogenes to utilize the pentose D-arabinose yield evidence against the presence in unadapted or partially adapted strains of the two distinct classes of normal and mutant cells. It has been found that the lag preceding colony formation by an unadapted strain on a solid medium is never less than the lag observed under comparable conditions in a liquid culture, but decreases continuously with the time of previous exposure to D-arabinose; that the presence of untrained cells does not inhibit the multiplication of trained cells; that the growth curve is not that characteristic of a simple mixture of normal cells and mutants; that at the end of the long lag phase the bacterial mass increases considerably before any detectable increase in cell number occurs, and that in favourable cases every cell present can become adapted. During the earliest stages of growth on D-arabinose no stably trained cells can be detected, all undergoing rapid reversion when grown in the presence of glucose under conditions where the selection of reverse mutants or of untrained cells could not be important. In mixtures of fully trained and normal cells there is no selective advantage in favour of the latter when prolonged subculture is made in glucose. The absence of reversion with fully trained cells can not, therefore, be explained in this way (a matter relevant to a previous study). Co-operative effects result in a variation in lag according to the conditions of culture, and show themselves in the influence of sterile filtrate from grown cultures. The statistical variations in the length of the lag phase have been examined. It is concluded that no simple theory of mutation and selection will account for the observations, which, on the other hand, are adequately explained by a hypothesis of direct adaptation, i. e. the development on growth of an alternative metabolic route in the normal cell.

Toxicity of BSA-stabilized Silver Nanoparticles on Immune Circulating Cells

2007 ◽  
Vol 1061 ◽  
Author(s):  
Imani Hayman ◽  
Patrick Mehl ◽  
Veena Kapoor ◽  
Otto Wilson
Keyword(s):  
Wound Healing ◽  
Silver Nanoparticles ◽  
Synthesis Method ◽  
Antimicrobial Properties ◽  
Cell Number ◽  
Dependent Manner ◽  
Size Dependent ◽  
Circulating Cells ◽  
Bactericidal Properties ◽  
Nanoparticles Concentration

ABSTRACTSilver nanoparticles have shown immense potential in many biomedical applications, specifically wound healing. These nanoparticles reduce the degree of inflammation in wounds and increase the rate of wound healing overall in a dose-dependent manner. Moreover, silver nanoparticles exhibit antibacterial and antimicrobial properties. While the mechanism of action for silver nanoparticles is not clear, current studies focus on the effect of silver nanoparticles on recipient cells and tissues. It is shown that silver nanoparticles are more toxic to these recipient cells in comparison to other metal nanoparticles. This suggests that the bactericidal properties of the silver nanoparticles are size dependent. Our present work investigates the toxicity level of silver nanoparticles on specific immune circulating cells. The approach is to report the LD50 level as a function of the ratio of the nanoparticles concentration (ppm) to the cell concentration (cell number/ml) used in the assays. This method allows a normalization of the LD50 capable to compare the toxicity of the nanoparticle on different types of cells. Next, the localization of the silver nanoparticles within the cells will be determined, and the toxic mode of action of the nanoparticles will be modulated by the modification of the synthesis method.

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