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Emergent Stratification in Solid Tumors Selects for Reduced Cohesion of Tumor Cells: A Multi-Cell, Virtual-Tissue Model of Tumor Evolution Using CompuCell3D.

Swat MH, Thomas GL, Shirinifard A, Clendenon SG, Glazier JA - PLoS ONE (2015)

Bottom Line: Our model includes essential cell behaviors, microenvironmental components and their interactions.Our model provides a platform for exploring selection pressures leading to the evolution of tumor-cell aggression, showing that emergent stratification into regions with different cell survival rates drives the evolution of less cohesive cells with lower levels of cadherins and higher levels of integrins.Such reduced cohesivity is a key hallmark in the progression of many types of solid tumors.

View Article: PubMed Central - PubMed

Affiliation: Biocomplexity Institute and Department of Physics, Indiana University, Bloomington, Indiana, USA.

ABSTRACT
Tumor cells and structure both evolve due to heritable variation of cell behaviors and selection over periods of weeks to years (somatic evolution). Micro-environmental factors exert selection pressures on tumor-cell behaviors, which influence both the rate and direction of evolution of specific behaviors, especially the development of tumor-cell aggression and resistance to chemotherapies. In this paper, we present, step-by-step, the development of a multi-cell, virtual-tissue model of tumor somatic evolution, simulated using the open-source CompuCell3D modeling environment. Our model includes essential cell behaviors, microenvironmental components and their interactions. Our model provides a platform for exploring selection pressures leading to the evolution of tumor-cell aggression, showing that emergent stratification into regions with different cell survival rates drives the evolution of less cohesive cells with lower levels of cadherins and higher levels of integrins. Such reduced cohesivity is a key hallmark in the progression of many types of solid tumors.

No MeSH data available.


Related in: MedlinePlus

Average lifetime of generalized cells, by initial generalized-cell type.In each bar, the black-red boundary is the minimum generalized-cell lifetime, the red-blue boundary is the median generalized-cell lifetime and the top of the blue portion is the maximum generalized-cell lifetime, all averaged over all cells of the specified initial generalized-cell type and over all replicas for a given Pm and δam.
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pone.0127972.g014: Average lifetime of generalized cells, by initial generalized-cell type.In each bar, the black-red boundary is the minimum generalized-cell lifetime, the red-blue boundary is the median generalized-cell lifetime and the top of the blue portion is the maximum generalized-cell lifetime, all averaged over all cells of the specified initial generalized-cell type and over all replicas for a given Pm and δam.

Mentions: Fig 14 shows the lifetimes for different initial generalized-cell types for different values of Pm and δam. As we expect, Necrotic generalized cells have short lifetimes and total travel distances, so the period a generalized cell spends in necrosis has a small effect on its total lifetime and travel distance. Quiescent non-stem generalized cells (QC) clearly have a lower probability of dying by senescence than proliferating non-stem generalized cells, since they do not divide, but, since quiescent generalized cells are closer to glucose-depleted regions than proliferating generalized cells, we might expect them also to have a higher probability of entering a glucose-depleted region and becoming necrotic, shortening their lifetime. However, in all cases, the proliferating non-stem-like generalized cells have a shorter lifetime than the quiescent non-stem-like generalized cells, indicating that necrosis is more important than starvation in determining their lifetime. As a result, initially quiescent non-stem-like generalized cells travel a longer total distance than initially proliferating non-stem-like generalized cells (Fig 15). Since stem-like generalized cells do not die from senescence, but are otherwise identical in properties to non-stem-like generalized cells, we would expect them to live longer than non-stem-like generalized cells, and, indeed, the typical lifetime of stem-like generalized cells is several-fold greater than that of non-stem-like generalized cells. As a result, initially proliferating stem-like generalized cells travel a longer total distance than proliferating non-stem-like generalized cells and quiescent stem-like generalized cells travel a longer total distance than quiescent non-stem-like generalized cells (Fig 15). The relationship between proliferating and quiescent stem-like generalized cells is more complex. Since these cells generalized do not experience senescence we would expect that proliferating stem-like generalized cells would have longer lifetimes than quiescent stem-like generalized cells. We see this relationship only for Pm = 0.2, δam = 0.5, Pm = 0.3, δam = 0.5 and Pm = 0.3 and δam = 1.0. In addition, for stem-like generalized cells, the relative lifetimes do not strictly correspond to the total travel distances, with the longer-lived type having a shorter total travel distance for Pm = 0.1, δam = 0.5, Pm = 0.2, δam = 0.5, Pm = 0.3, δam = 0.5.


Emergent Stratification in Solid Tumors Selects for Reduced Cohesion of Tumor Cells: A Multi-Cell, Virtual-Tissue Model of Tumor Evolution Using CompuCell3D.

Swat MH, Thomas GL, Shirinifard A, Clendenon SG, Glazier JA - PLoS ONE (2015)

Average lifetime of generalized cells, by initial generalized-cell type.In each bar, the black-red boundary is the minimum generalized-cell lifetime, the red-blue boundary is the median generalized-cell lifetime and the top of the blue portion is the maximum generalized-cell lifetime, all averaged over all cells of the specified initial generalized-cell type and over all replicas for a given Pm and δam.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4470639&req=5

pone.0127972.g014: Average lifetime of generalized cells, by initial generalized-cell type.In each bar, the black-red boundary is the minimum generalized-cell lifetime, the red-blue boundary is the median generalized-cell lifetime and the top of the blue portion is the maximum generalized-cell lifetime, all averaged over all cells of the specified initial generalized-cell type and over all replicas for a given Pm and δam.
Mentions: Fig 14 shows the lifetimes for different initial generalized-cell types for different values of Pm and δam. As we expect, Necrotic generalized cells have short lifetimes and total travel distances, so the period a generalized cell spends in necrosis has a small effect on its total lifetime and travel distance. Quiescent non-stem generalized cells (QC) clearly have a lower probability of dying by senescence than proliferating non-stem generalized cells, since they do not divide, but, since quiescent generalized cells are closer to glucose-depleted regions than proliferating generalized cells, we might expect them also to have a higher probability of entering a glucose-depleted region and becoming necrotic, shortening their lifetime. However, in all cases, the proliferating non-stem-like generalized cells have a shorter lifetime than the quiescent non-stem-like generalized cells, indicating that necrosis is more important than starvation in determining their lifetime. As a result, initially quiescent non-stem-like generalized cells travel a longer total distance than initially proliferating non-stem-like generalized cells (Fig 15). Since stem-like generalized cells do not die from senescence, but are otherwise identical in properties to non-stem-like generalized cells, we would expect them to live longer than non-stem-like generalized cells, and, indeed, the typical lifetime of stem-like generalized cells is several-fold greater than that of non-stem-like generalized cells. As a result, initially proliferating stem-like generalized cells travel a longer total distance than proliferating non-stem-like generalized cells and quiescent stem-like generalized cells travel a longer total distance than quiescent non-stem-like generalized cells (Fig 15). The relationship between proliferating and quiescent stem-like generalized cells is more complex. Since these cells generalized do not experience senescence we would expect that proliferating stem-like generalized cells would have longer lifetimes than quiescent stem-like generalized cells. We see this relationship only for Pm = 0.2, δam = 0.5, Pm = 0.3, δam = 0.5 and Pm = 0.3 and δam = 1.0. In addition, for stem-like generalized cells, the relative lifetimes do not strictly correspond to the total travel distances, with the longer-lived type having a shorter total travel distance for Pm = 0.1, δam = 0.5, Pm = 0.2, δam = 0.5, Pm = 0.3, δam = 0.5.

Bottom Line: Our model includes essential cell behaviors, microenvironmental components and their interactions.Our model provides a platform for exploring selection pressures leading to the evolution of tumor-cell aggression, showing that emergent stratification into regions with different cell survival rates drives the evolution of less cohesive cells with lower levels of cadherins and higher levels of integrins.Such reduced cohesivity is a key hallmark in the progression of many types of solid tumors.

View Article: PubMed Central - PubMed

Affiliation: Biocomplexity Institute and Department of Physics, Indiana University, Bloomington, Indiana, USA.

ABSTRACT
Tumor cells and structure both evolve due to heritable variation of cell behaviors and selection over periods of weeks to years (somatic evolution). Micro-environmental factors exert selection pressures on tumor-cell behaviors, which influence both the rate and direction of evolution of specific behaviors, especially the development of tumor-cell aggression and resistance to chemotherapies. In this paper, we present, step-by-step, the development of a multi-cell, virtual-tissue model of tumor somatic evolution, simulated using the open-source CompuCell3D modeling environment. Our model includes essential cell behaviors, microenvironmental components and their interactions. Our model provides a platform for exploring selection pressures leading to the evolution of tumor-cell aggression, showing that emergent stratification into regions with different cell survival rates drives the evolution of less cohesive cells with lower levels of cadherins and higher levels of integrins. Such reduced cohesivity is a key hallmark in the progression of many types of solid tumors.

No MeSH data available.


Related in: MedlinePlus