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Non-stem cancer cell kinetics modulate solid tumor progression.

Morton CI, Hlatky L, Hahnfeldt P, Enderling H - Theor Biol Med Model (2011)

Bottom Line: Solid tumors are heterogeneous in composition.Conversely, shorter generational life spans yield persistence-limited tumors, with symmetric division frequency of CSCs determining tumor growth rate.In our model, intermediate proliferative capacities give rise to the fastest-growing tumors, resulting in self-metastatic expansion driven by a balance between symmetric CSC division and expansion of the non-stem cancer population.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center of Cancer Systems Biology, St, Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA. heiko.enderling@tufts.edu

ABSTRACT

Background: Solid tumors are heterogeneous in composition. Cancer stem cells (CSCs) are believed to drive tumor progression, but the relative frequencies of CSCs versus non-stem cancer cells span wide ranges even within tumors arising from the same tissue type. Tumor growth kinetics and composition can be studied through an agent-based cellular automaton model using minimal sets of biological assumptions and parameters. Herein we describe a pivotal role for the generational life span of non-stem cancer cells in modulating solid tumor progression in silico.

Results: We demonstrate that although CSCs are necessary for progression, their expansion and consequently tumor growth kinetics are surprisingly modulated by the dynamics of the non-stem cancer cells. Simulations reveal that slight variations in non-stem cancer cell proliferative capacity can result in tumors with distinctly different growth kinetics. Longer generational life spans yield self-inhibited tumors, as the emerging population of non-stem cancer cells spatially impedes expansion of the CSC compartment. Conversely, shorter generational life spans yield persistence-limited tumors, with symmetric division frequency of CSCs determining tumor growth rate. We show that the CSC fraction of a tumor population can vary by multiple orders of magnitude as a function of the generational life span of the non-stem cancer cells.

Conclusions: Our study suggests that variability in the growth rate and CSC content of solid tumors may be, in part, attributable to the proliferative capacity of the non-stem cancer cell population that arises during asymmetric division of CSCs. In our model, intermediate proliferative capacities give rise to the fastest-growing tumors, resulting in self-metastatic expansion driven by a balance between symmetric CSC division and expansion of the non-stem cancer population. Our results highlight the importance of non-stem cancer cell dynamics in the CSC hypothesis, and may offer a novel explanation for the large variations in CSC fractions reported in vivo.

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The relative size of the CSC compartment of model tumors is inversely proportional to the generational life span of the non-stem cancer cell progeny. Top row, ps = 1%; bottom row, ps = 10%. From left to right, μ = 0, 5, 10, and 15 cell widths/day. Model tumors seeded by CSC with low replicative potentials depended more strongly on symmetric division for macroscopic expansion and as such comprised a higher CSC fraction than those comprising deeper mortal non-stem cancer cell hierarchies. Early high amplitude fluctuations are attributable to the stochastic nature of growth, but in all cases, CSC fraction approaches a pseudo steady-state composition consistent with self-metastatic expansion.
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Figure 7: The relative size of the CSC compartment of model tumors is inversely proportional to the generational life span of the non-stem cancer cell progeny. Top row, ps = 1%; bottom row, ps = 10%. From left to right, μ = 0, 5, 10, and 15 cell widths/day. Model tumors seeded by CSC with low replicative potentials depended more strongly on symmetric division for macroscopic expansion and as such comprised a higher CSC fraction than those comprising deeper mortal non-stem cancer cell hierarchies. Early high amplitude fluctuations are attributable to the stochastic nature of growth, but in all cases, CSC fraction approaches a pseudo steady-state composition consistent with self-metastatic expansion.

Mentions: The fraction of CSCs in tumors is directly dependent on the generational life span of CCs. With increasing ρmax, the CSC fraction decreases independently of any other parameter (Figure 7). When ρmax = 0, CCs die upon a first attempt at division, leading to a large CSC fraction. CCs, however, are still present as they arise from asymmetric CSC division with high frequency. Without migration, mature tumors comprised over 70% CSC at ρmax = 0. Increasing values of ρmax decreases CSC fractions to as low as 0.1% (ρmax = 10, μ = 15, and ps = 1%).


Non-stem cancer cell kinetics modulate solid tumor progression.

Morton CI, Hlatky L, Hahnfeldt P, Enderling H - Theor Biol Med Model (2011)

The relative size of the CSC compartment of model tumors is inversely proportional to the generational life span of the non-stem cancer cell progeny. Top row, ps = 1%; bottom row, ps = 10%. From left to right, μ = 0, 5, 10, and 15 cell widths/day. Model tumors seeded by CSC with low replicative potentials depended more strongly on symmetric division for macroscopic expansion and as such comprised a higher CSC fraction than those comprising deeper mortal non-stem cancer cell hierarchies. Early high amplitude fluctuations are attributable to the stochastic nature of growth, but in all cases, CSC fraction approaches a pseudo steady-state composition consistent with self-metastatic expansion.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3285090&req=5

Figure 7: The relative size of the CSC compartment of model tumors is inversely proportional to the generational life span of the non-stem cancer cell progeny. Top row, ps = 1%; bottom row, ps = 10%. From left to right, μ = 0, 5, 10, and 15 cell widths/day. Model tumors seeded by CSC with low replicative potentials depended more strongly on symmetric division for macroscopic expansion and as such comprised a higher CSC fraction than those comprising deeper mortal non-stem cancer cell hierarchies. Early high amplitude fluctuations are attributable to the stochastic nature of growth, but in all cases, CSC fraction approaches a pseudo steady-state composition consistent with self-metastatic expansion.
Mentions: The fraction of CSCs in tumors is directly dependent on the generational life span of CCs. With increasing ρmax, the CSC fraction decreases independently of any other parameter (Figure 7). When ρmax = 0, CCs die upon a first attempt at division, leading to a large CSC fraction. CCs, however, are still present as they arise from asymmetric CSC division with high frequency. Without migration, mature tumors comprised over 70% CSC at ρmax = 0. Increasing values of ρmax decreases CSC fractions to as low as 0.1% (ρmax = 10, μ = 15, and ps = 1%).

Bottom Line: Solid tumors are heterogeneous in composition.Conversely, shorter generational life spans yield persistence-limited tumors, with symmetric division frequency of CSCs determining tumor growth rate.In our model, intermediate proliferative capacities give rise to the fastest-growing tumors, resulting in self-metastatic expansion driven by a balance between symmetric CSC division and expansion of the non-stem cancer population.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center of Cancer Systems Biology, St, Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA. heiko.enderling@tufts.edu

ABSTRACT

Background: Solid tumors are heterogeneous in composition. Cancer stem cells (CSCs) are believed to drive tumor progression, but the relative frequencies of CSCs versus non-stem cancer cells span wide ranges even within tumors arising from the same tissue type. Tumor growth kinetics and composition can be studied through an agent-based cellular automaton model using minimal sets of biological assumptions and parameters. Herein we describe a pivotal role for the generational life span of non-stem cancer cells in modulating solid tumor progression in silico.

Results: We demonstrate that although CSCs are necessary for progression, their expansion and consequently tumor growth kinetics are surprisingly modulated by the dynamics of the non-stem cancer cells. Simulations reveal that slight variations in non-stem cancer cell proliferative capacity can result in tumors with distinctly different growth kinetics. Longer generational life spans yield self-inhibited tumors, as the emerging population of non-stem cancer cells spatially impedes expansion of the CSC compartment. Conversely, shorter generational life spans yield persistence-limited tumors, with symmetric division frequency of CSCs determining tumor growth rate. We show that the CSC fraction of a tumor population can vary by multiple orders of magnitude as a function of the generational life span of the non-stem cancer cells.

Conclusions: Our study suggests that variability in the growth rate and CSC content of solid tumors may be, in part, attributable to the proliferative capacity of the non-stem cancer cell population that arises during asymmetric division of CSCs. In our model, intermediate proliferative capacities give rise to the fastest-growing tumors, resulting in self-metastatic expansion driven by a balance between symmetric CSC division and expansion of the non-stem cancer population. Our results highlight the importance of non-stem cancer cell dynamics in the CSC hypothesis, and may offer a novel explanation for the large variations in CSC fractions reported in vivo.

Show MeSH
Related in: MedlinePlus