Non-stem cancer cell kinetics modulate solid tumor progression

Authored by Heiko Enderling, Lynn Hlatky, Philip Hahnfeldt, Charles I. Morton

Date Published: 2011-12-30

DOI: 10.1186/1742-4682-8-48

Sponsors: AACR United States National Institutes of Health (NIH)

Platforms: No platforms listed

Model Documentation: Other Narrative Flow charts

Model Code URLs: Model code not found

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.

Tags

Agent-based modeling Cancer stem cells Solid Tumor Growth Kinetics