Abstract
BackgroundSolid 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.ResultsWe 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.ConclusionsOur 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.
Highlights
The cancer stem cell (CSC) hypothesis is a conceptual construct of tumor initiation, composition, and clinical response
We assume that (i) CSCs are immortal with unlimited replicative potential, (ii) cancer cells (CCs) maximum proliferative capacity rmax is inherited from the parent CSC following an asymmetric division, (iii) the probability of symmetric and asymmetric (1 - ps) CSC division is constant and stochastic, and (iv) cells require adjacent available space to migrate or proliferate
The high variance in frequency of cancer cells expressing stem cell biomarkers within different tumors of the same tissue type can be attributed to intrinsic tumor hierarchy
Summary
The cancer stem cell (CSC) hypothesis is a conceptual construct of tumor initiation, composition, and clinical response. 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. Computational modeling in the context of the cancer stem cell hypothesis is an invaluable tool for assessing the relative contributions of basic cellular kinetics to macroscopic growth dynamics and composition of solid tumors. Understanding the oft-neglected contribution of the non-stem population within a heterogeneous tumor will help explain the large variations in cancer stem cell frequency reported in the literature, and help guide the design of appropriate treatments for patients with different disease presentations
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