Cancer stem cells have been shown to be critical to the development of a variety of solid cancers. The precise interplay mechanisms between cancer stem cells and the rest of a tissue are still not elucidated. To shed light on the interactions between stem and non-stem cancer cell populations we develop a two-population mathematical model, which is suitable to describe tumorsphere growth. Both interspecific and intraspecific interactions, mediated by the microenvironment, are included. We show that there is a tipping point, characterized by a transcritical bifurcation, where a purely non-stem cell attractor is replaced by a new attractor that contains both stem and differentiated cancer cells. The model is then applied to describe the outcome of a recent experiment. This description reveals that, while the intraspecific interactions are inhibitory, the interspecific interactions stimulate growth. This can be understood in terms of stem cells needing differentiated cells to reinforce their niches, and phenotypic plasticity favoring the de-differentiation of differentiated cells into cancer stem cells. We posit that this is a consequence of the deregulation of the quorum sensing that maintains homeostasis in healthy tissues.
Background Cancer stem cells are important for the development of many solid tumors. These cells receive promoting and inhibitory signals that depend on the nature of their environment (their niche) and determine cell dynamics. Mechanical stresses are crucial to the initiation and interpretation of these signals. Methods A two-population mathematical model of tumorsphere growth is used to interpret the results of a series of experiments recently carried out in Tianjin, China, and extract information about the intraspecific and interspecific interactions between cancer stem cell and differentiated cancer cell populations. Results The model allows us to reconstruct the time evolution of the cancer stem cell fraction, which was not directly measured. We find that, in the presence of stem cell growth factors, the interspecific cooperation between cancer stem cells and differentiated cancer cells induces a positive feedback loop that determines growth, independently of substrate hardness. In a frustrated attempt to reconstitute the stem cell niche, the number of cancer stem cells increases continuously with a reproduction rate that is enhanced by a hard substrate. For growth on soft agar, intraspecific interactions are always inhibitory, but on hard agar the interactions between stem cells are collaborative while those between differentiated cells are strongly inhibitory. Evidence also suggests that a hard substrate brings about a large fraction of asymmetric stem cell divisions. In the absence of stem cell growth factors, the barrier to differentiation is broken and overall growth is faster, even if the stem cell number is conserved. Conclusions Our interpretation of the experimental results validates the centrality of the concept of stem cell niche when tumor growth is fueled by cancer stem cells. Niche memory is found to be responsible for the characteristic population dynamics observed in tumorspheres. The model also shows why substratum stiffness has a deep influence on the behavior of cancer stem cells, stiffer substrates leading to a larger proportion of asymmetric doublings. A specific condition for the growth of the cancer stem cell number is also obtained
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.