Understanding the Influence of Substrate When Growing Tumorspheres

Abstract

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. A specific condition for the growth of the cancer stem cell number is also obtained.

Radial percolation reveals that Cancer Stem Cells are trapped in the core of colonies

“…From the point of view of the populations, the last two possibilities correspond to the birth of a new DCC, the parent cell either keeping (in the asymmetric duplication) or losing (in the symmetric case) its stemness. For example, writing the corresponding population dynamics differential equations, Benítez et al showed that a CSC will give birth to another CSC at a rate rp s which is estimated by fitting their mathematical model to the experimental data [9,10]. Since the probability of self-replication p s seems to be small in homeostasis and in most common culture media, then rp s will also be small, leading to quiescence, a main feature of CSCs.…”

“…The addition of stem cell maintenance factors such as EGF or bFGF to the culture medium is an example of this case. These limiting situations were previously studied both experimentally [11,18] and mathematically [9,10], focusing in the first case on technical aspects of the assay, and in the second case on recovery of the CSC fraction.…”