Elucidating the Role Played by Cancer Stem Cells in Cancer Growth

Abstract

The cancer stem cell hypothesis states that cancer growth is propelled by a relatively small number of cancer stem cells (CSCs). These CSCs have been shown to play a crucial role in the growth and recurrence of many tumor types. The possibility that their elimination becomes an efficient cancer control procedure has even led to new therapeutic paradigms. On the other hand, from their early stages, most solid tumors grow in stressed environments. The stress field impacts on tumor evolution, and it is likely to affect different cancer cell populations in different ways. It is therefore of great interest to determine the nature and strength of the interactions between CSCs and differentiated tumor cells and how these interactions are affected by the mechanical properties of the environment. We have developed a two-population mathematical model suitable to describe the initial stages of cancer growth and applied it to extract information from three different experiments. Two of these experiments involve tumorspheres (spheroids resulting from the proliferation of a single CSC). In these cases, the model validates the concept of CSC niche (the microenvironment responsible for signals that stimulate or inhibit CSC growth), shows that interspecific interactions stimulate growth, while intraspecific interactions are generally inhibitory, and indicates how substrate hardness modifies growth. In the third experiment analyzed, where stress-induced growth suppression was measured in multicellular tumor spheroids, we were able to reconstruct the (unobserved) CSC fraction and found that medium rigidity eventually forces all cell interactions to be competitive. We find that, under adverse environmental conditions the CSC fraction always remains nonzero. This lends support to the hypothesis of the existence of the niche as a regulatory maintenance mechanism whose understanding will be crucial to the development of a successful therapy based on CSC elimination.