Plasticity in cancer stem cells: the role of stochasticity, genetic instability, epigenetics and the microenvironment.

The cancer stem cell (CSC) theory proposes that a tumor is maintained and propagated by a cancer cell with stem cell-like properties. CSCs have been implicated to be the main driver for tumor initiation, propagation, metastasis and recurrence. Although a lot of work has been performed on identifying and characterizing CSCs, no unifiable markers for, and characteristics of CSCs, have been established to date. More recently, a rising number of studies provide evidence that stemness characteristics can be acquired by more differentiated cancer cells, giving rise to de novo CSCs. Therefore, the CSC theory shifts towards a model in which the CSC characteristics can be acquired by stochastic mechanisms, genetic and epigenetic changes and extrinsic factors from the microenvironment, which could also be defined as the CSC niche. Most studies on CSC plasticity have been performed using in vitro studies, serial transplants or xenograft assays. These methods represent another environment than the unperturbed tumor and are static models, making it challenging to study in vivo CSC dynamics. Intravital imaging techniques in combination with genetic lineage tracing will enable researchers to study CSCs over time and in the unperturbed and will most likely prove to be essential in studying CSC dynamics in vivo. To summarize, this thesis reviews current challenges in CSC identification and reviews mechanisms which have been found to induce de novo CSC generation. Additionally, future experimental setups and the therapeutic consequences of de novo generation of CSCs will be discussed