Self-Renewal and Differentiation Mechanisms
in Tumor Stem Cell Homeostasis
One of the crucial questions in tumor biology is the identity of the cell and cellular programme that drive tumor growth. Two models best describe the growth characteristics of tumors: the stochasctic and the hierarchy model (Fig. 1).
The stochastic model postulates that each cell within the tumor has the same capacity to proliferate and thus sustain tumor growth. Tumor heterogeneity is explained by the existence of multiple genetic tumor subclones, due to cumulative acquisition of genetic alterations. Conversely, the hierarchy model assumes that only a small subpopultation of tumor cells has the capacity to initiate and drive tumor growth, the so called tumor stem cells. This specialized cell type possesses the key stem cell characteristics, namely self renewal and multipotency. It gives rise to a more differentiated progeny that has lost the ability to initiate tumor growth. Thus, the hierarchy model adds stem cell differentiation as an additional factor to explain tumor heterogeneity. Consequently, the hierarchy model crucially challenges our current concept of tumor research and treatment, that has concentrated on the bulk of tumor cells, potentially missing out on the decisive mechanisms that regulate tumor stem cells. In analogy to physiological stem cell homeostasis, self renewal and differentiation mechanisms may critically influence tumor stem cell biology.
Our current research suggests that glioblastoma growth is determined by self renewal and differentiation mechanisms. We can demonstrate that glioblastomas, in vitro and in vivo, are composed of cell populations that are heterogeneous in the expression of stem cell and differentiation markers (Fig. 1). Moreover, using the side population technique, a functional assay that has been successfully employed to enrich for stem cells in different organs, we are able to isolate a subpopulation of tumor cells with stem cell characteristics, i.e. these cells show the ability to self renew and initiate tumor growth in vivo as well as the ability to give rise to a more differentiated progeny.
Our results support the validity of the tumor stem cell concept and the existence of a differentiation hierarchy in glioblastomas. Using gain- and loss-of-function experiments, we are currently further functionally characterizing how self renewal and differentiation mechanisms determine tumor stem cell homeostasis in glioblastomas.