Description
The adult human brain has been for many years thought to be a static, fully differentiated organ. Today, it is generally accepted that both neural stem cells (NCS) and glial progenitor cells in multiple regions of the adult brain persist throughout life. The self-renewing and multipotent neural stem cells (NSCs) have been isolated from subventricular zone, the lining of the lateral ventricles, the dentate gyrus and the hippocampus, as wells as the subcortical white matter (Doetsch et al. 1997; Fukuda et al. 2003; Gage 2000; Kim and Morshead 2003).
While NSCs comprise a relatively quiescent cell population, these cells have the potential to proliferate and migrate extensively, characterizing the adult brain as dynamic system with surprisingly high plasticity (Altman and Chorover 1963; Altman and Das 1965; Doetsch et al. 1999). NSCs have been associated with tissue repair after stroke and severe injuries, and have been suggested as tools for treatment of neurological disorders, such as Alzheimer’s disease. In the light of these facts, cancer can be considered organ system with aberrant activation of developmental and wound response pathways (Rich 2008; Rich and Eyler 2008). Recent evidence suggests that within the heterogeneous tumor mass, there is a cell subpopulation with the unique capacity for sustained self-renewal and tumor propagation in vivo.
Historically, the approach to cancer treatment has been to eradicate all cancerous cells, where individual cells are equal in respect to their potential to proliferate, self-renew, and drive tumor growth. This notion, known as the stochastic or clonal evolution model (Fig. 1.1a) of tumorigenesis, proposes that a transformed single cell gains unlimited proliferative capacity (Chen et al. 2010; Li et al. 2007a; Shackleton et al. 2009). During early stages of tumorigenesis, a single or very few cells transform, where “pro-survival” mutations allow for clonal expansion of the “fittest” cells, resulting in a symbiotic coexistence of various subpopulations within the heterogeneous tumor mass. Importantly, during the lifetime of the tumor, any of the cancer cells can participate in tumor progression or develop resistance resulting in disease recurrence. This model has been challenged by the recently revived hierarchical model or the cancer stem cell hypothesis (Reya et al. 2001; Rich 2008; Sanai et al. 2005). The cancer stem cell hypothesis (Fig. 1.1b) postulates that there is a rare subpopulation of cancer cells with stem-like cell properties, including the ability to self-renew, that gives rise to multi-differentiated progeny and sustained proliferation. In contrast to stochastic model, the multipotent nature of these cells results in heterogeneity within tumor as a result of aberrant differen-tiation and epigenetic modification of the progeny, whereas the vast majority of progeny does not contribute to tumor growth and recurrence after therapeutic intervention.
This concept is not new, as already in 1855, Rudolph Virchow followed by Julius Cohnheim proposed (Rahman et al. 2011) that cancer develops from activa-tion of dormant embryonic-tissue remnants. Their observations were based on the histological similarities (proliferation index and degree of differentiation) between fetal tissues and cancer. In the 1960s, ethically questionable experiments performed by Brunschwig, Southam, and Levin demonstrated a low frequency of tumor initiation when tumor cells harvested from patients with malignancy were injected subcutaneously into the same or different patients (Brunschwig et al. 1965). According to their results, tumors were formed only when more than 106 cells were injected. This and further reports showing (Bruce and Van Der Gaag 1963; Brunschwig et al. 1965) the clonogenic potential of lymphoma cells in vivo lead to hypothesis that tumor growth may be initiated and maintained by a minority of cancer cells, not the entire population. In 1994, John Dick and colleagues published their seminal findings that human acute myeloid leukemia is organized as a hierar-chy that originates from a primitive hematopoietic cell and this report turned into a paradigm for later studies, which proposed the existence of a similar model for solid tumors (Lapidot et al. 1994). The cancer stem cells (CSCs) hypothesis and clonal evolution model do not contradict each other, instead highlight the importance of abnormal differentiation program in tumorigenesis, thereby suggesting a key role of cellular hierarchy in tumor evolution.