A second area of confusion relates to assumptions regarding the nature of CSC properties. This problem tends to arise from the same misconception outlined above. In this case, the flawed inference is to propose that CSCs will exhibit all qualitative and quantitative traits present in normal systems, a view that often follows from the notion that CSCs derive from normal stem cells. For example, most normal stem cell systems behave according to relatively well-conserved and predictable rules, which typically include a hierarchical developmental process (i.e., a defined “parent-to-progeny” relationship). Features such as stem cell immunophenotype, frequency, response to extrinsic stimuli, etc., are reliably maintained among individuals in a given species. Indeed, at steady state, the size of a particular stem cell compartment does not generally vary much within defined lineages. However, increasing evidence indicates that these common properties may not be maintained in the context of cancer. That is to say, the relative frequency of CSC, their cell surface immunophenotype, and various other biological properties may not be stable during the course of disease progression or in cross-comparing patients with the same disease. For example, studies to estimate the prevalence of leukemia stem cells demonstrated a 500-fold range in multiple independent specimens (Bonnet and Dick, 1997
). These findings indicate that the size of the CSC compartment can be highly variable. In addition, analysis of leukemia populations with respect to cell surface markers associated with a primitive phenotype showed dramatic variability from patient to patient (Taussig et al., 2008
). Given this potential heterogeneity of surface markers, it is important to refrain from being overly rigid in attaching the label of CSCs to a population solely by virtue of phenotypic traits. As described above, stem cells are defined by their functionality, and the mere expression of a feature exhibited by known stem cell populations does not indicate that cancer stem cells are present in that tumor or tissue. Furthermore, any given type of CSCs may present a range of antigens commonly associated with primitive cells, but the specific expression pattern may vary from patient to patient. If so, then the properties of CSCs must be empirically determined for each patient. Notably, this exact scenario has been observed in leukemia studies that identified residual drug-resistant populations that contribute to relapse (Feller et al., 2004
Although not yet well described by experimental studies, it is also tempting to speculate that CSCs are relatively low-frequency in early stages of tumorigenesis but, during the course of pathogenesis, become an increasingly prevalent (or perhaps even dominant) component of the tumor population. If true, one would predict that the most aggressive or advanced forms of cancer would show the highest proportion of CSCs. Notably, recent studies of human melanoma indicate that in some types of cancer, advanced tumors are composed of a very high proportion of cells functionally defined as CSC (Quintana et al., 2008
If, indeed, the orderly and well-characterized developmental structure of normal stem cell systems is not maintained in the context of cancer, then the practical ramifications are profound. If CSC phenotype, frequency, and biological properties are in flux in an individual patient during disease progression, then characterization of such cells is vastly more difficult. Moreover, the lack of consistent biological features will inevitably lead to controversy and confusion, a phenomenon that appears to be increasingly evident for the CSC field.