Fig. 3.

Stages of CSC evolution. For many tumor types, the de novo mutations leading to primary CSC are varied. Thus, one would expect that the biology of primary CSCs may also be heterogeneous. Properties such as CSC frequency, cell-surface phenotype, and drug sensitivity may vary as a function of the specific mutations as well as the nature of the normal cell type in which the primary events occur. Next, neoplastic progression may occur either as a consequence of intrinsic tumor pathogenesis and/or challenge with chemotherapy. Selective pressures associated with neoplastic progression may lead to a higher frequency of functionally defined CSC in secondary or metastatic stages as well inter-patient and intra-patient variability of CSC properties.