Most mammalian tissues are organized into a hierarchical structure of stem,
progenitor, and differentiated cells. Tumors exhibit similar hierarchy, even if
it is abnormal in comparison with healthy tissue. In particular, it is believed
that a small population of cancer stem cells drives tumorigenesis in certain
malignancies. These cancer stem cells are derived from transformed stem cells or
mutated progenitors that have acquired stem-cell qualities, specifically the
ability to self-renew. Similar to their normal counterparts, cancer stem cells
are long-lived, can self-renew and differentiate, albeit aberrantly, and are
capable of generating tissue, resulting in tumor formation. Although identified
and characterized in several forms of malignancy, the specific multi-step
process that causes the formation of cancer stem cells is uncertain. Here, a
maturity-structured mathematical model is developed to investigate the
sequential order of mutations that causes the fastest emergence of cancer stem
cells. Using model predictions, we discuss conditions for which genetic
instability significantly speeds cancer onset and suggest that unbalanced
stem-cell self-renewal and inhibition of progenitor differentiation contribute
to aggressive forms of cancer. To our knowledge, this is the first continuous
maturity-structured mathematical model used to investigate mutation acquisition
within hierarchical tissue in order to address implications of cancer stem cells
in tumorigenesis.