  Cancer is increasingly perceived as a systems-level, network phenomenon. The
major trend of malignant transformation can be described as a two-phase
process, where an initial increase of network plasticity is followed by a
decrease of plasticity at late stages of tumor development. The fluctuating
intensity of stress factors, like hypoxia, inflammation and the either
cooperative or hostile interactions of tumor inter-cellular networks, all
increase the adaptation potential of cancer cells. This may lead to the bypass
of cellular senescence, and to the development of cancer stem cells. We propose
that the central tenet of cancer stem cell definition lies exactly in the
indefinability of cancer stem cells. Actual properties of cancer stem cells
depend on the individual "stress-history" of the given tumor. Cancer stem cells
are characterized by an extremely large evolvability (i.e. a capacity to
generate heritable phenotypic variation), which corresponds well with the
defining hallmarks of cancer stem cells: the possession of the capacity to
self-renew and to repeatedly re-build the heterogeneous lineages of cancer
cells that comprise a tumor in new environments. Cancer stem cells represent a
cell population, which is adapted to adapt. We argue that the high evolvability
of cancer stem cells is helped by their repeated transitions between plastic
(proliferative, symmetrically dividing) and rigid (quiescent, asymmetrically
dividing, often more invasive) phenotypes having plastic and rigid networks.
Thus, cancer stem cells reverse and replay cancer development multiple times.
We describe network models potentially explaining cancer stem cell-like
behavior. Finally, we propose novel strategies including combination therapies
and multi-target drugs to overcome the Nietzschean dilemma of cancer stem cell
targeting: "what does not kill me makes me stronger".
