  There is a widening recognition that cancer cells are products of complex
developmental processes. Carcinogenesis and metastasis formation are
increasingly described as systems-level, network phenomena. Here we propose
that malignant transformation is a two-phase process, where an initial increase
of system plasticity is followed by a decrease of plasticity at late stages of
carcinogenesis as a model of cellular learning. We describe the hallmarks of
increased system plasticity of early, tumor initiating cells, such as increased
noise, entropy, conformational and phenotypic plasticity, physical
deformability, cell heterogeneity and network rearrangements. Finally, we argue
that the large structural changes of molecular networks during cancer
development necessitate a rather different targeting strategy in early and late
phase of carcinogenesis. Plastic networks of early phase cancer development
need a central hit, while rigid networks of late stage primary tumors or
established metastases should be attacked by the network influence strategy,
such as by edgetic, multi-target, or allo-network drugs. Cancer stem cells need
special diagnosis and targeting, since their dormant and rapidly proliferating
forms may have more rigid, or more plastic networks, respectively. The
extremely high ability to change their rigidity/plasticity may be a key
differentiating hallmark of cancer stem cells. The application of early
stage-optimized anti-cancer drugs to late-stage patients may be a reason of
many failures in anti-cancer therapies. Our hypotheses presented here underlie
the need for patient-specific multi-target therapies applying the correct ratio
of central hits and network influences -- in an optimized sequence.
