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originally pioneered by Peter Nowell in a ground-breaking article which documents
cancer as an evolutionary process where tumors mostly arise as a result of stepwise
acquisition of mutational events within the original clone from a single cell of origin
allowing sequential selection of more persevering subclones leading to cancer pro-
gression. Moreover, the report claims that cells in the dominant subclone popula-
tions would retain comparable tumorigenic potential (Fig. 11.2) (Nowell 1976 ).
According to this model, the formation of tumors is dependent on the acquisition of
oncogenic mutations where it is believed that cancers arise through a Darwinian-
like clonal evolution. However, this gene centric clonal evolution model is chal-
lenged by the cancer stem cell model which affirms that the apparent phenotypic
and functional heterogeneity of tumor may be professed to the differences in the
differentiation status owing to both genetic and non-genetic or epigenetic variabil-
ity. The CSC model proposes that the genetic and epigenetic landscapes consider-
ably switch the somatic evolution on the road to the achievement of a lucrative
phenotype attuned to Lamarckian scheme offering a first-rate inheritable state for
better adaptation to the changing milieu; either a stem-like or/and drug-resistant
state (Fig. 11.2). The CSC model also postulates that cancers comprise of a hierarchy
of tumorigenic subpopulation of cancer stem cells along with the non-tumorigenic
Fig. 11.2 Tumor heterogeneity model. The first model or clonal evolution theory to explains that
various cancer cell populations evolve progressively by multistep acquisition of mutation finally
generating heterogeneous tumor with clonal expansion of dominant subclones. The second model
or cancer stem cell model describes that tumor heterogeneity arises due to the stem properties of a
rare population of cancer cells which may get differentiated into any cell type within the tumor.
Importantly, this model proposes that CSC-to-non-CSC conversion is a unidirectional process. The
third model or cancer cell plasticity model posits the bidirectional conversions between non-CSCs
and CSCs in response to the changing microenvironment
P.P. Naik et al.