Cancer is a complex set of diseases, driven by genomic instability overlaid with epigenetic modifications. Two
prevailing concepts, the stochastic theory and the hierarchical theory, are traditionally used to understand tumor progression.
These seemingly contradictory theories can be reconciled with the concept of cellular plasticity, such that certain genetic
mutations enable epigenetic alterations in cell fate. A growing body of evidence suggests that cancer cells co-opt
embryonic stem cell-associated regulatory networks in order to sustain tumor cell plasticity concomitant with growth and
progression. The expression of these stem cell associated factors is regulated by dynamic niches, characterized by cellderived
proteins as well as biophysical features such low oxygen tensions. In this review we describe specific embryoassociated
proteins such as NODAL, NOTCH, and canonical WNT, which cooperate to maintain stem cell phenotypes in
cancer. We also illustrate how biophysical factors, in particular oxygen, can orchestrate plasticity by modulating the expression
of stem cell-associated proteins. As the microenvironment is known to play a key role in cellular regulation, it is
essential to understand its role in cancer progression in order to improve and create new therapies.
Keywords: Cancer, microenvironment, NODAL, NOTCH, oxygen, plasticity, WNT
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