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Smigiel et al. J Cancer Metastasis Treat 2019;5:47 I http://dx.doi.org/10.20517/2394-4722.2019.26 Page 7 of 20

Figure 2. Malignant and Senescent Epithelial Cells Contribute to Metastasis. A: malignant cells respond to TME cytokines or intrinsic
genetic alterations in order to drive E-M/CSC plasticity, resulting in greater metastasis, enhanced disease recurrence, and therapeutic
resistance; B: pre-malignant cells undergo senescence in response to aberrant oncogene or cytokine signaling. However, in some
instances a small population of senescent cells may undergo E-M/CSC plasticity, and thus escape the tumor suppressive barrier of
senescence and further contribute to the metastatic phenotype

Given its importance in tissue remodeling and homeostasis, the normal processes governing cellular
plasticity are strictly regulated [177-179] .

As discussed above, senescence serves as an important tumor suppressive barrier to prevent transformation
and the outgrowth of a dysregulated and uncontrolled population. Interestingly, the induction of senescence
in normal cells often results in the simultaneous emergence of mesenchymal/stem-cell markers in conjunction
with senescence markers, and loss of proliferative capacity. For example, senescence leads to the induction of
CD44 expression, a cell surface marker regularly used to distinguish breast CSC from non-CSC, and often
expressed as malignant cells acquire MES/CSC properties and undergo plasticity [138,180-183] . As small subsets
of senescent cells dismantle the senescence program, the emergent population of proliferating cells can
harbor a mesenchymal/stem-cell phenotype that can persist throughout the remainder of the transformation
process, ultimately yielding a more invasive and aggressive cancer cell [184-187] . Li et al. demonstrated that
[15]
many of the transcriptional changes observed in BC are also initiated in normal HMEC as they escape
senescence. In their study, HMEC were shown to have a “pre-transformation” transcriptome and exhibited
a partial EMT following their senescence escape . Similarly, normal HMEC that have spontaneously
[15]
escaped replicative senescence exhibit a greater mesenchymal and CD24LO/CD44HI CSC-phenotype [16,188] .
Further studies have suggested cell cycle regulator Cyclin A1 and tumor suppressors p53 and p16 can act as
“gatekeepers” to maintain cells in an epithelial state. Dysregulation of these proteins in epithelial cells can
result in the initiation of the mesenchymal/stem-cell program, which interestingly corresponds with the
escape from senescence [189,190] . Moreover, induction of EMT (via Snail, Twist, and ZEB1 expression) prior
to a cell’s engagement of oncogene-induced senescence, prevents senescence altogether and results in the
induction of a CSC program and tumor initiation [191-196] .

In addition to pre-malignant cells, cytotoxic therapies can drive cancer cells into a therapy-induced senescence
(TIS). Again, cells that escape TIS have acquired a senescence-associated stemness [197-199] . Milanovic et al. [200]
have shown that cells undergoing TIS express a variety of stem-cell associated markers, and that TIS in
B-cell lymphomas exhibit a gene signature which mirrors that of adult tissue stem cells, conferring a highly
aggressive phenotype responsible for tumor relapse. The emergence of a stem-like population following the