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Page 4 of 20 Smigiel et al. J Cancer Metastasis Treat 2019;5:47 I http://dx.doi.org/10.20517/2394-4722.2019.26

Figure 1. The Heterogeneity of Breast Cancer. Breast cancer is a heterogeneous disease with a highly dynamic tumor micro-environment
(TME). Within the primary site, one can observe the presence of epithelial cells that have undergone E-M/CSC plasticity, malignant
epithelial cells, pre-malignant cells, senescent epithelial cells, stromal fibroblasts, infiltrating immune cells, and endothelial cells. The
presence of all of these diverse cell types results in a distinct and complex milieu of secreted factors within the TME that influence, tumor
progression, disease recurrence, and cell plasticity

conditions, the SASP-factors act in an autocrine manner to maintain the senescence program and recruit
immune cells into the local environment [80-83] . However, paracrine signaling by SASP components can also
influence the behavior of adjacent cells, engaging signaling programs that contribute to tumor progression
and therapy failure [64,84-89] . A collection of recent studies has demonstrated the ability of senescent cells
and SASP components in the TME to drive cellular E-M plasticity and the expansion of a CSC-like cell
population [90,91] . In fact, the SASP program can promote stemness within both senescent cells and neighboring
cells, both in vitro and in vivo, through secretion of potent inflammatory cytokines associated with disease
recurrence, and overall poor prognosis [92,93] . More specifically, less aggressive luminal MCF-7 cells were
treated with conditioned medium harvested from senescent populations experiencing SASP. Exposure
to conditioned media led to a more CD24LO/CD44HI invasive/stem like population similar to already
aggressive MDA-MB-231 cells, which was dependent upon IL6 and IL8, two well defined SASP-factors,
secretion . Furthermore, sustained hyper-activation of signal transducer and activator of transcription
[94]
3 (STAT3) by SASP components plays a critical role in induction of an invasive and stem-like program .
[95]
Taken together, the presence of malignant, pre-malignant, and senescent epithelial cells creates a diverse
TME suitable to drive E-M/CSC plasticity within the tumor and contribute to metastatic, therapy-resistant,
and tumor-initiating phenotypes. Below we will discuss how E-M/CSC plasticity contributes to these deadly
phenotypes responsible for patient mortality.

AN IDENTITY CRISIS: MESENCHYMAL VS . EPITHELIAL
Each step along the metastatic cascade presents a new environmental context and challenge that a potentially
metastatic cell must adapt to in order to thrive. This adaptation involves changes in a cell’s state. Cellular
plasticity is defined as the ability of a cell to acquire new biological properties due to intrinsic and extrinsic
cues. It is important to recognize that plasticity is most often a highly dynamic and reversible process that
can be used to describe multiple cellular changes (i.e., differentiation, metabolism, response to immune
cells, motility, and cell fate). Throughout this review, we will refer to cellular plasticity as the ability for
cells to undergo E-M/CSC plasticity, that is, cells shifting between epithelial/non-CSC and mesenchymal/
CSC states. E-M/CSC plasticity is important in imparting invasive and motile phenotypes as well as cells
acquiring tumor-initiating potential and reduced sensitivities to therapy.