EMT and Stemness in Tumor Dormancy and Outgrowth: Are They Intertwined Processes?

Abstract

Metastases are the major cause of cancer patients' mortality and can occur years and even decades following apparently successful treatment of the primary tumor. Early dissemination of cancer cells, followed by a protracted period of dormancy at distant sites, has been recently recognized as the clinical explanation for this very-long latency. The mechanisms that govern tumor dormancy at distant sites and their reactivation to proliferating metastases are just beginning to be unraveled. Tumor cells, that survive the immune surveillance and hemodynamic forces along their journey in the circulation and successfully colonize and adopt to the new and "hostile" microenvironment and survive in a quiescent dormant state for years before emerging to proliferative state, must display high plasticity. Here we will discuss whether the plasticity of dormant tumor cells is required for their long-term survival and outgrowth. Specifically, we will focus on whether epithelial mesenchymal transition and acquisition of stem-like properties can dictate their quiescent and or their proliferative fate. Deeper understanding of these intertwining processes may facilitate in the future the development of novel therapies.

Keywords: cancer recurrence; cancer stem cells; disseminated tumor cells; epithelial mesenchymal transition; mesenchymal epithelial transition; metastasis; stemness; tumor dormancy.

Scheme 1

EMT/MET transient state and CSC traits are intertwined processes: following model illustrates the different fluctuations between the EMT/MET states of early disseminated DTCs and their link to stemness and metastatic outgrowth. (I) Dormant DTCs with EMT/MET state lining toward more mesenchymal phenotype activate quiescence stemness. (II) DTCs with EMT/MET at “equilibrium” are highly plastic with self-renewal capacity resulting in the establishment of micrometastases. (III,VI) Macrometastases with EMT/MET state lining to epithelial phenotype proliferate and differentiate. (IV,V) Non-CSC (IV) undergo transient EMT endowing the cells with CSC-like traits and self-renewal capacity resulting in the establishment of micrometastases (V). This transition is mediated by signals arising at their niche (Col-I enriched fibrotic milieu, TGFβ1, Periostin, Tenancin C, inflammation, hypoxia) which in turn can activate accordingly EMT programs via expression of EMT-TF and/or LOXL2 resulting in acquisition of CSC-like traits.