Abstract
Tumor formation involves substantial cell division and genetic instability, but the relationship between quiescent cancer stem cells (CSC) and dividing progenitors in these events is poorly understood. Likewise, the implication of aneuploid cells in solid tumors is uncertain. CSCs are postulated to contribute to tumor dormancy and present a formidable obstacle in limiting treatment outcomes for a majority of cancers, whereas the genetic heterogeneity conjured by aneuploid cells may influence tumor drug resistance. However, direct confirmation of these events remains forthcoming. In the present study, we addressed the identification of tumor dormancy in terms of isolation of therapy-refractory residual tumor cells from tumors that persist in a state of quiescence as label-retaining cells. The choices of label were PKH67/PKH26 dyes that irreversibly bind to the lipid bilayer on cell membranes and get equally partitioned among daughter cells subsequent to each cell division. Consequent characterization revealed that label-retaining cells encompass two different populations capable of remaining in a state of quiescence, i.e., stem-like cells and aneuploid cells. The former express a reversibility of quiescence through retention of functionality and also exhibit therapeutic refractoriness; the latter seem to be either quiescent or proliferation-arrested at steady-state. Subsequent to exposure to selective pressure of chemotherapy, a fraction of these cells may acquire the potential to proliferate in a drug-refractory manner and acquire stem-like characteristics. Collectively, the findings of the present study reveal that tumor-derived CSCs and aneuploid populations contribute to drug resistance and tumor dormancy in cancer progression.
Highlights
Tumor dormancy represents a subclinical equilibrium achieved between host immunity and quiescent residual tumor cells [1], that can extend for up to decades after treatment followed by disease relapse [2, 3]
Through a convenient readout of label retention, we showed that stem cell activity is enriched in the quiescent fraction of a tumor that shows the capability to revert to a state of selfrenewal and regeneration
Our results further indicate that a specific surface expression may not be exclusively associated with cancer stem cells (CSC), and encompasses progenitor and aneuploid populations
Summary
Tumor dormancy represents a subclinical equilibrium achieved between host immunity and quiescent residual tumor cells [1], that can extend for up to decades after treatment followed by disease relapse [2, 3]. The use of membrane-labeling dyes such as PKH67/ PKH26 that have a good correlation with bromodeoxyuridine incorporation and slow-cycling cells is suggested [19,20,21] These vital dyes consist of a fluorophore attached to an aliphatic carbon backbone that irreversibly binds to the lipid bilayer on cell membranes. We explored the application of PKH label retention/quenching as an effective readout for the identification of quiescent cells in tumors. Such an assessment revealed CSCs and aneuploidy as two contrasting nonproliferative states in tumors that can be coaxed into regeneration, thereby providing a novel understanding of the cellular determinants of tumor dormancy
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