Cancer Stem Cells and Aneuploid Populations within Developing Tumors Are the Major Determinants of Tumor Dormancy

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 labelretaining 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. [Cancer Res 2009;69(24):9245-53]

Hes1: a key role in stemness, metastasis and multidrug resistance

“…3,[60][61][62] Indeed, it should be noted that cancer cell dormancy resulting from cell cycle arrest has been observed in solid tumors, while the quiescent stage is reached by several pathways, in addition to cell cycle arrest. 63 Experiments in vitro have shown the involvement of Notch receptor, Hes1, and p21 activities in the drug resistance of quiescent tumors. Notch1 activates the p21-induced cell-cyclearrest tumor model, which is identified as a drug-resistant phenotype.…”

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating–cancer stem cells: distinct, overlapping or same populations

“…No such cells were observed in cell culture conditions. This suggests that this population results from intrinsic and extrinsic elements in tumor formation, controlling a switch between different states, which itself may indicate a reversibility of quiescence (Kusumbe and Bapat, 2009). …”

Metastatic Dormancy and Progression in Thyroid Cancer: Targeting Cells in the Metastatic Frontier

“…This period of stability is regulated both by the expression of genes intrinsic to the cancer cells, by the metastatic microenvironment, or by other factors such as the immune system (see following text). It is possible that these cells may exhibit markers of ''stemness'' or reflect a slow-growing, treatment-resistant subpopulation of cells that remain in a quiescent phase in a G0-G1 arrest (11). Loss of dormancy can occur through a number of mechanisms intrinsic to the cancer cells, due to cells recruited to the local environment, and/or due to genetic or epigenetic changes in the microenvironment.…”