Quiescent, slow-cycling stem cell populations in cancer: a review of the evidence and discussion of significance

Abstract

Long-lived cancer stem cells (CSCs) with indefinite proliferative potential have been identified in multiple epithelial cancer types. These cells are likely derived from transformed adult stem cells and are thought to share many characteristics with their parental population, including a quiescent slow-cycling phenotype. Various label-retaining techniques have been used to identify normal slow cycling adult stem cell populations and offer a unique methodology to functionally identify and isolate cancer stem cells. The quiescent nature of CSCs represents an inherent mechanism that at least partially explains chemotherapy resistance and recurrence in posttherapy cancer patients. Isolating and understanding the cell cycle regulatory mechanisms of quiescent cancer cells will be a key component to creation of future therapies that better target CSCs and totally eradicate tumors. Here we review the evidence for quiescent CSC populations and explore potential cell cycle regulators that may serve as future targets for elimination of these cells.

Figure 1

Pulse Chase Labeling and Chemotherapy Survival of Stem Cells. (a) Cell suspensions are labeled with BrdU or other label ((i) and (ii)). As rapidly proliferating transit amplifying cells divide, label is diluted among the daughter cells and eventually becomes undetectable (iii). Slow dividing stem cells retain label occasionally producing a new transit amplifying cell that will quickly dilute out residual label (iv). (b) Heterogeneous tumors are predicted to contain a population of slow cycling label retaining cells (i). Conventional chemotherapies target and kill rapidly proliferating cells, while quiescent cells survive ((ii) and (iii)). Cancer stem cells that survive chemotherapy re-enter the cell cycle and re-establish the tumor.

Figure 2

Stem cell markers in Normal Sebaceous Gland and Sebaceous Tumor. Immunohistochemical staining for the skin stem cell marker Keratin 15 (K15). (a) Normal skin sebaceous gland with labeled stem cells (black arrows). (b) Sebaceous tumor with heterogeneous expression of K15.