Elsevier

Seminars in Cancer Biology

Volume 35, December 2015, Pages 191-199
Seminars in Cancer Biology

Review
Cancer stem cells and cell size: A causal link?

https://doi.org/10.1016/j.semcancer.2015.07.002Get rights and content

Abstract

The majority of normal animal cells are 10–20 μm in diameter. Many signaling mechanisms, notably PI3K/Akt/mTOR, Myc, and Hippo pathways, tightly control and coordinate cell growth, cell size, cell division, and cell number during homeostasis. These regulatory mechanisms are frequently deregulated during tumorigenesis resulting in wide variations in cell sizes and increased proliferation in cancer cells. Here, we first review the evidence that primitive stem cells in adult tissues are quiescent and generally smaller than their differentiated progeny, suggesting a correlation between small cell sizes with the stemness. Conversely, increased cell size positively correlates with differentiation phenotypes. We then discuss cancer stem cells (CSCs) and present some evidence that correlates cell sizes with CSC activity. Overall, a causal link between CSCs and cell size is relatively weak and remains to be rigorously assessed. In the future, optimizing methods for isolating cells based on size should help elucidate the connection between cancer cell size and CSC characteristics.

Section snippets

Stem cells and cell size

In multicellular organisms, homeostatic control mechanisms are regulated so that internal conditions ensuring cell number and size remain stable and relatively constant (reviewed in [1]). These control mechanisms are an integration of extracellular nutritional environments and multiple cell-specific growth, mitogenic, and survival signals that coalesce to create a balanced homeostatic state in terms of rates of synthesis and degradation of macromolecules, and thus cell size. The majority of

Cancer stem cells

Cancer is characterized by the excessive and uncontrolled expansion of abnormal, malignant cells that display morphological, proliferative, and functional heterogeneity. Morphological heterogeneity is further manifested in tumor cells of variegating size, shape, thickness, nucleus/cytoplasm ratio, etc. In order to explain this tumor cell heterogeneity, two models have been proposed, one being the cancer stem cell (CSC) concept [47], [48]. This model postulates that, akin to growth of normal

Cancer stem cells and cell size

Tumors generally contain multiple clones, in which differentially sized tumor cells can be easily observed. It seems reasonable to speculate, a priori, that a certain population of cells in tumors with certain sizes might be endowed with particular characteristics to promote survival and longevity. In other words, can cell size be used as a determinant of CSCs vs. non-CSCs? Very few studies by far have been conducted to prospectively address this interesting question. A group recently generated

Perspectives

Significant progress has been made in the identification of three key and inter-connected regulatory pathways, i.e., mTOR, Myc, and Hippo, that control normal cell growth, and this has given us clues as to how cell size is controlled in homeostasis and how cancer cells might have abnormal cell size control mechanisms (Figure 4). The PI3K/AKT/mTOR signaling pathway is a major regulator of cell growth and thus a key determinant of cell size [62]. Critical inputs regulating this pathway include

Conflict of interest

None.

Acknowledgements

Work in the authors’ lab was supported, in part, by grants from NIH (NCI R01-CA155693), DOD (W81XWH-13-1-0352 and W81XWH-14-1-0575), CPRIT (RP120380), and MDACC Center for Cancer Epigenetics (all to D.G.T). X. Chen was supported, in part, by a DOD postdoc fellowship PC141581. We apologize to the colleagues whose work was not cited due to space constraint.

References (73)

  • J. Ratajczak et al.

    Adult murine bone marrow-derived very small embryonic-like stem cells differentiate into the hematopoietic lineage after coculture over OP9 stromal cells

    Exp. Hematol.

    (2011)
  • M. Miyanishi et al.

    Do pluripotent stem cells exist in adult mice as very small embryonic stem cells?

    Stem Cell Rep.

    (2013)
  • A. Kreso et al.

    Evolution of the cancer stem cell model

    Cell. Stem Cell

    (2014)
  • R.N. Aravalli et al.

    Establishment and characterization of a unique 1 microm diameter liver-derived progenitor cell line

    Biochem. Biophys. Res. Commun.

    (2010)
  • J. Qin

    The PSA-/lo prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration

    Cell. Stem Cell

    (2012)
  • M. Laplante

    Sabatini DM. mTOR signaling in growth control and disease

    Cell

    (2012)
  • L.A. Johnston et al.

    Drosophila myc regulates cellular growth during development

    Cell

    (1999)
  • K. Tumaneng et al.

    Organ size control by Hippo and TOR pathways

    Curr. Biol.

    (2012)
  • R.K. Mortimer et al.

    Life span of individual yeast cells

    Nature

    (1959)
  • J. Yang et al.

    Cell size and growth rate are major determinants of replicative lifespan

    Cell Cycle

    (2011)
  • S.M. Phipps et al.

    Aging cell culture: methods and observations

    Methods Mol. Biol.

    (2007)
  • C.M. Coelho et al.

    Do growth and cell division rates determine cell size in multicellular organisms?

    J. Cell Sci.

    (2000)
  • A.M. Hunt

    The Cell Cycle

    (1993)
  • S. Son et al.

    Direct observation of mammalian cell growth and size regulation

    Nat. Methods

    (2012)
  • B. Rouzaire-Dubois et al.

    Cell size-proliferation relationship in rat glioma cells

    Glia

    (2004)
  • H. Dolznig et al.

    Evidence for a size-sensing mechanism in animal cells

    Nat. Cell Biol.

    (2004)
  • A. Tzur et al.

    Cell growth and size homeostasis in proliferating animal cells

    Science

    (2009)
  • T. Matsuoka et al.

    Electron microscopic identification of hemopoietic progenitor cells by exploiting their sugar-recognizing receptors using a newly developed minibead technique

    Exp. Hematol.

    (1989)
  • A.C. Berardi et al.

    Functional isolation and characterization of human hematopoietic stem cells

    Science

    (1995)
  • M.P. Vacanti et al.

    Identification and initial characterization of spore-like cells in adult mammals

    J. Cell. Biochem.

    (2001)
  • H.E. Young et al.

    Clonogenic analysis reveals reserve stem cells in postnatal mammals. II. Pluripotent epiblastic-like stem cells

    Anat. Rec. A

    (2004)
  • E.K. Zuba-Surma et al.

    Morphological characterization of very small embryonic-like stem cells (VSELs) by ImageStream system analysis

    J. Cell. Mol. Med.

    (2008)
  • J.R. Smith et al.

    Isolation of a highly clonogenic and multipotential subfraction of adult stem cells from bone marrow stroma

    Stem Cells

    (2004)
  • S.C. Hung et al.

    Isolation and characterization of size-sieved stem cells from human bone marrow

    Stem Cells

    (2002)
  • G. D’Ippolito et al.

    Sustained stromal stem cell self-renewal and osteoblastic differentiation during aging

    Rejuvenation Res.

    (2006)
  • F.B. Gao et al.

    Cell size control and a cell-intrinsic maturation program in proliferating oligodendrocyte precursor cells

    J. Cell Biol.

    (1997)

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