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First published online August 16, 2005
doi: 10.1242/10.1242/jcs.02532

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On mammary stem cells

Wendy A. Woodward^1,*, Mercy S. Chen^2,*, Fariba Behbod² and Jeffrey M. Rosen^2,

¹ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-3498, USA
² Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Place, M638a DeBakey, Houston, TX 77030, USA

View larger version (77K): [in a new window]   Fig. 1. The terminal end bud (TEB). The TEB appears at the onset of puberty, undergoing rapid growth and differentiation. (A) Expression of Sca1 is enriched in TEBs (arrows) and ducts of six-week-old mice. Micrograph showing live imaging of GFP expression in Sca1-GFP knock-in mice (Sca1-GFP mice kindly provided by T. A. Graubert, Washington University; glands prepared and image captured with help from M. T. Lewis, Baylor College of Medicine). (B) Schematic view of the TEB. A cap cell layer surrounds the body cells. The cap cells can take on either a myoepithelial lineage or a luminal epithelial lineage and therefore are thought to be multipotent stem cells. Differentiated myoepithelial and luminal epithelial cells line the neck of the TEB and the subtending duct. (C) Section, stained with hematoxylin and eosin, of a midpregnant mammary gland from C57BL/6 mice indicating the locations of the ductal and alveolar cells. (D) Schematic view of the ductal and alveolar cells during midpregnancy. The ducts are surrounded by a basal layer of overlapping myoepithelial cells, whereas the alveoli cells are surrounded by a basket-like layer of myoepithelial cells.

View larger version (25K): [in a new window]   Fig. 2. Mammary gland stem/progenitor-cell fate. The degree of stemness potentially decreases from top to bottom: as the cell becomes more committed, the cell gradually loses its stemness. The stem cells are able to self-renew and proliferate within the niche, maintained in their un-differentiated state by cell-matrix and cell-cell interactions with the niche cells, involving integrins and cadherins, respectively. These cells can be distinguished by their long-term label-retaining cell (LT-LRC) properties, which are thought to reflect a state of quiescence. Responding to stimuli, stem cells exit the niche by becoming short-term (ST)-LRCs. These actively cycle and express stem cell markers such as p21cip, Msi1 and CK19. As they become further committed, they become the transit-amplifying progenitors (TAs), comprising the side population (SP) that are able to efflux the Hoechst dye. The SP/TAs express bipotential markers, such as K18+ and K14+, or EMA– CALLA–, and may be steroid receptor positive. The SP/TA cells eventually give rise to more committed progenitors that are Sca1+. The Sca1+ population differentiates into luminal and myoepithelial cells. Stem cells are thought to possess many of the features that constitute the tumor phenotype, including self-renewal and unlimited replicative potential. Tumorigenic mutations are presumably sustained in the expanding SP/TA population. These cells give rise to tumorigenic progenitor cells. CD44+ CD24– may be markers that distinguish tumorigenic progenitor cells from normal progenitor cells.

View larger version (31K): [in a new window]   Fig. 3. Cancer therapy that does not kill tumor stem cells may provide gratifying initial results but ultimately result in recurrence. Conventional therapies target proliferating, terminally differentiated cells may leave tumor stem cells, which could lead to recurrence. Ideally, tumor stem cell therapies would specifically target tumor stem cells. Used alone, they might lead to tumor regression, but not dissolve tumor bulk, leading to questions regarding response rates and potentially untreated tumor-related symptoms. Combining conventional therapy with treatment targeting tumor stem cells may effectively eliminate both tumor bulk and tumor stem cells that might otherwise lead to recurrence.