Article

ALDH1 Is a Marker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical Outcome

Department of Internal Medicine, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Cell Stem Cell (Impact Factor: 22.15). 12/2007; 1(5):555-67. DOI: 10.1016/j.stem.2007.08.014
Source: PubMed

ABSTRACT Application of stem cell biology to breast cancer research has been limited by the lack of simple methods for identification and isolation of normal and malignant stem cells. Utilizing in vitro and in vivo experimental systems, we show that normal and cancer human mammary epithelial cells with increased aldehyde dehydrogenase activity (ALDH) have stem/progenitor properties. These cells contain the subpopulation of normal breast epithelium with the broadest lineage differentiation potential and greatest growth capacity in a xenotransplant model. In breast carcinomas, high ALDH activity identifies the tumorigenic cell fraction, capable of self-renewal and of generating tumors that recapitulate the heterogeneity of the parental tumor. In a series of 577 breast carcinomas, expression of ALDH1 detected by immunostaining correlated with poor prognosis. These findings offer an important new tool for the study of normal and malignant breast stem cells and facilitate the clinical application of stem cell concepts.

Download full-text

Full-text

Available from: Gabriela Dontu, Jul 26, 2015
1 Follower
 · 
404 Views
  • Source
    • "Combinations of cell surface markers that have been used to detect cell populations enriched in these properties include CD49f high EpCAM low (Eirew et al., 2008; Lim et al., 2009), CD73+CD90– (Roy et al., 2013), CD10+ (Keller et al., 2012), and CD49f+DLL1+DNER+ (Pece et al., 2010). Functional properties used to identify stem cells are high aldehyde dehydrogenase (ALDH) activity (Ginestier et al., 2007) and the ability to survive and proliferate in anchorage-independent conditions (Dontu et al., 2003; Pece et al., 2010). Some of these markers (i.e., ALDH+ and CD49f+) correlate with poor clinical outcome when highly expressed in breast tumors (Ali et al., 2011; Ginestier et al., 2007), possibly because they also identify a cancer stem cell population. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Characterization of normal breast stem cells is important for understanding their role in breast development and in breast cancer. However, the identity of these cells is a subject of controversy and their localization in the breast epithelium is not known. In this study, we utilized a novel approach to analyze the morphogenesis of mammary lobules, by combining one-dimensional theoretical models and computer-generated 3D fractals. Comparing predictions of these models with immunohistochemical analysis of tissue sections for candidate stem cell markers, we defined distinct areas where stem cells reside in the mammary lobule. An increased representation of stem cells was found in smaller, less developed lobules compared to larger, more mature lobules, with marked differences in the gland of nulliparous versus parous women and that of BRCA1/2 mutation carriers versus non-carriers. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Stem Cell Reports 03/2015; DOI:10.1016/j.stemcr.2015.02.013
  • Source
    • "CSCs have the capability of being resistant to chemotherapy and radiotherapy by many molecular mechanisms. For example, it has been established that increases in the aldehyde dehydrogenase (ALDH) activity in CSC seem to mediate their resistance to particular chemotherapeutics (Hilton 1984; Ginestier et al. 2007). Additionally, CSCs chemo/radiotherapy resistance is depicted to be reliant on interleukin-4 (IL-4) signaling pathway since upregulation of IL-4 on these cells results in resistance to apoptosis (Francipane et al. 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer stem cells (CSCs) need to survive cancer treatments with a specific end goal to provide new, more differentiated, metastatic-prone cancerous cells. This happens through diverse signals delivered within the tumor microenvironment where ample evidence indicates that altered developmental signaling pathways play an essential role in maintaining CSCs and accordingly the survival and the progression of the tumor itself. This review summarizes findings on the immunobiological properties of CSCs as compared with cancerous non-stem cells involving the expression of immunological molecules, cytokines and tumor antigens as well as the roles of the Notch, Wnt and Hedgehog pathways in the brain, breast and colon CSCs. We concluded that if CSCs are the main driving force behind tumor support and growth then understanding the molecular mechanisms and the immunological properties directing these cells for immune tolerance is of great clinical significance. Such knowledge will contribute to designing better targeted therapies that could prevent tumor recurrence and accordingly significantly improve cancer treatments and patient survival.
    Cytotechnology 12/2014; DOI:10.1007/s10616-014-9830-0 · 1.45 Impact Factor
  • Source
    • "Interestingly, BCC 199a and BCC 199a/214 displayed enhanced resistance to suspension-induced cell death in a minimal serum tumbling assay, exhibiting >50% survival rates after 24 hr of suspension, and a corresponding >50% reduction in their apoptosis rates as measured by 7-aminoactinomycin D (7AAD; Figure 2D). In addition , BCC 199a and BCC 199a/214 displayed increased abilities to grow in low-attachment mammosphere growth conditions after serial passages (Figure 2E), and they showed multifold increases in the expression levels of the CSC-associated marker ALDH1 (Ginestier et al., 2007), as determined by rtPCR (Figure S2G) and by ALDEFLUOR-based FACS assays (Figures 2F). Most importantly, however, BCC 199a and BCC 199a/214 possessed markedly enhanced tumor-initiating capabilities in limiting-dilution tumor assays in Nude mice, forming tumors at 100 cells per injection at $2–3 times the rate of their BCC null controls (Figure 2G). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mesenchymal stem/stromal cells (MSCs) are progenitor cells shown to participate in breast tumor stroma formation and to promote metastasis. Despite expanding knowledge of their contributions to breast malignancy, the underlying molecular responses of breast cancer cells (BCCs) to MSC influences remain incompletely understood. Here, we show that MSCs cause aberrant expression of microRNAs, which, led by microRNA-199a, provide BCCs with enhanced cancer stem cell (CSC) properties. We demonstrate that such MSC-deregulated microRNAs constitute a network that converges on and represses the expression of FOXP2, a forkhead transcription factor tightly associated with speech and language development. FOXP2 knockdown in BCCs was sufficient in promoting CSC propagation, tumor initiation, and metastasis. Importantly, elevated microRNA-199a and depressed FOXP2 expression levels are prominent features of malignant clinical breast cancer and are associated significantly with poor survival. Our results identify molecular determinants of cancer progression of potential utility in the prognosis and therapy of breast cancer. Copyright © 2014 Elsevier Inc. All rights reserved.
    Cell Stem Cell 12/2014; 15(6):762-774. DOI:10.1016/j.stem.2014.10.001 · 22.15 Impact Factor
Show more