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Breast Anatomy and Development | PHYSIOLOGY | Menopause | null | C H A P T E R 2 |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | null | null | null | Clinical Perspectives |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | null | null | null | Maria Ouzounova, Suling Liu, and Max S. Wicha |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | CHAPTER CONTENTS | null | null | Identification of Normal Breast Stem Cells Breast Carcinogenesis |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | CHAPTER CONTENTS | null | null | Isolation and Characterization of Breast Cancer Stem Cells BCSC Markers |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | CHAPTER CONTENTS | null | null | Aldehyde Dehydrogenase 1 |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | CHAPTER CONTENTS | null | null | Lineage Tracing |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | CHAPTER CONTENTS | null | null | Therapeutic Implications of Breast Cancer Stem Cells Notch Pathway |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | CHAPTER CONTENTS | null | null | Hedgehog Pathway Other Pathways |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | CHAPTER CONTENTS | null | null | There has been accumulating evidence for the existence of a subcomponent of cancer cells that have stem cell prop- erties and have been termed “cancer stem cells.” Although the concept that cancer originates from the transformation of “germ cells” or “stem cells” was first proposed over 150 years ago, it is only recent... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | CHAPTER CONTENTS | null | null | Based on this definition, cancer stem cells retain key stem cell properties. These properties include self-renewal, which initiates and drives tumorigenesis, and differentia- tion, albeit aberrant, which contributes to cellular hetero- geneity (3) |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | CHAPTER CONTENTS | null | null | In breast cancer, the discovery of tumor cells that dis- play stem cell properties provides a possible explanation as to why cancer may be so difficult to eradicate, as well as suggesting strategies for the targeting of this cell popu- lation. This chapter will examine the implications of the cancer stem cell hypothesi... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | IDENTIFICATION OF NORMAL BREAST STEM CELLS | null | null | The existence of adult mammary stem cells was established nearly 50 years ago when DeOme et al. (4) observed that tissue fragments of epithelium isolated from several differ- ent regions of the mammary gland were able to reconstitute the entire mammary ductal tree upon transplantation. Later, serial transplantation exp... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | IDENTIFICATION OF NORMAL BREAST STEM CELLS | null | null | 15 |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | IDENTIFICATION OF NORMAL BREAST STEM CELLS | null | null | Further analysis of the CD24loCD29hi cells revealed that this was a basal population of cells that was ER-negative (9). Limiting dilution transplantation experiments by Smalley and co-workers (10) illustrated that CD24lo ER-negative basal cells displayed the highest stem cell activity (as defined by mammary repopulat... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | IDENTIFICATION OF NORMAL BREAST STEM CELLS | null | null | Ginestier et al. (14) have described the expression of aldehyde dehydrogenase 1 (ALDH1) as a stem cell marker that can be utilized to isolate human mammary stem cells. ALDH1 is a detoxifying enzyme responsible for the oxida- tion of intracellular aldehydes. This enzyme may play a role in early differentiation of stem c... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | IDENTIFICATION OF NORMAL BREAST STEM CELLS | null | null | The identification of mammary stem cell markers and |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | IDENTIFICATION OF NORMAL BREAST STEM CELLS | null | null | the development of in vitro and murine models utilizing these cells should facilitate the study of adult breast stem cells to elucidate their role in mammary development. Furthermore, defining the pathways that regulate mammary stem cell self-renewal and differentiation should shed light on events involved in breast ca... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | BREAST CARCINOGENESIS | null | null | Traditionally, cancer has been considered as a multistep process defined by the sequential mutation of key genes driving the uncontrolled clonal expansion of a cell. However, important recent progress in basic research has challenged these concepts at different levels. First, the role of the tumor microenvironment is n... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | BREAST CARCINOGENESIS | null | null | the interaction with the extracellular matrix (ECM) and the immune system (18,19). Indeed, epithelial cells are depen- dent on interactions with specific components of the ECM for survival, proliferation, and differentiation. In addition, the initial steps in tumor establishment are associated with a deficiency in the ... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ISOLATION AND CHARACTERIZATION | null | null | OF BREAST CANCER STEM CELLS |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ISOLATION AND CHARACTERIZATION | null | null | Even though important progress has been made, the isola- tion and characterization of cancer stem cells remains a challenge. In order to validate the method selected as an appropriate technique to isolate cancer stem cells, it is crucial to use assays that can assess the stem cell proper- ties of self-renewal and diffe... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ISOLATION AND CHARACTERIZATION | null | null | A B FIGURE 2-1 Two Models of Breast Carcinogenesis. A: According to the sto- chastic model any mam- mary epithelial cell can be transformed by the right |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ISOLATION AND CHARACTERIZATION | null | null | Normal breast epithelium |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ISOLATION AND CHARACTERIZATION | null | null | Malignant breast epithelium |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ISOLATION AND CHARACTERIZATION | null | null | combination of mutations and resultant cancer cells of different phenotypes have extensive proliferation |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ISOLATION AND CHARACTERIZATION | null | null | potential. B: According to the stem cell hierarchical model, cancers originate from the malignant transformation |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ISOLATION AND CHARACTERIZATION | null | null | of a normal breast stem/ progenitor cell. Most can- cer cells have only limited proliferative potential, but cancer stem cells that have self-renewal capacity drive tumorigenesis. |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ISOLATION AND CHARACTERIZATION | null | null | Ductal epithelial cell |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ISOLATION AND CHARACTERIZATION | null | null | Breast cancer stem cell Breast cancer cell |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ISOLATION AND CHARACTERIZATION | null | null | Myoepithelial cell Adult stem/progenitor cell |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ISOLATION AND CHARACTERIZATION | null | null | Malignant transformations |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ISOLATION AND CHARACTERIZATION | null | null | of in vitro assays such as the mammosphere assay has been also used for enrichment of cancer stem cell popula- tion. This method is a nonadherent colony forming assay developed by Dontu et al. (30) where only cells with self- renewal capacity are able to survive and grow in anchor- age-independent conditions while diff... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ISOLATION AND CHARACTERIZATION | null | null | In summary, several different techniques have been uti- lized to enrich for and identify breast cancer stem cells. The in vitro cancer stem cell assays provide an important tool for mechanistic studies as well as for screening of specific drugs targeting this population. However, at this time, self-renewal can only be ... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | BCSC MARKERS | null | null | The first evidence for the existence of cancer stem cells in human solid tumors came from the study of Al-Hajj et al. |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | BCSC MARKERS | null | null | (32) where they utilized techniques based on seminal stud- ies identifying leukemic stem cells by Bonnet and Dick (33). Utilizing cell surface markers and flow cytometry, these authors isolated a tumorigenic population of cells in human breast cancer that displayed cancer stem cell properties. This population was defin... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | BCSC MARKERS | null | null | did not display this phenotype failed to generate tumors. Tumors that formed in mice recapitulated the phenotypic heterogeneity of the initial tumor. The ability to serially transplant the tumors from an enriched stem cell population provides strong support for the existence of stem cells in breast cancers. CD44 appear... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | BCSC MARKERS | null | null | Recently it has been suggested that expression of the cell surface markers EpCAM and CD49f can be used to define functional populations of normal mouse and human mammary cells. Based on in vitro and mouse fat pad re-implantation studies it has been suggested that EpCAM CD49f+ cells represent mammary stem cells, EpCAM+... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | BCSC MARKERS | null | null | Xenotransplantation B Cancer stem cell isolation |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | BCSC MARKERS | null | null | FIGURE 2-2 Isolation and characterization of breast cancer stem cells. A: The xeno- graft model involves introduction of tumor cells into the cleared fat pad of not otherwise specified/severe combined immunodeficiency (NOD/SCID) mice that have been human- ized by the introduction of human mammary fibroblasts. B: When t... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | BCSC MARKERS | null | null | C: When transplanted, the cancer stem cell population initiates and maintains tumor growth upon serial passage, whereas the tumor cell population depleted of the cancer stem cell population fails to generate tumors D. |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | BCSC MARKERS | null | null | have a mesenchymal morphology, are largely quiescent, invasive, and characterized by expression of the CSC mark- ers CD24CD44+ and are EpCAMCD49f+. In contrast, the MET (mesenchymal epithelial transition) state of CSCs is characterized by active self-renewal and expression of the CSC markers ALDH and EpCAM+CD49f+. A ... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ALDEHYDE DEHYDROGENASE 1 | null | null | ALDH enzymatic activity has been recently used to isolate normal human breast stem and progenitors cells (14). The authors demonstrated that ALDEFLUOR-positive cells iso- lated from human breast cancer display properties of can- cer stem cells shown by the ability of these cells, but not ALDEFLUOR-negative cells, to ge... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | ALDEHYDE DEHYDROGENASE 1 | null | null | of the initial tumor. Interestingly, the ALDEFLUOR-positive cell population detected in breast tumors has a small overlap with the previously described cancer stem cell, CD44+/CD24/lin phenotype (32). In the tumors investigated, the overlap rep- resented approximately 1% or less of the total cancer cell population. T... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | LINEAGE TRACING | null | null | Recent studies utilizing mouse models of glioblastoma, skin and intestinal tumors provide important validation of the cancer stem cell model (39–41). These studies provide the first evidence that CSC arise de novo during tumor develop- ment in intact organs. Lineage tracing methods take advan- tage of fluorescent marki... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | LINEAGE TRACING | null | null | development. In accordance with this idea Driessens et al. observed enrichment of the CSC population and a concomi- tant decrease in the non-stem cell population during cancer progression. Together these results suggest that prevention of the increase in the stem-like compartment would retard tumor progression. |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | THERAPEUTIC IMPLICATIONS OF BREAST CANCER STEM CELLS | null | null | Although advances have been made in the treatment of localized breast cancer, there has been less progress in the treatment of advanced metastatic disease. Some of this lack of progress may be due to the failure of current therapies to target cancer stem cells (Fig. 2-3). The cancer stem cell hypothesis has important i... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | THERAPEUTIC IMPLICATIONS OF BREAST CANCER STEM CELLS | null | null | CSC may also express increased levels of antiapoptotic |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | THERAPEUTIC IMPLICATIONS OF BREAST CANCER STEM CELLS | null | null | molecules such as survivin and BCL2-family proteins (46). Current clinical trial designs have largely been based on |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | THERAPEUTIC IMPLICATIONS OF BREAST CANCER STEM CELLS | null | null | FIGURE 2-3 Therapeutic implications of breast cancer stem cells. Current therapies may shrink tumors by killing cells forming the tumor bulk. Because cancer stem cells are less sensitive to these therapies, they remain viable after therapy and re-establish the tumor. In contrast, therapies that target the cancer stem c... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | THERAPEUTIC IMPLICATIONS OF BREAST CANCER STEM CELLS | null | null | strategies aimed at producing tumor regression. Indeed, the Response Evaluation Criteria in Solid Tumors (RECIST) cri- teria measuring tumor response have been utilized to assess the efficacy of new therapeutic agents (47). |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | THERAPEUTIC IMPLICATIONS OF BREAST CANCER STEM CELLS | null | null | However, in breast cancer, as is the case with other malignancies, tumor regression does not correlate well with patient survival (48). In the neoadjuvant setting, only a com- plete pathologic response correlates with recurrence and survival, whereas partial response does not (49). Together with studies demonstrating r... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | THERAPEUTIC IMPLICATIONS OF BREAST CANCER STEM CELLS | null | null | The clinical efficiency of ERBB2 inhibitors provides evi- dence for the effectiveness of agents capable of targeting breast cancer stem cells. In addition, elucidation of other pathways that regulate breast cancer stem cells, such as Notch and Hedgehog may provide new targets for therapeu- tic development. |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | NOTCH PATHWAY | null | null | In mammals, there are four Notch receptors (Notch1 to Notch4), which interact with surface bound or secreted ligands (Delta-like 1, Delta-like 3, Delta-like 4, Jagged 1 and |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | NOTCH PATHWAY | null | null | Jagged 2). Upon ligand binding, Notch receptors are acti- vated by serial cleavage events involving members of the ADAM protease family followed by intramembranous cleav- age regulated by -secretase (presenilin). Following proteo- lytic cleavage, the intracellular domain of Notch translocates to the nucleus to act on ... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | NOTCH PATHWAY | null | null | -secretase inhibitor form spheres at lower efficiency com- pared to untreated cells (58). These studies show important interactions between the Notch and HER2 pathways, both of which are involved in the regulation of cancer stem cells. As in the previously discussed studies, it was shown that lapatinib was able to red... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | HEDGEHOG PATHWAY | null | null | The Hedgehog pathway is critical for many developmen- tal processes. In the absence of Hedgehog, a cell-surface transmembrane protein Patched (PTCH) acts to prevent high expression and activity of a seven membrane spanning receptor Smoothened (SMO). When extracellular Hedgehog is present, it binds to, and inhibits, PTC... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | HEDGEHOG PATHWAY | null | null | Hedgehog pathway is required for normal development. Alterations in Hedgehog signaling result in defects in both embryonic and postnatal mammary gland development. Utilizing in vitro culture systems and NOD/SCID mice, Liu et al. (61) demonstrated that hedgehog signaling mediated by the polycomb gene BMI1 regulates the ... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | OTHER PATHWAYS | null | null | Other pathways that regulate the self-renewal and fate of cancer stem cells are being elucidated. In addition to path- ways such as Wnt, Notch, and Hedgehog, known to regu- late self-renewal of normal stem cells, tumor suppressor genes such as PTEN (phosphatase and tensin homolog on chromosome 10) and p53 have also bee... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | OTHER PATHWAYS | null | null | Studies by Singh and colleagues (65) further our understanding of these pathways by showing interactions between the IL-8/CXCR1/2 axis and HER2 signaling in the |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | OTHER PATHWAYS | null | null | regulation of BCSCs. These studies confirm previous work showing independent roles for these pathways in regulating the self-renewal of BCSCs. CXCR1 is a receptor for the cyto- kine interleukin-8 (IL-8), and it has been shown that recom- binant IL-8 increased BCSC self-renewal as determined by the ability of these cell... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | OTHER PATHWAYS | null | null | (66). On the basis of this, a phase I clinical trial combin- ing reparixin with chemotherapy in women with advanced breast cancers has been initiated. Moreover, the studies of Singh and colleagues suggest that HER2 blocking agents may synergize with CXCR1/2 inhibitors in targeting the BCSC population. The simultaneous... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | OTHER PATHWAYS | null | null | In summary, the cancer stem cell model suggests that it may be necessary to target and eliminate cancer stem cells in order to eradicate cancers. Drugs that interfere with stem cell self-renewal or survival may prove effective in targeting these cell populations. Because normal and tumoral stem cells share many common ... |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | OTHER PATHWAYS | null | null | REFERENCES |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | OTHER PATHWAYS | null | null | Smalley M, Ashworth A. Stem cells and breast cancer: A field in transit. Nat Rev Cancer 2003;3(11):832–844. |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | OTHER PATHWAYS | null | null | Dontu G, El-Ashry D, Wicha MS. Breast cancer, stem/progenitor cells and the estrogen receptor. Trends Endocrinol Metab 2004;15(5):193–197. |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | OTHER PATHWAYS | null | null | Reya T, Morrison SJ, Cark MF, et al. Stem cells, cancer, and cancer stem cells. Nature 2001;414(6859):105–111. |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | OTHER PATHWAYS | null | null | DeOme KB, Faulkin LJ, Bern HA, et al. Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. Cancer Res 1959;19(5):515–520. |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | OTHER PATHWAYS | null | null | Young LJ, Medina D, DeOme KB, et al. The influence of host and tissue age on life span and growth rate of serially transplanted mouse mammary gland. Exp Gerontol 1971;6(1):49–56. |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | OTHER PATHWAYS | null | null | Smith GH, Medina D. A morphologically distinct candidate for an epithe- lial stem cell in mouse mammary gland. J Cell Sci 1988;90(Pt 1):173–183. |
Stem Cells in Breast Development and Carcinogenesis: Concepts and | OTHER PATHWAYS | null | null | Shackleton M, Vaillant F, Simpson KJ, et al. Generation of a functional mammary gland from a single stem cell. Nature 2006;439(7072):84–88. |
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