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Journal ArticleDOI

Detection and analysis of mammary gland stem cells.

01 Jan 2009-The Journal of Pathology (J Pathol)-Vol. 217, Iss: 2, pp 229-241
TL;DR: Assays used to detect mammary stem and progenitor cells, some of the properties of these cells and their progeny and how they relate to the cancer stem cells that drive breast tumour growth are focused on.
Abstract: Emerging evidence from a variety of tissue types, including the mammary gland, suggests that normal stem and progenitor cells are the likely targets for malignant transformation, and that these transformed cells can function as cancer stem cells that drive tumour growth. In order to develop therapies that target these cancer stem cells, it is essential to determine the molecular mechanisms that regulate the growth and differentiation of these cells and their normal counterparts. To this end, a number of quantitative robust clonal assays have been developed that can detect the presence of human and mouse mammary stem and progenitor cells. These assays, when used in conjunction with cell-sorting strategies, have permitted the prospective isolation and characterization of a variety of cell types, including stem cells. Evidence to date indicates that these stem cells exhibit properties of basal mammary cells, possess extensive self-renewal properties, and are capable of generating a large number of phenotypically-distinct progenitor cells, many of which display characteristics of luminal cells. This review article will focus on the assays used to detect mammary stem and progenitor cells, some of the properties of these cells and their progeny and how they relate to the cancer stem cells that drive breast tumour growth.
Citations
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Journal ArticleDOI
TL;DR: The issues surrounding the use of breast cancer cell lines as experimental models are discussed, in light of these revised clinical classifications, and suggestions for improving their use in translational breast cancer research are put forward.
Abstract: Breast cancer is a complex and heterogeneous disease. Gene expression profiling has contributed significantly to our understanding of this heterogeneity at a molecular level, refining taxonomy based on simple measures such as histological type, tumour grade, lymph node status and the presence of predictive markers like oestrogen receptor and human epidermal growth factor receptor 2 (HER2) to a more sophisticated classification comprising luminal A, luminal B, basal-like, HER2-positive and normal subgroups. In the laboratory, breast cancer is often modelled using established cell lines. In the present review we discuss some of the issues surrounding the use of breast cancer cell lines as experimental models, in light of these revised clinical classifications, and put forward suggestions for improving their use in translational breast cancer research.

1,276 citations


Cites background from "Detection and analysis of mammary g..."

  • ...Nowadays, breast CSCs are identifi ed by one or more of the following features: their ability to form tumours in vivo; mammosphere formation in vitro; expression of aldehyde dehydrogenase; or through expression of cell surface biomarkers, usually the CD44+/CD24–/low phenotype [30]....

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Journal ArticleDOI
TL;DR: It is demonstrated that normal and CSC-like cells can arise de novo from more differentiated cell types and that hierarchical models of mammary stem cell biology should encompass bidirectional interconversions between stem and nonstem compartments.
Abstract: Current models of stem cell biology assume that normal and neoplastic stem cells reside at the apices of hierarchies and differentiate into nonstem progeny in a unidirectional manner. Here we identify a subpopulation of basal-like human mammary epithelial cells that departs from that assumption, spontaneously dedifferentiating into stem-like cells. Moreover, oncogenic transformation enhances the spontaneous conversion, so that nonstem cancer cells give rise to cancer stem cell (CSC)-like cells in vitro and in vivo. We further show that the differentiation state of normal cells-of-origin is a strong determinant of posttransformation behavior. These findings demonstrate that normal and CSC-like cells can arise de novo from more differentiated cell types and that hierarchical models of mammary stem cell biology should encompass bidirectional interconversions between stem and nonstem compartments. The observed plasticity may allow derivation of patient-specific adult stem cells without genetic manipulation and holds important implications for therapeutic strategies to eradicate cancer.

1,091 citations


Cites background from "Detection and analysis of mammary g..."

  • ...The human mammary gland contains at least three distinct epithelial cell types: luminal cells (CD44CD49fCD24ESA), basal/myoepithelial cells (CD44CD49fCD24 ESA), and bipotent progenitor/stem cells (CD44CD24ESA) (10, 16)....

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Journal ArticleDOI
TL;DR: A historical perspective of the evolution of the neurosphere assay is provided and limitations in the use of sphere-forming assays in the context of neurospheres are highlighted.

788 citations


Cites background from "Detection and analysis of mammary g..."

  • ...Furthermore, this pattern has also been observed Cell Stem Cell 8, May 6, 2011 ª2011 Elsevier Inc. 491 with spheres that arise from isolated mammary populations, termed mammospheres (Stingl, 2009)....

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Journal ArticleDOI
10 Nov 2011-Nature
TL;DR: In postnatal unperturbed mammary gland, both luminal and myoepithelial lineages contain long-lived unipotent stem cells that display extensive renewing capacities, as demonstrated by their ability to clonally expand during morphogenesis and adult life as well as undergo massive expansion during several cycles of pregnancy.
Abstract: The mammary epithelium is composed of several cell lineages including luminal, alveolar and myoepithelial cells. Transplantation studies have suggested that the mammary epithelium is maintained by the presence of multipotent mammary stem cells. To define the cellular hierarchy of the mammary gland during physiological conditions, we performed genetic lineage-tracing experiments and clonal analysis of the mouse mammary gland during development, adulthood and pregnancy. We found that in postnatal unperturbed mammary gland, both luminal and myoepithelial lineages contain long-lived unipotent stem cells that display extensive renewing capacities, as demonstrated by their ability to clonally expand during morphogenesis and adult life as well as undergo massive expansion during several cycles of pregnancy. The demonstration that the mammary gland contains different types of long-lived stem cells has profound implications for our understanding of mammary gland physiology and will be instrumental in unravelling the cells at the origin of breast cancers.

765 citations

Journal ArticleDOI
TL;DR: The associations between the molecular taxonomy of breast cancer and histological special types are reviewed, the possible origins of the heterogeneity of breast cancers are discussed, and an approach for the identification of novel therapeutic targets based on the study of histologicalspecial types of Breast cancer is proposed.

424 citations


Cites background from "Detection and analysis of mammary g..."

  • ...The identification of normal adult stem cells in the mouse mammary gland (reviewed in Stingl (2009)) and of tumourigenic cells within human breast tumours bymeans of cell surface markers and transplantation assays in immunodeficient mice has fuelled the concept that cancers are initiated and…...

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  • ...…human breast tumours bymeans of cell surface markers and transplantation assays in immunodeficient mice has fuelled the concept that cancers are initiated and maintained by a population of tumour cells with stem celllike features (i.e. ‘cancer stem cells’) (Stingl, 2009; Al-Hajj et al., 2003)....

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References
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Journal ArticleDOI
17 Aug 2000-Nature
TL;DR: Variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals were characterized using complementary DNA microarrays representing 8,102 human genes, providing a distinctive molecular portrait of each tumour.
Abstract: Human breast tumours are diverse in their natural history and in their responsiveness to treatments. Variation in transcriptional programs accounts for much of the biological diversity of human cells and tumours. In each cell, signal transduction and regulatory systems transduce information from the cell's identity to its environmental status, thereby controlling the level of expression of every gene in the genome. Here we have characterized variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals, using complementary DNA microarrays representing 8,102 human genes. These patterns provided a distinctive molecular portrait of each tumour. Twenty of the tumours were sampled twice, before and after a 16-week course of doxorubicin chemotherapy, and two tumours were paired with a lymph node metastasis from the same patient. Gene expression patterns in two tumour samples from the same individual were almost always more similar to each other than either was to any other sample. Sets of co-expressed genes were identified for which variation in messenger RNA levels could be related to specific features of physiological variation. The tumours could be classified into subtypes distinguished by pervasive differences in their gene expression patterns.

14,768 citations

Journal ArticleDOI
TL;DR: Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.
Abstract: The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome. A total of 85 cDNA microarray experiments representing 78 cancers, three fibroadenomas, and four normal breast tissues were analyzed by hierarchical clustering. As reported previously, the cancers could be classified into a basal epithelial-like group, an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression. A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups, each with a distinctive expression profile. These subtypes proved to be reasonably robust by clustering using two different gene sets: first, a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and, second, a gene set that highly correlated with patient outcome. Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.

10,791 citations

Journal ArticleDOI
TL;DR: The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival and strategies designed to target this population may lead to more effective therapies.
Abstract: Breast cancer is the most common malignancy in United States women, accounting for >40,000 deaths each year. These breast tumors are comprised of phenotypically diverse populations of breast cancer cells. Using a model in which human breast cancer cells were grown in immunocompromised mice, we found that only a minority of breast cancer cells had the ability to form new tumors. We were able to distinguish the tumorigenic (tumor initiating) from the nontumorigenic cancer cells based on cell surface marker expression. We prospectively identified and isolated the tumorigenic cells as CD44+CD24−/lowLineage− in eight of nine patients. As few as 100 cells with this phenotype were able to form tumors in mice, whereas tens of thousands of cells with alternate phenotypes failed to form tumors. The tumorigenic subpopulation could be serially passaged: each time cells within this population generated new tumors containing additional CD44+CD24−/lowLineage− tumorigenic cells as well as the phenotypically diverse mixed populations of nontumorigenic cells present in the initial tumor. The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival. Furthermore, because these cells drive tumor development, strategies designed to target this population may lead to more effective therapies.

10,058 citations


"Detection and analysis of mammary g..." refers background in this paper

  • ...For example, assuming that in vivo engraftment in the original Al-Hajj manuscript followed single-hit engraftment kinetics, the frequency of these tumour-initiating cells was <1% within the EpCAM+CD44+CD24−/low subpopulation [74]....

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  • ...In 2003 a manuscript was published which demonstrated that human breast tumours have a cancer stem cell (CSC) component and these cells have an EpCAM+CD44+CD24−/low phenotype, at least in eight of the nine tumour samples examined [74]....

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Journal ArticleDOI
01 Nov 2001-Nature
TL;DR: Stem cell biology has come of age: Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine.
Abstract: Stem cell biology has come of age. Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine. Perhaps the most important and useful property of stem cells is that of self-renewal. Through this property, striking parallels can be found between stem cells and cancer cells: tumours may often originate from the transformation of normal stem cells, similar signalling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells may include 'cancer stem cells' - rare cells with indefinite potential for self-renewal that drive tumorigenesis.

8,999 citations

Journal ArticleDOI
TL;DR: It is demonstrated that the cell capable of initiating human AML in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID mice) — termed the SCID leukemia-initiating cell, or SL-IC — possesses the differentiate and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell.
Abstract: On the subject of acute myeloid leukemia (AML), there is little consensus about the target cell within the hematopoietic stem cell hierarchy that is susceptible to leukemic transformation, or about the mechanism that underlies the phenotypic, genotypic and clinical heterogeneity. Here we demonstrate that the cell capable of initiating human AML in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID mice) - termed the SCID leukemia-initiating cell, or SL-IC - possesses the differentiative and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell. The SL-ICs from all subtypes of AML analyzed, regardless of the heterogeneity in maturation characteristics of the leukemic blasts, were exclusively CD34++ CD38-, similar to the cell-surface phenotype of normal SCID-repopulating cells, suggesting that normal primitive cells, rather than committed progenitor cells, are the target for leukemic transformation. The SL-ICs were able to differentiate in vivo into leukemic blasts, indicating that the leukemic clone is organized as a hierarchy.

6,709 citations


"Detection and analysis of mammary g..." refers background in this paper

  • ...Studies in the haematopoietic field have demonstrated that haematopoietic stem cells (HSCs) are the likely target for oncogenic mutation in human acute myeloid leukaemia (AML), since both the normal HSCs and the AML-CSCs share the same CD34+CD38− phenotype [79]....

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  • ...Committed progenitors can also function as the cell of origin in human acute promyelocytic leukaemia and mouse acute myelogenous leukaemia [79,87,88]....

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