Philippa D. Darbre's research while affiliated with University of Reading and other places

Publications (129)

Chapter
This chapter describes the mechanisms of action of several intracellular ligand-activated transcription factors: progesterone receptor (PR), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), peroxisome proliferator-activated receptors (PPARs), pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon recep...
Chapter
This chapter gives an overview of the mechanisms of estrogen action and describes assay strategies to determine how and where environmental chemicals might mimic or interfere in these processes. At a molecular level, environmental compounds may compete with estrogen for binding to intracellular estrogen receptors (ERs), leading to effects on gene e...
Chapter
This chapter discusses the potential for endocrine-disrupting chemicals (EDCs) to influence the development of cancer in female endocrine-sensitive tissues of the breast, endometrium, ovary, and cervix, and in male hormone-regulated tissues of the prostate, testis, and breast. Hanahan and Weinberg have established a framework for understanding the...
Chapter
This chapter discusses evidence that exposure to endocrine-disrupting chemicals (EDCs) can interfere in endocrine regulation of energy metabolism, and in so doing, lead to the development of obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. The prevalence of obesity has increased markedly in recent decades, and although gene...
Chapter
This chapter provides an introduction to the importance of hormones to the healthy functioning of the human body and an overview of the varied types and sources of environmental chemicals that can interfere in their action. Such compounds, termed endocrine-disrupting chemicals (EDCs), may occur naturally, but the majority are man-made compounds tha...
Chapter
This chapter outlines some of the principles on which regulation of endocrine disrupting chemicals (EDCs) depends, and provides an introduction to the concepts of hazard, weight of evidence, and risk. Challenges for the regulation of chemicals which act through endocrine mechanisms are discussed. The value and limitations of different types of evid...
Chapter
This chapter provides an overview of the dependence of development and maintenance of the male phenotype (masculinization) on testicular hormones and emphasizes its vulnerability to endocrine disruption, particularly in perturbations to the balance of androgen to estrogen. Evidence for consequences to male reproductive health following fetal exposu...
Chapter
The human population is exposed to endocrine-disrupting chemicals (EDCs) as complex mixtures through inhalation (air), oral intake (water, food), or dermal applications (household and personal care products), and the measurement of so many hundreds of EDCs in human body tissues implies that adverse effects on human endocrine health must also be con...
Chapter
Endocrine-disrupting chemicals (EDCs) occur in air as volatile or semivolatile compounds in the gas phase or attached to particulate matter. They include industrial chemicals (polychlorinated biphenyls), products of combustion (polychlorinated dibenzodioxins/furans, polycyclic aromatic hydrocarbons), pesticides, herbicides alkyl phenols, components...
Chapter
This chapter provides an overview of the chemical components of personal care products (PCPs) that possess endocrine-disrupting activity and cites evidence that such endocrine-disrupting chemicals (EDCs) can be absorbed from application to human skin. Reported cases are described where absorption of EDCs from PCPs has affected human endocrine healt...
Chapter
This chapter provides an overview of evidence suggesting a role for endocrine-disrupting chemicals (EDCs) in altered timing of female puberty, disorders of ovarian function, and benign abnormalities of the uterus and breast. Evidence that prenatal exposure to exogenous estrogen can affect female reproductive health after birth is demonstrated by th...
Chapter
This chapter begins with an overview of the extent to which endocrine-disrupting chemicals (EDCs) can enter human tissues from environmental exposure. Retention of EDCs in body tissues may be influenced both by their route of entry and by their resistance to physiological clearance processes. Their endocrine-disrupting activity and biological avail...
Chapter
Many hundreds of endocrine disrupting chemicals (EDCs) have been measured as entering human breast tissue from a range of environmental sources, and this review focuses on discussion of mechanisms by which such EDCs may be contributing to the globally rising incidence of breast cancer. Many of the distinguishing features of breast cancer may be acc...
Article
Full-text available
Extensive use of triclosan (2,4,4′‐trichloro‐2′‐hydroxydiphenyl ether) as an antimicrobial agent in household and personal care products has resulted in global exposure of the human population. Its presence in human tissues, including milk, and its oestrogen‐disrupting properties raise concerns for an involvement in breast cancer. Because metastati...
Article
Full-text available
Bisphenol A and phthalate esters are used as additives in the manufacture of plastic materials, but their ability to leach out with age and heat has resulted in their becoming ubiquitous contaminants of the ecosystem including within human body tissues. Over recent years, these compounds have been shown to possess endocrine disrupting properties wi...
Article
Full-text available
Estrogen disrupting chemicals are environmental compounds which mimic, antagonize or interfere in the action of physiological estrogens. They occur naturally (plant phytoestrogens) but the majority are man-made compounds, which, through their use in agricultural, industrial and consumer products, have become widely present in human tissues includin...
Article
This mini-review offers a historical perspective on the emergence of endocrine disruption as a multidisciplinary research area, encompassing studies from ecotoxicology to medicine and from field observations to molecular cell biology. Endocrine-disrupting chemicals (EDCs) are environmental compounds which interfere in the actions of hormones. Some...
Article
Full-text available
Background: Phenolic endocrine-disrupting compounds (EDCs) have long been suspected of increasing human breast cancer risk, via aromatase up-regulation; however, the metabolic effects upon aromatase in human breast cells exposed to environmentally relevant concentrations of phenolic compounds, have not been addressed. Objectives: To examine the...
Article
Full-text available
Philippa D Darbre School of Biological Sciences, University of Reading, Reading, UK Abstract: Over recent years, many environmental pollutant chemicals have been shown to possess the ability to interfere in the functioning of the endocrine system and have been termed endocrine disrupting chemicals (EDCs). These compounds exist in air as volatile or...
Article
Benzophenone (BP)-1, BP-2, BP-3, octylmethoxycinnamate (OMC), 4-methylbenzilidenecamphor and homosalate are added to personal care products to absorb ultraviolet light. Their presence in human milk and their oestrogenic activity suggests a potential to influence breast cancer development. As metastatic tumour spread is the main cause of breast canc...
Article
Full-text available
Purpose of review: The purpose of this review was to summarise current evidence that some environmental chemicals may be able to interfere in the endocrine regulation of energy metabolism and adipose tissue structure. Recent findings: Recent findings demonstrate that such endocrine-disrupting chemicals, termed "obesogens", can promote adipogenes...
Article
Full-text available
Dermal absorption of components of personal care products (PCPs) may contribute to breast cancer development. Cyclic volatile methylsiloxanes (cVMS) are used widely in the formulation of PCPs, and their presence has been recently detected in human blood. The objectives of this study were to investigate any genotoxic effects after short- (1 week) or...
Article
The human population is exposed to aluminium (Al) from diet, antacids and vaccine adjuvants, but frequent application of Al-based salts to the underarm as antiperspirant adds a high additional exposure directly to the local area of the human breast. Coincidentally the upper outer quadrant of the breast is where there is also a disproportionately hi...
Article
This chapter outlines some of the principles on which regulation of endocrine disrupting chemicals (EDCs) depends, and provides an introduction to the concepts of hazard, weight of evidence and risk. Challenges for the regulation of chemicals which act through endocrine mechanisms are discussed. The value and limitations of different types of evide...
Article
This chapter discusses emerging evidence that exposure to endocrine-disrupting chemicals (EDCs) can interfere in endocrine regulation of energy metabolism, and in so doing, lead to the development of obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. The prevalence of obesity has increased markedly in recent decades, and alth...
Article
This chapter discusses the potential for endocrine-disrupting chemicals (EDCs) to influence the development of cancer in female endocrine-sensitive tissues of the breast, endometrium, ovary, and cervix, and in male hormone-regulated tissues of the prostate, testis, and breast. Hanahan and Weinberg have established a framework for understanding the...
Article
This chapter gives an overview of the mechanisms of estrogen action and describes assay strategies to determine how and where environmental chemicals might mimic or interfere in these processes. At a molecular level, environmental compounds may compete with estrogen for binding to intracellular estrogen receptors (ERs), leading to effects on gene e...
Chapter
This chapter provides an overview of the dependence of development and maintenance of the male phenotype (masculinization) on testicular hormones and emphasizes its vulnerability to endocrine disruption, particularly in perturbations to the balance of androgen to estrogen. Evidence for consequences to male reproductive health following fetal exposu...
Article
This chapter provides an introduction to the importance of hormones to the healthy functioning of the human body and an overview of the varied types and sources of environmental chemicals that can interfere in their action. Such compounds, termed endocrine-disrupting chemicals (EDCs), may occur naturally, but the majority are artificial compounds t...
Article
This chapter provides an overview of the chemical components of personal care products (PCPs) that possess endocrine-disrupting activity, and cites evidence that such endocrine-disrupting chemicals (EDCs) can be absorbed from application to human skin. Reported cases are described where absorption of EDCs from PCPs has affected human endocrine heal...
Article
This chapter begins with an overview of the extent to which endocrine-disrupting chemicals (EDCs) can enter human tissues from environmental exposure. Retention of EDCs in body tissues may be influenced both by their route of entry and by their resistance to physiological clearance processes. Their endocrine-disrupting activity and biological avail...
Article
This chapter provides an overview of evidence suggesting a role for endocrine-disrupting chemicals (EDCs) in altered timing of female puberty, disorders of ovarian function, and benign abnormalities of the uterus and breast. Evidence that prenatal exposure to exogenous estrogen can affect female reproductive health after birth is demonstrated by th...
Article
Aluminium (Al) has been measured in human breast tissue, and may be a contributory factor in breast cancer development. At the 10th Keele meeting, we reported that long-term exposure to Al could increase migratory properties of oestrogen-responsive MCF-7 human breast cancer cells suggesting a role for Al in the metastatic process. We now report tha...
Article
Full-text available
Use of underarm aluminium (Al)-based antiperspirant salts may be a contributory factor in breast cancer development. At the 10th Keele meeting, Al was reported to cause anchorage-independent growth and double strand DNA breaks in MCF10A immortalised non-transformed human breast epithelial cells. We now report that exposure of MCF10A cells to Al chl...
Article
This chapter describes the mechanisms of action of several intracellular ligand-activated transcription factors: progesterone receptor (PR), glucocorticoid receptor (GR), peroxisome proliferator-activated receptors (PPAR), pregnane X receptor (PXR), and aryl hydrocarbon receptor (AhR). Environmental endocrine-disrupting chemicals (EDCs) have been s...
Article
Alkyl esters of p–hydroxybenzoic acid (parabens) are widely used as preservatives in personal care products, foods and pharmaceuticals. Their oestrogenic activity, their measurement in human breast tissue and their ability to drive proliferation of oestrogen-responsive human breast cancer cells has opened a debate on their potential to influence br...
Article
A framework for understanding the complexity of cancer development was established by Hanahan and Weinberg in their definition of the hallmarks of cancer. In this review, we consider the evidence that parabens can enable development in human breast epithelial cells of four of six of the basic hallmarks, one of two of the emerging hallmarks and one...
Article
Efficacy of endocrine therapy is compromised when human breast cancer cells circumvent imposed growth inhibition. The model of long-term oestrogen-deprived MCF-7 human breast cancer cells has suggested the mechanism results from hypersensitivity to low levels of residual oestrogen. MCF-7 cells were maintained for up to 30 weeks in phenol-red-free m...
Article
Aluminium (Al) has been measured in human breast tissue, nipple aspirate fluid and breast cyst fluid, and recent studies have shown that at tissue concentrations, aluminium can induce DNA damage and suspension growth in human breast epithelial cells. This paper demonstrates for the first time that exposure to aluminium can also increase migratory a...
Article
The alkyl esters of p-hydroxybenzoic acid (parabens), which are used as preservatives in consumer products, possess oestrogenic activity and have been measured in human breast tissue. This has raised concerns for a potential involvement in the development of human breast cancer. In this paper, we have investigated the extent to which proliferation...
Article
Parabens (alkyl esters of p-hydroxybenzoic acid) are used extensively as preservatives in consumer products, and intact esters have been measured in several human tissues. Concerns of a potential link between parabens and breast cancer have been raised, but mechanistic studies have centred on their oestrogenic activity and little attention has been...
Chapter
Environmental estrogens are compounds that can mimic or interfere in the action of the female hormone estrogen and are found in food either as natural components of plant material (phytoestrogens) or as man-made chemicals (xenoestrogens) - the latter entering food from environmental pollution or from storage procedures. This review discusses the so...
Article
Full-text available
The incidence of breast cancer has risen worldwide to unprecedented levels in recent decades, making it now the major cancer of women in many parts of the world.1 Although diet, alcohol, radiation and inherited loss of BRCA1/2 genes have all been associated with increased incidence, the main identified risk factors are life exposure to hormones inc...
Article
Growth responses to oestrogen can be reproducibly obtained using a selection of oestrogen-receptor-containing human breast cancer cell lines, and molecular mechanisms have been shown to include modulation to growth factor/receptor/signalling pathways, cell-cycle proteins, apoptosis, differentiation, adhesion, motility and migration. Considerable pr...
Article
The concentrations of five esters of p-hydroxybenzoic acid (parabens) were measured using HPLC-MS/MS at four serial locations across the human breast from axilla to sternum using human breast tissue collected from 40 mastectomies for primary breast cancer in England between 2005 and 2008. One or more paraben esters were quantifiable in 158/160 (99%...
Chapter
This article discusses recent research showing that component chemicals of personal care products can mimic or interfere with estrogen action, can enter the human body from dermal application, and can be detected in the human breast. Lifetime exposure to estrogen is an established risk factor in the development of breast cancer, and exposure to est...
Article
The human breast is exposed to aluminium from many sources including diet and personal care products, but dermal application of aluminium-based antiperspirant salts provides a local long-term source of exposure. Recent measurements have shown that aluminium is present in both tissue and fat of the human breast but at levels which vary both between...
Article
Aluminium is not a physiological component of the breast but has been measured recently in human breast tissues and breast cyst fluids at levels above those found in blood serum or milk. Since the presence of aluminium can lead to iron dyshomeostasis, levels of aluminium and iron-binding proteins (ferritin, transferrin) were measured in nipple aspi...
Article
Full-text available
MCF-7, T-47-D, ZR-75-1 human breast cancer cell lines are dependent on oestrogen for growth but can adapt to grow during long-term oestrogen deprivation. This serves as a model for identification of therapeutic targets in endocrine-resistant breast cancer. An overlooked complication of this model is that it involves more than non-addition of oestro...
Article
Full-text available
Human breast cancer cells (MCF-7, T-47-D and ZR-75-1) can adapt to circumvent any reduced growth rate during long-term oestrogen deprivation, and this provides three model systems to investigate mechanisms of endocrine resistance in breast cancer. In this paper we report consistent differences in the effects of three growth inhibitors following lon...
Article
Unlabelled: Many environmental compounds with oestrogenic activity are measurable in the human breast and oestrogen is a known factor in breast cancer development. Exposure to environmental oestrogens occurs through diet, household products and cosmetics, but concentrations of single compounds in breast tissue are generally lower than needed for a...
Article
Cellular effects of oestrogen are mediated by two intracellular receptors ERα and ERβ. However, to compare responses mediated through these two receptors, experimental models are needed where ERα and ERβ are individually stably overexpressed in the same cell type. We compared the effects of stable overexpression of ERα and ERβ in the MCF10A cell li...
Article
Clinical studies dating back decades report a disproportionately high number of female breast cancers originating in the upper outer quadrant of the breast [1], and although this is attributed to a greater amount of epithelial tissue in that region, it is also the area to which underarm cosmetic products are applied [2,3]. Early studies reported 31...
Article
Benzyl salicylate, benzyl benzoate and butylphenylmethylpropional (Lilial) are added to bodycare cosmetics used around the human breast. We report here that all three compounds possess oestrogenic activity in assays using the oestrogen-responsive MCF7 human breast cancer cell line. At 3 000 000-fold molar excess, they were able to partially displac...
Article
Over the years, the MCF7 human breast cancer cell line has provided a model system for the study of cellular and molecular mechanisms in oestrogen regulation of cell proliferation and in progression to oestrogen and antioestrogen independent growth. Global gene expression profiling has shown that oestrogen action in MCF7 cells involves the coordina...
Article
Gross cystic breast disease (GCBD) is the most common benign breast disorder, but the molecular basis of cyst formation remains to be identified. If the use of aluminium-based antiperspirant salts is involved in the etiology of gross breast cyst formation, it might be expected that aluminium would be at elevated levels in human breast cyst fluid (B...
Article
This toxicology update reviews research over the past four years since publication in 2004 of the first measurement of intact esters of p-hydroxybenzoic acid (parabens) in human breast cancer tissues, and the suggestion that their presence in the human body might originate from topical application of bodycare cosmetics. The presence of intact parab...
Article
Full-text available
The phytoestrogens genistein, daidzein and the daidzein metabolite equol have been shown previously to possess oestrogen agonist activity. However, following consumption of soya diets, they are found in the body not only as aglycones but also as metabolites conjugated at their 4'- and 7-hydroxyl groups with sulphate. This paper describes the effect...
Conference Paper
Growth of MCF7McGrath human breast cancer cells (MCF7) under conditions of long-term oestrogen deprivation results in loss of dependence on oestrogen for growth (MCF7-ED) and provides a model system to study the molecular basis of endocrine resistance in breast cancer. MCF7-ED cells have raised levels of phosphoMAPK compared with oestrogen-maintain...
Article
As a consequence of its widespread use as an antimicrobial agent in consumer goods, triclosan has become distributed ubiquitously across the ecosystem, and recent reports that it can cause endocrine disruption in aquatic species has increased concern. It is reported here that triclosan possesses intrinsic oestrogenic and androgenic activity in a ra...
Article
Aluminium is omnipresent in everyday life and increased exposure is resulting in a burgeoning body burden of this non-essential metal. Personal care products are potential contributors to the body burden of aluminium and recent evidence has linked breast cancer with aluminium-based antiperspirants. We have used graphite furnace atomic absorption sp...
Article
Since the alkyl esters of p-hydroxybenzoic acid (parabens) can be measured intact in the human breast and possess oestrogenic properties, it has been suggested that they could contribute to an aberrant burden of oestrogen signalling in the human breast and so play a role in the rising incidence of breast cancer. However, although parabens have been...
Article
Cell culture models of antioestrogen resistance often involve applying selective pressures of oestrogen deprivation simultaneously with addition of tamoxifen or fulvestrant (Faslodex, ICI 182,780) which makes it difficult to distinguish events in development of antioestrogen resistance from those in loss of response to oestrogen or other components...
Article
Many compounds in the environment have been shown capable of binding to cellular oestrogen receptors and then mimicking the actions of physiological oestrogens. The widespread origin and diversity in chemical structure of these environmental oestrogens is extensive but to date such compounds have been organic and in particular phenolic or carbon ri...
Article
The established role of oestrogen in the development and progression of breast cancer raises questions concerning a potential contribution from the many chemicals in the environment which can enter the human breast and which have oestrogenic activity. A range of organochlorine pesticides and polychlorinated biphenyls possess oestrogen-mimicking pro...
Article
Aluminium salts are used as the active antiperspirant agent in underarm cosmetics, but the effects of widespread, long term and increasing use remain unknown, especially in relation to the breast, which is a local area of application. Clinical studies showing a disproportionately high incidence of breast cancer in the upper outer quadrant of the br...
Article
This paper addresses the question of whether p-hydroxybenzoic acid, the common metabolite of parabens, possesses oestrogenic activity in human breast cancer cell lines. The alkyl esters of p-hydroxybenzoic acid (parabens) are used widely as preservatives in consumer products to which the human population is exposed and have been shown previously to...
Article
The upper outer quadrant (UOQ) of the breast is the most frequent site for incidence of breast cancer, but the reported disproportionate incidence in this quadrant appears to rise with year of publication. In order to determine whether this increasing incidence in the UOQ is an artifact of different study populations or is chronological, data have...
Article
Previous studies have compared the oestrogenic properties of phytoestrogens in a wide variety of disparate assays. Since not all phytoestrogens have been tested in each assay, this makes inter-study comparisons and ranking oestrogenic potency difficult. In this report, we have compared the oestrogen agonist and antagonist activity of eight phytoest...
Article
Although risk factors are known to include the loss of function of the susceptibility genes BRCA1/BRCA2 and lifetime exposure to oestrogen, the main causative agents in breast cancer remain unaccounted for. It has been suggested recently that underarm cosmetics might be a cause of breast cancer, because these cosmetics contain a variety of chemical...
Article
Full-text available
Parabens are used as preservatives in many thousands of cosmetic, food and pharmaceutical products to which the human population is exposed. Although recent reports of the oestrogenic properties of parabens have challenged current concepts of their toxicity in these consumer products, the question remains as to whether any of the parabens can accum...
Article
Previous work has demonstrated that the alkyl esters of p-hydroxybenzoic acid (parabens) possess oestrogenic activity, which increases with length of alkyl chain from methylparaben to n-butylparaben and with branching in the alkyl chain from n-butylparaben to isobutylparaben. This study reports on the oestrogenic activity of benzylparaben in a vari...
Article
The alkyl esters of p-hydroxybenzoic acid (parabens) are used widely as preservatives in foods, pharmaceuticals and cosmetics to which the human population is exposed. Recent studies have reported that methylparaben, ethylparaben, n-propylparaben and n-butylparaben all possess oestrogenic activity in several in vitro assays and in animal models in...
Article
Parabens (4-hydroxybenzoic acid esters) have been recently reported to have oestrogenic activity in yeast cells and animal models. Since the human population is exposed to parabens through their widespread use as preservatives in foods, pharmaceuticals and cosmetics, we have investigated here whether oestrogenic activity of these compounds can also...
Article
The Shionogi 115 (S115) mouse mammary tumor cells express the MMTV-specific 1.7 kb mRNA (orf) at a high level in the presence of androgens. In lymphoid cells the orf-gene encodes a superantigen which has an important role in establishing self-tolerance but in mammary and breast cancer cells the function of the orf gene is unclear. In the present wo...
Article
Full-text available
This work describes a reciprocal relationship between cell density and levels of insulin-like growth factor receptors (IGFR) in MCF7 human breast cancer cells, which adds a new dimension to the mechanism of cross-talk between estrogen and insulin-like growth factors in the regulation of breast cancer cell growth. The reduced binding of both (125)I-...
Article
CD63 is a member of the transmembrane-4-superfamily (TM4SF) of tetraspanin proteins involved in integrin-mediated cell migration and has been shown to be a marker of the early stages of melanoma progression where it may act as a tumour suppressor gene to limit metastasis. Using differential display, we have previously identified CD63 as a novel mar...
Article
Although retinoids are known to be inhibitory to breast cancer cell growth, a key remaining question is whether they would remain effective if administered long-term. We describe here the long-term effects of all- trans retinoic acid on two oestrogen-dependent human breast cancer cell lines MCF7 and ZR-75-1. Although both cell lines were growth inh...
Article
The vitamin E component of palm oil provides a rich source of tocotrienols which have been shown previously to be growth inhibitory to two human breast cancer cell lines: responsive MCF7 cells and unresponsive MDA-MB-231 cells. Data presented here shows that the tocotrienol-rich fraction (TRF) of palm oil and individual fractions (alpha, gamma and...
Article
Previous transfection experiments using a zinc-inducible expression vector have shown that overexpression of insulin-like growth factor II (IGFII) in MCF7 human breast cancer cells can reduce dependence on oestrogen for cell growth in vitro. Parallel transfections now performed into another oestrogen-dependent human breast cancer cell line (ZR-75-1...
Article
Screening by differential display of oestrogen-sensitive MCF7 human breast cancer cells grown in the short-term (6 days) and long-term (70 weeks) absence of oestrogen has led to the identification of a new oestrogen-regulated mRNA. The cDNA isolated by differential display has 100% homology from nucleotides 615 to 859 of the published sequence for...
Article
Regulation of the growth of breast cancer cells is the result of a complex interaction between steroid hormones and growth factors, and in particular of oestrogen and insulin-like growth factors (IGF). Alteration of any one mitogenic component can affect the cell response to other pathways. Previous work has shown that increased autocrine productio...

Citations

... This Special Issue on Breast Cancer Metastasis is a compendium of 17 review articles, 13 original articles, and 3 case reports that collectively cover a wide spectrum of topics associated with the development and treatment of breast cancer metastases. Among the review topics presented herein are thought-provoking discussions on the potential impact of estrogen disrupting agents [10] and ESR1 mutations to engage the metastatic cascade [11] , as well as eloquent analyses of how fluidity [12] and plasticity [13] within the hierarchy of normal and malignant stems cells drives breast cancer development and metastatic progression. Similarly, Robinson et al. [14] provide an elegant perspective on how alternations in telomere maintenance mechanisms influence the metastatic evolution of breast cancer stem cells. ...