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Contents lists available at ScienceDirect
Seminars in Cell & Developmental Biology journal homepage: www.elsevier.com/locate/semcdb
Review
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Stromal regulation of embryonic and postnatal mammary epithelial development and differentiation
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Beatrice A. Howard a,∗ , Pengfei Lu b
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Division of Breast Cancer Research, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK
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Article history: Available online xxx
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Keywords: Mammary development Mammary differentiation Epithelial–stromal interactions Stromal microenvironment Breast cancer normalisation
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Contents
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The stroma, which is composed of supporting cells and connective tissue, comprises a large component of the local microenvironment of many epithelial cell types, and influences several fundamental aspects of cell behaviour through both tissue interactions and niche regulation. The significance of the stroma in development and disease has been increasingly recognised. Whereas normal stroma is essential for various developmental processes during vertebrate organogenesis, it can be deregulated and become abnormal, which in turn can initiate or promote a disease process, including cancer. The mouse mammary gland has emerged in recent years as an excellent model system for understanding stromal function in both developmental and cancer biology. Here, we take a systematic approach and focus on the dynamic interactions that the stroma engages with the epithelium during mammary specification, cell differentiation, and branching morphogenesis of both the embryonic and postnatal development of the mammary gland. Similar stromal–epithelial interactions underlie the aetiology of breast cancer, making targeting the cancer stroma an increasingly important and promising therapeutic strategy to pursue for breast cancer treatment. © 2014 Published by Elsevier Ltd.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Development of the mammary gland stroma is a dynamic process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mesenchymal signals with regulatory roles in embryonic mammary development identified . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stromal signals essential for epithelial morphogenesis and differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The ECM is an essential stromal component during mammary gland postnatal development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abnormal mammary gland stroma promotes breast cancer development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Intrinsic and extrinsic causes in cancer stroma formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Basis of stromal contribution to breast cancer development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Cancer stroma is a promising therapeutic target for breast cancer treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: CAF, cancer associated fibroblast; ECM, extracellular matrix; EDA, Ectodysplasin; ER␣, oestrogen receptor alpha; FGF, fibroblast growth factor; FPP, fat pad precursor; MPE, mammary primordial epithelium; MEC, mammary epithelial cell; MM, mammary mesenchyme; MP, mammary primordium; NRG3, Neuregulin3; PTH1R, parathyroid hormone 1 receptor; PTHRP, parathyroid hormone related protein. ∗ Corresponding author. Tel.: +44 2071535177; fax: +44 7740374338. Q3 E-mail addresses:
[email protected] (B.A. Howard),
[email protected] (P. Lu). 1084-9521/$ – see front matter © 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.semcdb.2014.01.004
Please cite this article in press as: Howard BA, Lu P. Stromal regulation of embryonic and postnatal mammary epithelial development and differentiation. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcdb.2014.01.004
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1. Introduction Understanding the mechanisms whereby the stroma influences the fundamental aspects of cell and tissue behaviour is an area of intense research efforts in both developmental biology and cancer biology. The importance of mesenchymal influence on organ identity was demonstrated in a number of classic embryological studies that showed that the fate of the epithelium originating from another organ type is determined by the organ type of the embryonic mesenchyme, when the two tissues were surgically recombined [1–3]. While this concept of stromal influence on epithelial cells was recognised relatively more slowly in cancer biology, it has been increasingly accepted that normal stroma is essential for cell fate maintenance during organ homeostasis and function, whereas abnormal stroma promotes cancer initiation and progression [4]. As an ectodermal appendage, the mouse mammary gland is a non-vital organ, and embryological studies are amenable to a variety of experimental techniques such as, genetic and transgenic manipulation, transplantation surgery, and ex vivo culture. In recent years the mouse mammary gland emerged as a powerful model to understand the genetic and cellular basis of stromal function. For example, embryonic mammary mesenchyme and its postnatal derivative, often referred to as mammary stroma, are both essential for organ specification, cell differentiation, morphogenesis, and other important aspects of mammary gland development [3,5–8]. For the purpose of simplicity, throughout this review we use the term “stroma” in a broad sense that refers to both embryonic mesenchyme and postnatal stroma. Decades of research of vertebrate organs have shown that epithelial development is a dynamic and complex process. Importantly, the stroma is intricate and constantly changing as it develops together with the epithelium. Their association is indispensable for differentiation and morphogenesis of the epithelium. Such developmental synchrony is accomplished by constant and persistent niche–epithelial crosstalk throughout different stages of mammary gland formation and tissue homeostasis. As is also observed with the epithelium, stromal composition increases in complexity during development as stromal cells mature and differentiate and cellular products, including paracrine factors and the extracellular matrices (ECM), start to accumulate and elaborate [9]. In light of its important influences on cell behaviour, the dynamic and complex nature of the stroma has posed a great challenge to understanding its function in mammary gland biology as taking cells out of their native microenvironment is routinely done for practical purposes in experimental studies. Here, we take a holistic approach to examine mammary gland development, emphasising the changes that the stroma undergoes throughout critical embryonic and postnatal stages. We highlight recent progress in understanding the mechanism whereby abnormal stroma, especially deregulated ECM biology, facilitates the formation of the tumour microenvironment and promotes breast cancer formation.
2. Development of the mammary gland stroma is a dynamic process The emergence of the mammary gland is a late event during metazoan evolution [10–12]. Coinciding with its position along the evolutionary timeline is the relatively late development of the mammary gland during embryogenesis and postnatal life. The ectodermal appendages reviewed in this issue initiate relatively late in development. In mouse, which is the most widespread model organism used in mammary gland developmental studies, and the basis for most of the experimental studies reviewed here. The first
morphological indication of mouse mammary gland development, does not occur until mid-gestation at around embryonic day (E) 11, when most other vertebrate organs have been patterned and are well in the process of cell differentiation [13]. Likewise, epithelial branching morphogenesis of the mammary gland does not start until late gestation and persists for weeks after birth, whereas in most other branched organs, such as the lungs, the process occurs only during embryogenesis [14]. The embryonic mammary organ is referred to as the mammary primordium (MP) (Fig. 1A–C). In the E11.0-stage mouse embryo, the MP is comprised of a multilayered lens-shaped epithelium with non-descript mesenchyme underlying it [13,15,16]. By E13.0-stage, several layers of dermal mesenchyme adjacent to the mammary bud epithelium have condensed and aligned into a concentric orientation. Mesenchymal condensation is critical for organogenesis, yet little is known about how this process is controlled. Coinciding with this morphological change is the expression of distinguishing molecular markers, including oestrogen receptor-alpha (ER␣), that provide evidence that these cells have differentiated into the primary mammary mesenchyme (MM) (Fig. 1B). Several important events occur starting at E15.5-stage when the MP forms a sprout and invades the underlying stroma. A morphologically distinct population of cells referred to as the secondary mammary mesenchyme or the fat pad precursor (FPP) tissue joins the primary MM and becomes a part of the embryonic stroma surrounding the invading mammary sprout which invades into it (Fig. 1C). At present, the early developmental events of the white adipose tissue, an essential cell population of the mammary gland stroma, remain largely unclear [17,18]. Within a few days after birth, however, the FPP appears to have differentiated into mature adipocytes [19]. By birth, a primitive epithelial tree can be found in the proximal area of the fat-pad (FP) [14]. The primitive ductal epithelial tree develops very slowly in the first a few weeks until puberty at three weeks of age. At puberty, the mammary epithelial cells respond to hormonal stimulation by a phase of rapid invasive growth into the stromal fat-pad with concurrent bifurcation of the terminal end bud (TEB) at the tip of each primary duct until the FP is completely filled with the epithelial tree within ten weeks after birth (Fig. 1D–I) [20]. The FP barely changes in size after birth and enlarges only in proportion with the overall growth of the whole organism, such that the ratio of the fat pad to body size is constant. The cellular composition of FP, however, increases in complexity during its maturation. For example, in addition to adipocytes, periductal fibroblasts, and endothelial and nerve cells, the mammary stroma is also composed of a variety of immune cells including macrophages and eosinophils, which both play an important role in postnatal branching [21–23]. Mouse mammary stroma is highly distinct from that found in the human breast. Mouse mammary epithelium is surrounded small number of fibroblasts, which are in turn, encompassed by a very large amount of fat cells. Human breast epithelium is closely associated with dense accumulations of fibroblasts, such that a distinct fibrous stromal component surrounding the mammary epithelium is found embedded within fatty tissue [24,25]. In both species, another essential component of the stroma is the extracellular matrix (ECM), which is composed of the basement membrane separating the epithelium and stroma, and the interstitial matrix filling the spaces among the non-adherent stromal cells. The ECM is a highly dynamic and functionally versatile structure that constantly undergoes a remodelling process owing to enzymes secreted by both the epithelium and stromal cells [9]. The epithelium continues to undergo further morphogenetic and differentiation events, including formation of alveoli and generation of milk producing cells during pregnancy [7]. During pregnancy, mammary stroma undergoes dramatic changes, especially in adipocyte morphology, which decrease in size, in order
Please cite this article in press as: Howard BA, Lu P. Stromal regulation of embryonic and postnatal mammary epithelial development and differentiation. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcdb.2014.01.004
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Fig. 1. Development of the mammary gland stroma during embryonic and postnatal stages. (A) Whole-mount of E12.5 stage s-SHIP-GFP embryo with each of the 5 mammary primordia on the right ventral flank indicated numerically (1–5). (B) The classic molecular marker for the mammary mesenchyme (MM) ER-alpha (red stain) is expressed in the mesenchymal cells surrounding the mammary primordial epithelium starting at E12.5. (C) At E16.5, ER-alpha (red stain) marks MM cells; distal branches are surrounded by fat pad precursor (FPP) cells. Green marks sSHIP-GFP expression in MPE cells within the duct and nipple. (D) Carmine-stained whole-mount of mammary gland 1 week after birth; a small ductal tree has formed during prenatal development that occupies a small proportion of the fat pad. Higher magnification of ductal tree in black rectangle is shown in the right inset. (E) Histological section of mammary gland 1 week after birth. Epithelial ducts and adipocytes appear blue with haematoxylin staining; other components of the stroma are visible only with special stains or specific markers. (F–I) Carmine-stained whole-mount of mammary gland 4 weeks (F) or 6 weeks (H) after birth; terminal end buds invade into the fat pad in a directional (proximal to distal) manner. (G) Histological section showing terminal end bud (TEB) and adjacent stroma during puberty. (I) Histological section showing mammary epithelial ducts with side-branches and adjacent stroma from a mature postnatal mammary gland. LacZ staining (blue) marks epithelial cells as mammary tissue was derived from mice carrying the MMTV-Cre allele and the Cre-reporter R26RFL/FL allele. (J) Carmine-stained whole-mount of mammary gland during late pregnancy (17.5 day); the mammary alveoli have expanded and filled most of the fat pad. (K) Histological section showing mammary alveoli and adjacent stroma during late-pregnancy. LN denotes lymph node; N denotes nipple; S denotes stroma. Mammary glands are oriented such that proximal is to the right, distal to the left.
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to accommodate the expansion of epithelial cells (Fig. 1J–K). One interesting study suggested that, adipocytes can directly transdifferentiate into and participate in alveolar formation of the epithelium [26]. Conversely, the same study reported that a certain population of mammary epithelial cells is able to revert to an adipocyte fate during involution as adipocytes regain normal morphology and cell number [26]. Similar stromal-to-epithelial transition has been reported in endometrial regeneration, which occurs during the menstrual cycle and after parturition [27]. In both studies, stromal-derived epithelial cells or epithelial-derived stromal cells were marked by either stromal- or epithelial-“specific” Cre lines [26,27]. It thus remains possible that the observed transdifferentiation between stromal and epithelial cells is a result of the Cre lines being leaky. A conclusive demonstration of reversible transdifferentiation between epithelial cells and adipocytes would add yet another layer of complexity in understanding stromal biology of the mammary gland and its plasticity. Classic tissue recombination studies demonstrated key roles for embryonic mesenchyme in inductive signalling. Propper and colleagues were the first to suggest that mammary mesenchyme provides the inductive signal to initiate mammary primordial formation and studies using mesenchyme isolated from the rabbit mammary-forming region supported an inductive role for the mesenchyme in mammary organogenesis [1,2]. Results from heterotypic tissue recombination experiments in which mouse embryonic mesenchyme from the ventral flank were cultured ex vivo combined with surface ectoderm from rat embryos were also highly informative. These tissue recombinants formed branched epithelial structures consisting solely of rat cells, which indicated the ectodermal origin of the mammary epithelium and the ability of mesenchymal cells to induce mammary gland development even across species [28]. Later stages of embryonic mammary morphogenesis are also dependent on the mesenchyme. Klaus Kratochwil showed that when epithelium from MP was separated from the underlying mesenchymal tissue, it would not grow in tissue culture; similarly isolated mammary epithelial tissue did grow when recombined with mesenchymal tissues which influenced glandular structure depending on the organ type it was isolated from [29]. Other studies have recombined mesenchyme from a number of embryonic organs including mammary gland, salivary gland, and chick facial primordia (that form the adult beak) with other types of epithelium; analyses of the outgrowths produced from these tissue recombinants all led to the conclusion that the origin of the mesenchyme influences epithelial morphology [28,30]. One notable example is the study in which isografts of E16 mouse mammary epithelium were combined with either E14 salivary mesenchyme or E16 mammary mesenchyme and transplanted into syngeneic recipients. Salivary gland mesenchyme and mammary epithelium recombinants showed branching patterns typical of salivary glands although they were capable of secreting milk [31]. These studies suggest that cell differentiation and branch pattern are differentially controlled by both intrinsic and extrinsic factors. It is possible that extrinsic factors from the mesenchyme reprogramme cell fate and morphogenesis differentially because the kinetics of reprogramming is different in these two processes. More recent molecular studies support the notion that mesenchymal tissues can influence epithelial tissue identity as shown when prostate mesenchyme was recombined with mammary epithelium and resulted in epithelial expression of transcription factors typical of prostate as well as mammary tissue identities within the tissue recombinants [32]. Together, these studies demonstrate that epithelial tissues remain responsive to mesenchymal signals after lineage specification and suggest that one function of mesenchymal and stromal signals is to continually promote and maintain lineage identity. These studies also demonstrate
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that there are stage-specific differences in the ability of the epithelium to respond to the mesenchymal cues. Less is known about FPP tissue. FPP tissue can support organ growth of a wide spectrum of epithelial organs including colon, intestine, pancreas, salivary gland, and stomach. However upon maturation (when mature adipocytes form), the FPP tissue can no longer support organ growth besides the mammary gland [33]. This loss of ability to permit development of multiple organ types suggests a distinct and more permissive microenvironment for epithelial growth in the prenatal FPP tissue.
3. Mesenchymal signals with regulatory roles in embryonic mammary development identified
Consistent with the mammary gland being a recent evolutionary event, studies have now shown that many of the same molecules 239 essential for the ontogeny of most other vertebrate organs have 240 been co-opted and utilised for the formation of the mammary gland 241 [10]. Indeed, several major signalling pathways, including WNT and 242 BMP signalling and various transcription factors, are now known to 243 be important for mammary gland development [34–36]. Receptor 244 tyrosine kinase (RTK) signalling, including fibroblast growth fac245 tor (FGF) signalling, is yet another major pathway that is essential 246 for various stages of mammary gland development, whereas its 247 deregulation causes breast cancer [37]. 248 Mice with genetic deficiencies and alterations of gene expres249 sion that result in abnormal development of embryonic mammary 250 primordia have led to identification of a number of mesenchy251 mal signals that are involved in the induction of mammary 252 gland organogenesis in vivo. Prior to the initial multilayering of 253 the mammary epithelium, fibroblast growth factor 10 (FGF10) 254 is secreted by the hypaxial compartment of the somite and 255 leads to stimulation of FGFR2B, one isoform of FGFR2 that is 256 expressed in the overlying epithelium [13,38]. This interaction 257 is required for formation of mammary primordium (MP) 2 and 258 3, two of the five pairs of MP that form during mouse devel259 opment. The mechanisms by which the other MP form, that are 260 also dependent on FGF10-FGFR2B signalling (MP1, MP2, MP5), 261 are likely to be similar, although neither the precise origin of 262 the FGF10 signal, nor the roles of other FGFs and FGFRs is 263 known [37]. Fgf7 and Fgfr1 are expressed by mesenchymal cells 264 of the MP and may also contribute to inductive tissue interactions 265 [13,39]. 266 Neuregulin3 (Nrg3), a RTK ligand, is another key mediator of 267 embryonic mammary gland development with a role promot268 ing mammary specification of MP3 [40,41]. Nrg3 is expressed in 269 the dermal mesenchyme between E10.5–E11.0 underling the site 270 where the mammary primordium will subsequently form [42]. 271 Nrg3 hypomorphic mutants (Nrg3ska ) either fail to form MP3 or 272 form a hypoplastic MP3. MP3 formation can be restored when 273 Nrg3ska embryos are cultured ex vivo in the presence of the recom274 binant EGF domain of Nrg3. Supernumerary mammary glands are 275 observed in K14-Nrg3 mice which express Nrg3 throughout the 276 developing epithelium; this finding confirmed the role of Nrg3 277 as a promoter of mammary organ formation during embryogen278 esis [43]. Our most recent results indicate that key functions of 279 Nrg3 during mammary specification can be partially attributed to 280 its ability to promote both local migration/aggregation and cell 281 Q4 spreading of epithelial progenitor cells (Kogata et al., in prepara282 tion). 283 Another mesenchymal factor with links to induction of mam284 mary development is Ectodysplasin (Eda), a component of a 285 signalling network whose activation leads to NFKB-mediated tran286 scription [44]. During embryonic mammary development, Eda 287 238
expression is mesenchymal whilst its receptor, Edar is expressed in surface epithelium and MP epithelium [45,46]. Transgenic mice that mis-express Eda throughout the developing epithelium with the K14 promoter form supernumerary MP along the mammary line demonstrating that Eda promotes mammary organ formation [47,48]. Reports of absent breasts in some women with EDAR mutations support a crucial role for Eda/Edar in inductive mammary signalling [49,50]. Eda and NFKB signalling enhance both embryonic and prepubertal ductal growth and branching [45]. Fgf20 and Pthlh have been identified as putative Eda targets and future studies are likely to provide insights into how the major signalling networks converge during inductive mammary signalling [41,44]. Although great progress has been made in terms of identifying key components of the embryonic mammary stroma, a number of important issues remain unresolved. It is not yet clear whether a single master regulatory mesenchymal signal or mechanism exists that acts as a switch that leads to onset of specification of the mammary epithelium. It seems plausible that a number of genes encompassing a variety of signalling pathways could also promote a microenvironment that is permissive for induction and establishment of the initial signalling centres that lead to formation of the MP. Other mechanisms such as mechanochemical control of mammary organ formation also need to be considered: during embryonic tooth organ formation, mechanical compression of mesenchyme is sufficient to induce the expression of several toothmesenchyme specific genes [51]. Another outstanding issue is how plastic or committed the MP cells are with respect to their organ identity.
4. Stromal signals essential for epithelial morphogenesis and differentiation Like embryonic mesenchyme, mammary gland stroma is indispensible for the continued morphogenesis and differentiation of epithelial cells as well as tissue homeostasis during postnatal life. Mammary epithelia from different mouse strains often show characteristically varying degrees of branching and alveolar differentiation [52]. When the mammary epithelium from a mouse strain that characteristically has highly branched mammary glands were recombined with adult fat pads of a strain that has poorly branched glands, or vice versa, their branching pattern reflected the genetic background of the mammary stroma in which they were grown rather than that of the donor epithelium or host mouse [52]. Thus, stromal rather than epithelial or systemic factors, are responsible for the different adult mammary side-branching patterns and alveolar differentiation that distinguish different strains of mice [53]. Consistent with these data, human breast epithelial cells will only undergo proper differentiation process and form functional ductal, lobular, and acinar structures when transplanted to chimeric “humanised” fat pads that contain human breast fibroblasts [54] or within collagen gels that contain normal human or mouse mammary fibroblasts [55]. A recurring theme in developmental biology is that essential genes and pathways are used repeatedly throughout various stages of vertebrate organogenesis. In addition to participating in embryonic MP formation, RTK signalling plays an essential role in postnatal mammary gland development. Of the four members in their family, for example, both Fgfr1 and Fgfr2 are expressed in the mammary epithelium [56]. Targeted removal of Fgfr1 from the epithelium delays mammary branching [57], suggesting that Fgfr1 regulates branching morphogenesis; the observation that mammary epithelium lacking Fgfr1 can undergo branching, after a delay, suggests that a redundant mechanism, possibly via Fgfr2, may be at work in the absence of Fgfr1. Indeed, an analysis based on
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Fig. 2. Stromal–epithelial interactions during postnatal branching. (A) A diagram depicting a pubertal mammary gland wherein epithelial branching is ongoing. The postnatal stroma features a diverse group of cell types, whose interactions with the epithelium are essential for cell fate differentiation and maintenance (not shown) and branching morphogenesis. Pr, proximal; Di, distal. (B) Cellular components and ECM dynamics at the terminal end bud (TEB), the complex mammary ductal terminal structure found at the epithelial invasion front. Note the basement membrane (pink line) is actively being remodelled (pink dotted line) to facilitate branching. (C) Genes involved in the crosstalk between the epithelium and mammary stroma. Both stromal FGFs and IGF target the epithelial FGFR and IGF1R signalling and direct epithelial branching. Meanwhile, the epithelium-derived ligands of the EGF family, including TGF-alpha and amphiregulin (AREG) target the stroma via EGFR signalling.
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Cre-mediated recombination to permit mosaic inactivation of Fgfr2 from Fgfr2 heterozygous mammary epithelia, showed that Fgfr2 also regulates epithelial branching and promotes cell proliferation in the invading TEBs (Fig. 2) [56]. Consistent with their role in mediating stromal–epithelial crosstalk, epithelial FGFR1/2 are activated by stromal FGFs. As is also observed in embryonic development, Fgf10 is the most abundant Fgf ligand expressed at the RNA level. Unlike its role in regulating MP formation, however, our unpublished data suggest
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that FGF10 acts as guidance cue and regulates directional epithelial migration during branching morphogenesis. In addition to FGFs, mammary stroma also provides other RTK ligands required for vertebrate branching. Insulin growth factor (IGF) signalling appears to function downstream of female hormones to promote epithelial branching [58,59]. Hepatocyte growth factor (HGF) has also been proposed to play a role in mammary branching based on gain-offunction studies [60], although this idea has yet to be tested through loss-of-function analysis. Importantly, for mammary stroma to provide RTK ligands and support epithelial branching, it must be stimulated by epitheliumderived RTK ligands as well. Specifically, studies have shown that mammary glands lacking one or more ligands of the EGF family, including amphiregulin (AREG), EGF, and TGF-␣, causes deficiencies during postnatal branching [61]. These data are consistent with reports showing that EGFR function is required in the mammary stroma for epithelial branching [62,63]. Together, the data indicate that stromal–epithelial bi-directional crosstalk depends on FGFR and EGFR signalling, which target the epithelium and stroma, respectively (Fig. 2). While embryonic mesenchyme instructs epithelial cells to adopt initial cell fate decisions, studies have shown that postnatal stroma is essential for cell fate maintenance during postnatal life. When mammary stroma becomes abnormal, for example during generation of cancer-associated fibroblasts (CAF), epithelial cells associated with them lose their marker expression, dedifferentiate, and become cancerous. CAFs are found in many breast cancers, and promote invasion and metastasis through the production of soluble factors and matrix remodelling [64]. Matrix remodelling sometimes leads to the generation of tracks through the ECM that permit subsequent cancer cell invasion [65]. Once formed, CAFs can maintain their carcinogenic potentials and promote normal cells to undergo cancer formation both in vitro and in vivo [66,67]. These findings thus imply that an important function of mammary stroma is to actively maintain epithelial cell fate during organ homeostasis, and clearly show that the mature postnatal mammary gland is not a static entity and instead is composed of actively signalling cell populations and tissues that promptly respond to perturbations. Recent transplantation studies have shown that adult stem cells exist in the basal epithelium of the postnatal mammary gland [68,69]. It remains unclear whether they are a rare population of naïve stem cells that form and are set aside during embryonic development, or are cell types whose stem cell potential is reawakened when undergoing transplantation into the cleared FP via surgical manipulation. Regardless of this, the ability of these MECs to repopulate cleared fat pads suggest that the postnatal stroma either produces the factors necessary for epithelial cell differentiation or retains the ability to produce these once stimulated by epithelial cells. It remains unclear whether such signals are instructive, as observed with embryonic mesenchyme, or permissive during the process of cell differentiation. Evidence exists that some stromal-derived signals can be instructive since certain non-mammary gland cells, including testicular cells and neural stem cells, adopt mammary gland fate when they are transplanted into the mammary gland stroma. In these cases, however, cell fate transdifferentiation occurs only when mammary epithelial cells are co-transplanted with the non-mammary gland cells [70–74]. The role of mammary epithelial cells in the co-transplants remains unclear at present. They may, like mammary stroma, produce factors that directly target foreign/non-mammary cells and participate in their transdifferentiation; alternatively, they may activate naïve mammary stroma, which when activated produce transdifferentiation factors. Thus, in the latter scenario, co-transplanted MECs indirectly participate in foreign cell transdifferentiation.
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5. The ECM is an essential stromal component during mammary gland postnatal development
6. Abnormal mammary gland stroma promotes breast cancer development
A major stromal component of the mammary gland that has gained increasing research interests is the ECM. Its unique physical, biochemical, and biomechanical properties have made the ECM a versatile structure essential for a wide variety of fundamental cell behaviour, including migration, signalling, and mechanosensing [9]. As such, ECM remodelling is highly regulated and plays important roles in many developmental processes including mammary epithelial branching and differentiation. For example, during ductal branching, the ECM protein fibronectin is specifically expressed at the future site where epithelium invaginates to split the epithelial tip. Loss of fibronectin reduces branch number, suggesting that localised fibronectin deposition participates in epithelial bifurcation [75]. Likewise, loss of function studies indicate that collagen [76] and laminin [77], also play a role in epithelial branching. Consistent with these data, mice lacking or over-expressing Mmps or Timps, which encode ECM remodelling enzymes, show defects in branched organs, suggesting that ECM dynamics are involved in general regulation of epithelial branching morphogenesis [78–80]. Several membrane-type matrix metalloproteases (MMPs) are expressed in the branching epithelium of the mammary gland [81]. Additionally, Mmp-2 is expressed at the epithelial ductal tip and mice lacking Mmp-2 show stunted primary ducts but not side branching [82]. In both submandibular and mammary glands, Mmp-15 is expressed at the epithelial tip of the duct. Interestingly, Mmp-15 is required to digest collagen IV to generate the derivative NC1, which is essential to sustain the high proliferation rate of tip cells of the salivary gland [83]. However, MMP activities do not always promote epithelial branching, as the data mentioned thus far might appear to indicate. Indeed, excess MMP activities, due to loss of TIMP3 function, can inhibit branching morphogenesis in the mouse lung [84]. These data thus suggest that ECM dynamics plays multiple roles, including promotion of collective epithelial migration and cell proliferation, during epithelial branching. In addition to regulating epithelial branching, the ECM is an essential component of the stem cell microenvironment and ECM dynamics regulate stem cell differentiation. Loss of function of the ECM receptor integrin, by ablation of genes encoding integrins in the fly germ line and testis [85,86] or their transcription regulator such as c-Myc in the mouse epidermis [87], causes reduction of stem cell numbers in the epidermis. These data suggest that ECM binding is essential for the maintenance and probably establishment of stem cell properties in the niche. ECM components can also directly influence stem cell biology. Mesenchymal stem cells (MSCs) grown on polymer gels with similar elasticity as found in the brain express neuronal markers and morphology, whereas those grown on gels that are semicompliant, such as smooth and skeletal muscle tissues, or rigid as the bone, express muscle or bone proteins, respectively [88]. Likewise, functional differentiation of mammary epithelial cells requires laminin-induced polarisation of PI3-kinase [89]. On the other hand, studies based on protein microarrays show that ECM molecules can maintain stem cell state or promote basal or luminal differentiation, depending on ECM composition in vitro [90]. Taken together, the mammary gland stroma is indispensible for branching of the epithelial tree during postnatal development. This is in part due to stroma–epithelial interactions based on paracrine signalling, including RTK signalling, and in part due to the versatile functions of stromal ECM, which is highly dynamic and tightly regulated throughout development. Mammary stroma also plays an important role in cell fate maintenance, however the basis of such a role remains largely unclear at present.
Like most biological systems, the mammary stroma is very robust and can sustain epithelial development despite drastic physiological changes that occur during different phases of normal growth and development. With age or under diseased conditions, its ability to withstand various environmental fluctuations and insults can be compromised and, as a consequence, mammary stroma can become cancer-promoting. Recent studies have highlighted the stromal influences in disease progression, including every phase of cancer formation, e.g. initiation and metastasis. 6.1. Intrinsic and extrinsic causes in cancer stroma formation A number of studies have investigated whether the stroma can influence the behaviour of mammary epithelial cells in tumours and whether the stromal tissue can contribute to mammary tumour formation. Recombination of normal mammary epithelium with stroma that has been treated with carcinogen can lead to tumour formation in the epithelium [91,92]. Radiation-induced changes in the stromal microenvironment can contribute to neoplastic progression in vivo [92]. Likewise, targeted removal of the receptor for transforming growth factor beta (TGFßR), which is expressed in the stroma of the prostate, forestomach, and mammary gland, promotes epithelial neoplasia [93,94]. These data suggest that TGF-ß signalling normally functions in the stromal cells to prevent epithelial cells from undergoing tumourigenesis. In these cases, intrinsic changes occur within the stroma due to effects of carcinogen, ion radiation or genetic manipulations. Mammary stroma can also become cancer promoting due to extrinsic changes that happen within the epithelium. Specifically, studies have shown that exposure of the mammary stroma to breast cancer cells can turn otherwise normal stromal cells into cancerpromoting ones. Once cells become cancer-promoting, for example, during formation of CAFs, mutant stroma can retain such properties over prolonged periods of time and promote cancer progression [66,67]. As discussed below, both intrinsic and extrinsic factors could lead to deregulation of paracrine signalling and ECM remodelling, resulting in the formation of cancer stroma. Together, these data highlight the importance of recognising stromal roles in cancer progression and considering the stroma when designing novel treatments. 6.2. Basis of stromal contribution to breast cancer development A number of studies have shown that cancer stroma plays an important role throughout different stages of breast cancer development. For example, epithelial cells lacking function of TGFßR over-produce HGF, suggesting that HGF over-abundance causes epithelial cell over-proliferation and contributes to cancer initiation [93,94]. In addition, deregulated ECM dynamics play an important role in cancer initiation and progression. As a potent facilitator and modifier, the ECM can promote many growth factor signalling pathways including WNT, FGF and Hedgehog signalling, all of which have potent oncogenic potentials when expressed at excessively high levels. Many ECM components, such as Heparan sulfate proteoglycans (HSPG), that facilitate growth factor signalling, are frequently expressed at higher levels in cancers than in normal tissues [95,96]. A tumour can be considered a disorganised organ, which develops by using many of the same cellular and developmental processes essential for organogenesis [97,98]. For example, for a tumour to increase in size, tumour cells face the same increasing demand for nutrient, oxygen and waste exchange as normal cells do in a growing organ during development. As in normal development,
Please cite this article in press as: Howard BA, Lu P. Stromal regulation of embryonic and postnatal mammary epithelial development and differentiation. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcdb.2014.01.004
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such a demand is met by angiogenesis, the process whereby new blood vessels sprout from the existing stromal vasculature [99]. Furthermore, tumour vasculature, and together with the lymphatic system, are the main routes through which cancer cells metastasise and immune cells infiltrate. Consequently, tumour-associated angiogenesis and lymphangiogenesis, the processes whereby lymphatic vessels in the stroma are generated, are important aspects of cancer progression [100]. Another important process during cancer development is cancer-associated inflammation, which is characterised by an influx of immune cells to the tumour stroma [101]. Interestingly, although their initial function is supposed to suppress tumour growth, immune cells including macrophages are often altered and recruited by tumour cells at later stages to promote cancer. Studies have shown that abnormal immune cells play an important role in cancer progression both at the primary and metastatic sites [101].
6.3. Cancer stroma is a promising therapeutic target for breast cancer treatment Functional studies of the mammary mesenchyme demonstrated its profound role in directing and maintaining normal mammary epithelial tissue differentiation and architecture. Mammary mesenchyme can also restore some features of differentiated tissue to mouse mammary tumours when grown together in co-culture [102,103]. This suggests that studies of the mammary mesenchyme could be useful for identifying soluble factors and other tissue components that promote mammary differentiation and are candidates to also promote breast cancer normalisation. A recent study of note has shown that ECM isolated from cultured mammary mesenchyme from early stage (E12.5–13.5) MP is sufficient to induce mammary tumour normalisation to the same extent as co-culture with living cells in vitro and in vivo [104]. Inductive ECMs were analysed using a proteomic approach to identify potential inductive signals as prospective cancer normalising agents. The results demonstrated that biglycan is sufficient to induce tumour normalisation and that siRNA knockdown of biglycan expression in cultured embryonic mesenchyme results in loss of the ECM’s inductive activity. The findings are important as they confirm that embryonic mammary mesenchyme retains the ability to induce partial breast cancer reversion and that this ability is restricted to MM isolated from early stage MP and lost at later stages of development. This study also shows the feasibility of using a cross-species approach and that molecules that have been identified in the mouse mesenchyme also promote differentiation of human breast cancer cells. Use of both proteomic and transcriptomic approaches to define the molecular profiles of the inductive mammary mesenchyme and the postnatal stroma have enormous potential to identify other regulators of mammary differentiation and candidates for use in designing normalising therapies for breast cancers [39,105–107].
7. Conclusions Our understanding of cancer biology has taken remarkable strides and the enormous influence of the stroma on epithelial cell behaviour is now recognised and a highly active area of research. There has been a shift in thinking from the initial belief that the intrinsic properties of cancer cells determine most major aspects of cancer initiation and progression. Cancer is now generally regarded as a heterogeneous disease where multiple cell types, in addition to cancer cells and non-cellular components, need to be mobilised and coordinated to support the survival, growth, and invasion of cancer cells.
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The embryonic mammary mesenchyme provides inductive signals and controls the form of developing mammary epithelial tissues. Stromal signals also mediate key phases of postnatal mammary epithelial development. The mature postnatal mammary epithelial tissue is not a static entity and the postnatal stroma continues to transmit signals and contributes to normal mammary tissue architecture and homeostasis. Normal and malignant mammary epithelium is receptive to stromal signals and provides the biological basis for the design of strategies to induce normalisation of breast cancers. The possibility of devising differentiation therapies for use to treat breast cancer patients to prevent disease progression and recurrence holds great promise and remains to be investigated. Further studies of the embryonic and postnatal mammary stroma and their ability to modify epithelial cell phenotypes will lead to a better understanding of the molecular basis of mammary cell differentiation. Acknowledgements We apologise to those authors whose work has not been cited due to space limitations. This work was supported by grants from Breakthrough Breast Cancer to B.A.H. and P.L. References [1] Propper A, Gomot L. Control of chick epidermis differentiation by rabbit mammary mesenchyme. Experientia 1973;29:1543–4. [2] Propper A, Gomot L. Tissue interactions during organogenesis of the mammary gland in the rabbit embryo. CR Acad Sci Hebd Seances Acad Sci D 1967;264:2573–5. [3] Howard BA. In the beginning: the establishment of the mammary lineage during embryogenesis. Semin Cell Dev Biol 2012;23:574–82. [4] Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol 2012;196:395–406. [5] Propper AY, Howard BA, Veltmaat JM. Prenatal morphogenesis of mammary glands in mouse and rabbit. J Mammary Gland Biol Neoplasia 2013;18:93–104. [6] Cowin P, Wysolmerski J. Molecular mechanisms guiding embryonic mammary gland development. Cold Spring Harbor Perspect Biol 2010;2:a003251. [7] Watson CJ, Khaled WT. Mammary development in the embryo and adult: a journey of morphogenesis and commitment. Development 2008;135:995–1003. [8] Macias H, Hinck L. Mammary gland development. Wiley Interdiscip Rev Dev Biol 2012;1:533–57. [9] Pasic L, Eisinger-Mathason TS, Velayudhan BT, Moskaluk CA, Brenin DR, Macara IG, et al. Sustained activation of the HER1-ERK1/2-RSK signaling pathway controls myoepithelial cell fate in human mammary tissue. Genes Dev 2011;25:1641–53. [10] Mikkola ML, Millar SE. The mammary bud as a skin appendage: unique and shared aspects of development. J Mammary Gland Biol Neoplasia 2006;11:187–203. [11] Mikkola ML. Genetic basis of skin appendage development. Semin Cell Dev Biol 2007;18:225–36. [12] Oftedal OT, Dhouailly D. Evo-devo of the mammary gland. J Mammary Gland Biol Neoplasia 2013;18:105–20. [13] Mailleux AA, Spencer-Dene B, Dillon C, Ndiaye D, Savona-Baron C, Itoh N, et al. Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo. Development 2002;129:53–60. [14] Lu P, Sternlicht MD, Werb Z. Comparative mechanisms of branching morphogenesis in diverse systems. J Mammary Gland Biol Neoplasia 2006;11:213–28. [15] Balinsky B. On the developmental processes in mammary glands and other epidermal structures. Trans R Soc Edinburgh 1949–1950;62:1–31. [16] Balinsky BI. On the prenatal growth of the mammary gland rudiment in the mouse. J Anat 1950;84:227–35. [17] Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white Q5 adipose tissue development, expansion and regeneration. Nat Med 2013. [18] Berry DC, Stenesen D, Zeve D, Graff JM. The developmental origins of adipose tissue. Development 2013;140:3939–49. [19] Sakakura T, Sakagami Y, Nishizuka Y. Dual origin of mesenchymal tissues participating in mouse mammary gland embryogenesis. Dev Biol 1982;91:202–7. [20] Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev 2007;87:905–31. [21] Lu P, Werb Z. Patterning mechanisms of branched organs. Science 2008;322:1506–9. [22] Gouon-Evans V, Rothenberg ME, Pollard JW. Postnatal mammary gland development requires macrophages and eosinophils. Development 2000;127:2269–82.
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Please cite this article in press as: Howard BA, Lu P. Stromal regulation of embryonic and postnatal mammary epithelial development and differentiation. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcdb.2014.01.004
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