-
Oncotarget Feb 2017The mammary gland is an organ comprising two primary lineages, specifically the inner luminal and the outer myoepithelial cell layers. Mammary gland stem cells (MaSCs)... (Review)
Review
The mammary gland is an organ comprising two primary lineages, specifically the inner luminal and the outer myoepithelial cell layers. Mammary gland stem cells (MaSCs) are highly dynamic and self-renewing, and can give rise to these mammary gland lineages. The lineages are responsible for gland generation during puberty as well as expansion during pregnancy. In recent years, researchers have focused on understanding how MaSCs are regulated during mammary gland development and transformation of breast cancer. Here, we summarize the identification of MaSCs, and how they are regulated by the signaling transduction pathways, mammary gland microenvironment, and non-coding RNAs (ncRNAs). Moreover, we debate the evidence for their serving as the origin of breast cancer, and discuss the therapeutic perspectives of targeting breast cancer stem cells (BCSCs). In conclusion, a better understanding of the key regulators of MaSCs is crucial for the clinical treatment of breast cancer.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Differentiation; Cell Lineage; Cell Proliferation; Cell Self Renewal; Female; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Humans; Mammary Glands, Animal; Mammary Glands, Human; Neoplastic Stem Cells; Phenotype; Signal Transduction; Stem Cell Niche; Stem Cells; Tumor Microenvironment
PubMed: 27793013
DOI: 10.18632/oncotarget.12893 -
Breast Cancer Research : BCR Sep 2020Breast cancer arises within specific regions in the human breast referred to as the terminal duct lobular units (TDLUs). These are relatively dynamic structures...
BACKGROUND
Breast cancer arises within specific regions in the human breast referred to as the terminal duct lobular units (TDLUs). These are relatively dynamic structures characterized by sex hormone driven cyclic epithelial turnover. TDLUs consist of unique parenchymal entities embedded within a fibroblast-rich lobular stroma. Here, we established and characterized a new human breast lobular fibroblast cell line against its interlobular counterpart with a view to assessing the role of region-specific stromal cues in the control of TDLU dynamics.
METHODS
Primary lobular and interlobular fibroblasts were transduced to express human telomerase reverse transcriptase (hTERT). Differentiation of the established cell lines along lobular and interlobular pathways was determined by immunocytochemical staining and genome-wide RNA sequencing. Their functional properties were further characterized by analysis of mesenchymal stem cell (MSC) differentiation repertoire in culture and in vivo. The cells' physiological relevance for parenchymal differentiation was examined in heterotypic co-culture with fluorescence-activated cell sorting (FACS)-purified normal breast primary luminal or myoepithelial progenitors. The co-cultures were immunostained for quantitative assessment of epithelial branching morphogenesis, polarization, growth, and luminal epithelial maturation. In extension, myoepithelial progenitors were tested for luminal differentiation capacity in culture and in mouse xenografts. To unravel the significance of transforming growth factor-beta (TGF-β)-mediated crosstalk in TDLU-like morphogenesis and differentiation, fibroblasts were incubated with the TGF-β signaling inhibitor, SB431542, prior to heterotypic co-culture with luminal cells.
RESULTS
hTERT immortalized fibroblast cell lines retained critical phenotypic traits in culture and linked to primary fibroblasts. Cell culture assays and transplantation to mice showed that the origin of fibroblasts determines TDLU-like and ductal-like differentiation of epithelial progenitors. Whereas lobular fibroblasts supported a high level of branching morphogenesis by luminal cells, interlobular fibroblasts supported ductal-like myoepithelial characteristics. TDLU-like morphogenesis, at least in part, relied on intact TGF-β signaling.
CONCLUSIONS
The significance of the most prominent cell type in normal breast stroma, the fibroblast, in directing epithelial differentiation is largely unknown. Through establishment of lobular and interlobular fibroblast cell lines, we here demonstrate that epithelial progenitors are submitted to stromal cues for site-specific differentiation. Our findings lend credence to considering stromal subtleties of crucial importance in the development of normal breast and, in turn, breast cancer.
Topics: Adult; Animals; Breast; Breast Neoplasms; Cell Differentiation; Cell Line; Coculture Techniques; Epithelial Cells; Female; Fibroblasts; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Stem Cells; Stromal Cells; Xenograft Model Antitumor Assays; Young Adult
PubMed: 32993755
DOI: 10.1186/s13058-020-01344-0 -
Cell Proliferation Oct 2003Although experimental data clearly confirm the existence of self-renewing mammary stem cells, the characteristics of such progenitor cells have never been satisfactorily... (Review)
Review
Although experimental data clearly confirm the existence of self-renewing mammary stem cells, the characteristics of such progenitor cells have never been satisfactorily defined. Using a double immunofluorescence technique for simultaneous detection of the basal cytokeratin 5, the glandular cytokeratins 8/18 and the myoepithelial differentiation marker smooth muscle actin (SMA), we were able to demonstrate the presence of CK5+ cells in human adult breast epithelium. These cells have the potential to differentiate to either glandular (CK8/18+) or myoepithelial cells (SMA+) through intermediary cells (CK5+ and CK8/18+ or SMA+). We therefore proceeded on the assumption that the CK5+ cells are phenotypically and behaviourally progenitor (committed adult stem) cells of human breast epithelium. Furthermore, we furnish evidence that most of these progenitor cells are located in the luminal epithelium of the ductal lobular tree. Based on data obtained in extensive analyses of proliferative breast disease lesions, we have come to regard usual ductal hyperplasia as a progenitor cell-derived lesion, whereas most breast cancers seem to evolve from differentiated glandular cells. Double immunofluorescence experiments provide a new tool to characterize phenotypically progenitor (adult stem) cells and their progenies. This model has been shown to be of great value for a better understanding not only of normal tissue regeneration but also of proliferative breast disease. Furthermore, this model provides a new tool for unravelling further the regulatory mechanisms that govern normal and pathological cell growth.
Topics: Adult; Breast; Cell Lineage; Epithelial Cells; Female; Humans; Stem Cells
PubMed: 14521517
DOI: 10.1046/j.1365-2184.36.s.1.7.x -
Environmental Health Perspectives Mar 1989The fully differentiated cells of the rat mammary parenchyma, the ductal epithelial, alveolar, and myoepithelial cells, are distinguished by their ultrastructure and by... (Review)
Review
The fully differentiated cells of the rat mammary parenchyma, the ductal epithelial, alveolar, and myoepithelial cells, are distinguished by their ultrastructure and by their accumulation of immunocytochemically detectable marker proteins. The different cell types probably develop from primative ductal structures called terminal end buds, which are present in the developing rat mammary glands, and these structures contain relatively undifferentiated cells. Clonal epithelial stem cell lines, obtained from normal rat mammary glands or benign mammary tumors, differentiate under appropriate conditions along a pathway to droplet-cell/doming cultures of primative alveolarlike cells. Under different culture conditions, the epithelial stem cells differentiate along a separate pathway to myoepitheliallike cells. They accumulate some of the specific marker proteins of myoepithelial cells in vivo, including type IV collagen, laminin, and Thy-1 antigen. In addition, these myoepitheliallike cells in culture contain an abundance of a potential calcium-binding protein, p9Ka, which also occurs in myoepithelial cells of histological sections from mammary glands. The accumulation of type IV collagen, laminin, Thy-1, and p9Ka occurs asynchronously along the pathway to the myoepitheliallike cells in vitro. Furthermore, the steady-state levels of these different marker proteins arise by alterations in the controls at the transcriptional, the posttranscriptional processing, and the translational stages of their production. These results suggest a stepwise control of synthesis of myoepithelial cell marker proteins, and in the case of p9Ka and Thy-1 antigen, this altered control may arise through their possession of novel transcriptional promoters.
Topics: Amino Acid Sequence; Animals; Base Sequence; Calcium-Binding Proteins; Cell Differentiation; Female; In Vitro Techniques; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Molecular Sequence Data; Neoplastic Stem Cells; Rats; Stem Cells
PubMed: 2647483
DOI: 10.1289/ehp.898039 -
Cancer Cytopathology Aug 2021The cytologic diagnosis of papillary lesions of the breast is challenging because of the diverse morphology, including epithelial hyperplasia, atypia, low-grade...
BACKGROUND
The cytologic diagnosis of papillary lesions of the breast is challenging because of the diverse morphology, including epithelial hyperplasia, atypia, low-grade malignancy, and neuroendocrine differentiation; also, traditional malignant features such as necrosis and myoepithelial cell loss can be lacking. Thus, the diagnostic criteria for papillary lesions may differ from those for other breast lesions. This study evaluated various cytologic parameters in a large cohort to identify useful diagnostic features.
METHODS
Cytologic preparations of papillary lesions with histologic follow-up were reviewed for features related to cellularity, epithelial cohesiveness, cellular and stromal architecture, cytomorphology, and background. Corresponding histologic slides were also reviewed.
RESULTS
In all, 153 cases were included. Epithelial discohesion, solid and cribriform patterns, atypical nuclear features, and mitoses (P ≤ .001 to P = .017) were associated with malignancy. Cell balls, monolayer sheets, and features of cystic change (P < .001 to P = .016) were associated with benign lesions. Complex (P = .031) and slender (P = .026) papillae and neuroendocrine features (P < .001) were associated with malignancy. Hemorrhage, background, and infiltrating neutrophils (P < .001 to P = .025) were associated with malignancy; fibrotic broad papillary stromal fragments (naked papillary fronds [NPFs]; P = .043) were associated with benignity. The presence of any single parameter, including the absence of myoepithelial cells within epithelial structure, the presence of cytoplasmic granules, an increased amount of cytoplasm, and a nuclear to cytoplasmic (N/C) ratio greater than 0.7, which were identified by principal component analysis, yielded a sensitivity of 95.1% and a specificity of 100.0% in predicting malignancy.
CONCLUSIONS
Methodological assessment of multiple features is recommended. Myoepithelial cells, cytoplasmic granules, the amount of cytoplasm, and the N/C ratio are key features for diagnosis.
Topics: Breast; Carcinoma, Papillary; Diagnosis, Differential; Epithelial Cells; Fibroadenoma; Humans
PubMed: 33561323
DOI: 10.1002/cncy.22412 -
Anatomical Record (Hoboken, N.J. : 2007) Mar 2012The parotid histological structure includes acinar, ductal, and myoepithelial cells, surrounded by a connective stromal component. The parotid stroma is mostly regarded... (Comparative Study)
Comparative Study
The parotid histological structure includes acinar, ductal, and myoepithelial cells, surrounded by a connective stromal component. The parotid stroma is mostly regarded as an inert shell, consisting of septa, which divide the parenchyma. Telocytes were recently identified as a new stromal cell type in various organs, including exocrine pancreas. We aimed to evaluate telocytes presence in parotid stroma and whether their topographical features might support an involvement in parotid function modulation. Serial ultrathin sections of human and rat parotid glands were studied and compared by transmission electron microscopy. Two-dimensional concatenation of sequenced micrographs allowed the ultrastructural identification of parotid telocytes, with their specific long, thin, and moniliform prolongations (telopodes). Telocyte location appeared frequently as a strategic one, in close contact or vicinity of both secretory (acini and ducts) and regulatory (nerves and blood vessels) apparatuses. They were also found in the interacinar and the subductal stroma. Two previously reported telocyte markers (c-kit/CD117 and vimentin) were assayed by immunohistochemistry. Actin expression was also evaluated. Telocytes are making a network, especially by branching of their long telopodes. Elements of this telocyte network are interacting with each other (homocellular connections) as well as with other cell types (heterocellular connections). These interactions are achieved either by direct contact (stromal synapse), or mediated via shed microvesicles/exosomes. Since telocyte connections include both neurovascular and exocrine elements (e.g., acini and ducts), it is attractive to think that telocytes might mediate and integrate neural and/or vascular input with parotid function.
Topics: Animals; Connective Tissue; Humans; Parotid Gland; Rats; Stromal Cells
PubMed: 22174191
DOI: 10.1002/ar.21540 -
Reproduction, Nutrition, Development 2002This paper reviews data on mammary leptin and leptin receptor gene expression as well as on blood and milk leptin levels during the pregnancy-lactation cycle in humans,... (Review)
Review
This paper reviews data on mammary leptin and leptin receptor gene expression as well as on blood and milk leptin levels during the pregnancy-lactation cycle in humans, rodents and ruminants, with the aim of better understanding milk leptin origin and functions. The few published papers report that leptin may be produced by different cell types in the mammary tissue, and may act as a paracrine factor on mammary epithelial cell proliferation, differentiation and/or apoptosis via adipose-epithelial and/or myoepithelial-epithelial cellular interactions. In addition to leptin synthesis, epithelial cells may transfer leptin from the blood, and these two mechanisms may account for the presence of leptin in the milk. The respective parts of these two processes remain to be determined, as well as the true milk leptin levels. Indeed, reported concentrations for milk leptin vary strongly according to species and mainly according to the milk fractions and the assay methods used. If leptin levels in milk (and specially colostrum) are found to be significant, this hormone could be involved in neonate physiology.
Topics: Adipocytes; Animals; Epithelial Cells; Female; Gene Expression Regulation; Humans; Lactation; Leptin; Mammary Glands, Animal; Milk; Pregnancy; Receptors, Cell Surface; Receptors, Leptin; Rodentia; Ruminants
PubMed: 12537253
DOI: 10.1051/rnd:2002034 -
Cancer Dec 2004Lesions that contain abundant myoepithelial cells may present as a diagnostic challenge in fine-needle aspiration (FNA) specimens. Potential diagnostic problems may...
BACKGROUND
Lesions that contain abundant myoepithelial cells may present as a diagnostic challenge in fine-needle aspiration (FNA) specimens. Potential diagnostic problems may arise due to morphologic heterogeneity of myoepithelial cell-rich lesions and difficulty in predicting malignancy in FNA specimens. An accurate diagnosis is important, because malignant myoepithelial cell-rich lesions require a wider local excision and lymph node dissection. The authors characterized the cytologic features of myoepithelial cell-rich lesions in an attempt to define the criteria that facilitate distinction between benign and malignant tumors.
METHODS
FNA biopsies of myoepithelial cell-rich lesions with corresponding histologic specimens were selected. The cytology specimens were evaluated for the following criteria: cellularity, cell morphology, pleomorphism, chromatin pattern, presence of nucleoli, background material, necrotic debris, and presence of mitotic figures. A review of the histologic sections was performed for diagnostic confirmation.
RESULTS
Seventeen specimens from 17 different patients were selected. The histologic diagnoses were myoepithelial carcinoma (n = 6 patients), malignant mixed tumor with predominant myoepithelial carcinoma (n = 2 patients), epithelial-myoepithelial carcinoma (n = 1 patient), and benign mixed tumor (n = 8 patients). The primary sites included the parotid gland (n = 10 patients), submandibular gland (n = 3 patients), minor salivary gland (n = 3 patients), and breast (n = 1 patient). Most specimens, whether they were benign or malignant, were very cellular. Pleomorphism, coarse chromatin, prominent nucleoli, mitotic figures, and necrosis were observed only in malignant specimens. Background material and ductal cells were seen in both benign and malignant specimens.
CONCLUSIONS
The presence of pleomorphism, coarse chromatin, prominent nucleoli, mitotic figures, and/or necrosis should raise the possibility of myoepithelial carcinoma in FNA specimens from myoepithelial cell-rich lesions.
Topics: Aged; Biopsy, Needle; Carcinoma; Cell Nucleolus; Chromatin; Diagnosis, Differential; Female; Humans; Lung Diseases; Lung Neoplasms; Male; Middle Aged; Mitosis; Myoepithelioma; Necrosis
PubMed: 15476290
DOI: 10.1002/cncr.20642 -
Scientific Data May 2021Understanding how cancer cells interact with the surrounding microenvironment early in breast cancer development can provide insight into the initiation and progression...
Understanding how cancer cells interact with the surrounding microenvironment early in breast cancer development can provide insight into the initiation and progression of invasive breast cancers. The myoepithelial cell layer surrounding breast ducts acts as a physical barrier in early breast cancer, preventing cancer cells from invading the surrounding stroma. Changes to the expression profile and properties of myoepithelial cells have been implicated in progression to invasive carcinoma. Identifying the molecular drivers of myoepithelial cell-mediated tumour suppression may offer new approaches to predict and block the earliest stages of cancer invasion. We employed a high-content approach to knock down 87 different genes using siRNA in an immortalised myoepithelial cell line, prior to co-culture with invasive breast cancer cells in 3D. Combined with high-content imaging and a customised analysis pipeline, this system was used to identify myoepithelial proteins that are necessary to control cancer cell invasion. This dataset has identified prospective myoepithelial suppressors of early breast cancer invasion which may be used by researchers to investigate their clinical validity and utility.
Topics: Breast Neoplasms; Cell Line, Tumor; Coculture Techniques; Epithelial Cells; Female; Gene Knockdown Techniques; Humans; Neoplasm Invasiveness; RNA, Small Interfering; Tumor Suppressor Proteins
PubMed: 34050191
DOI: 10.1038/s41597-021-00924-9 -
Advanced Healthcare Materials Apr 2022Progress in the development of salivary gland regenerative strategies is limited by poor maintenance of the secretory function of salivary gland cells (SGCs) in vitro....
Encapsulation of Primary Salivary Gland Acinar Cell Clusters and Intercalated Ducts (AIDUCs) within Matrix Metalloproteinase (MMP)-Degradable Hydrogels to Maintain Tissue Structure and Function.
Progress in the development of salivary gland regenerative strategies is limited by poor maintenance of the secretory function of salivary gland cells (SGCs) in vitro. To reduce the precipitous loss of secretory function, a modified approach to isolate intact acinar cell clusters and intercalated ducts (AIDUCs), rather than commonly used single cell suspension, is investigated. This isolation approach yields AIDUCs that maintain many of the cell-cell and cell-matrix interactions of intact glands. Encapsulation of AIDUCs in matrix metalloproteinase (MMP)-degradable PEG hydrogels promotes self-assembly into salivary gland mimetics (SGm) with acinar-like structure. Expression of Mist1, a transcription factor associated with secretory function, is detectable throughout the in vitro culture period up to 14 days. Immunohistochemistry also confirms expression of acinar cell markers (NKCC1, PIP and AQP5), duct cell markers (K7 and K5), and myoepithelial cell markers (SMA). Robust carbachol and ATP-stimulated calcium flux is observed within the SGm for up to 14 days after encapsulation, indicating that secretory function is maintained. Though some acinar-to-ductal metaplasia is observed within SGm, it is reduced compared to previous reports. In conclusion, cell-cell interactions maintained within AIDUCs together with the hydrogel microenvironment may be a promising platform for salivary gland regenerative strategies.
Topics: Acinar Cells; Hydrogels; Matrix Metalloproteinases; Salivary Glands
PubMed: 34994104
DOI: 10.1002/adhm.202101948