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Journal of Cancer 2023Breast cancer development and progression are believed to be a sequential process, from normal to hyperplastic, to , and to invasive and metastatic stages. Given that...
Breast cancer development and progression are believed to be a sequential process, from normal to hyperplastic, to , and to invasive and metastatic stages. Given that over 90% of cancer deaths are caused by invasive and metastatic lesions, countless factors and multiple theories have been proposed as the triggering factor for the cascade of actions of cancer invasion. However, those factors and theories are largely based on the studies of cell lines or animal models. In addition, corresponding interventions based on these factors and theories have failed to reduce the incidence rate of invasive and metastatic lesions, suggesting that previous efforts may have failed to arm at the right target. Considering these facts and observations, we are proposing "A focal aberrant degeneration in the myoepithelial cell layer (MECL) as the most likely triggering factor for breast cancer invasion". Our hypothesis is based on our recent studies of breast and multiple other cancers. Our commentary provides the rationale, morphologic, immunohistochemical, and molecular data to support our hypotheses. As all epithelium-derived cancers share a very similar architecture, our hypothesis is likely to be applicable to invasion of all cancer types. We believe that human tissue-derived data may provide a more realistic roadmap to guide the clinic practice.
PubMed: 37057291
DOI: 10.7150/jca.82291 -
Indian Journal of Otolaryngology and... Oct 2022The pleomorphic adenoma arising in the parotid gland is a benign neoplasm that is aptly named because of its histomorphological diversity. The stromal component can...
The pleomorphic adenoma arising in the parotid gland is a benign neoplasm that is aptly named because of its histomorphological diversity. The stromal component can contain chondromyxoid material, amyloid, and elastic fibers, along with a few rare reports of crystalline structures present in this tumor. Especially, the crystalline components are rarely encountered or appreciated in routine pathology reporting. Here, we report a case of pleomorphic adenoma of the parotid gland, in which tyrosine-rich crystalloids were identified in abundance and were confirmed with special stains and electron microscopy. Though their exact source is not yet known, crystallization of the stromal or myoepithelial cell secretion has been hypothesized. This comprehensive report is to make the histopathologists aware of this rare morphological observation in pleomorphic adenomas so that more cases are identified and followed-up to reveal the impact of their presence in a subset of pleomorphic adenomas.
PubMed: 36452597
DOI: 10.1007/s12070-020-01807-y -
Normal and Sjogren's syndrome models of the murine lacrimal gland studied at single-cell resolution.Proceedings of the National Academy of... Oct 2023The lacrimal gland is of central interest in ophthalmology both as the source of the aqueous component of tear fluid and as the site of autoimmune pathology in the...
The lacrimal gland is of central interest in ophthalmology both as the source of the aqueous component of tear fluid and as the site of autoimmune pathology in the context of Sjogren's syndrome (SjS). To provide a foundational description of mouse lacrimal gland cell types and their patterns of gene expression, we have analyzed single-cell transcriptomes from wild-type (Balb/c) mice and from two genetically based SjS models, and (nonobese diabetic), and defined the localization of multiple cell-type-specific protein and mRNA markers. This analysis has uncovered a previously undescribed cell type, Car6+ cells, which are located at the junction of the acini and the connecting ducts. More than a dozen secreted polypeptides that are likely to be components of tear fluid are expressed by acinar cells and show pronounced sex differences in expression. Additional examples of gene expression heterogeneity within a single cell type were identified, including a gradient of Claudin4 along the length of the ductal system and cell-to-cell heterogeneity in transcription factor expression within acinar and myoepithelial cells. The patterns of expression of channels, transporters, and pumps in acinar, Car6+, and ductal cells make strong predictions regarding the mechanisms of water and electrolyte secretion. In and lacrimal glands, distinctive changes in parenchymal gene expression and in immune cell subsets reveal widespread interferon responses, a T cell-dominated infiltrate in the model, and a mixed B cell and T cell infiltrate in the model.
Topics: Female; Mice; Male; Animals; Sjogren's Syndrome; Lacrimal Apparatus; Mice, Inbred MRL lpr; Mice, Inbred NOD; Mice, Inbred BALB C; Disease Models, Animal
PubMed: 37812717
DOI: 10.1073/pnas.2311983120 -
Journal of Inflammation Research 2023Adenomyosis (AM) is a common benign uterine disorder that has deleterious effects on women's health. However, the pathogenesis of AM is not clearly understood. We aimed...
PURPOSE
Adenomyosis (AM) is a common benign uterine disorder that has deleterious effects on women's health. However, the pathogenesis of AM is not clearly understood. We aimed to investigate the pathophysiological changes and molecular mechanism in AM.
METHODS
Single-cell RNA sequencing (scRNA-seq) was employed to construct a transcriptomic atlas of various cell subsets from the ectopic endometrium (EC) and eutopic endometrium (EM) of one AM patient and evaluate differential expression. The Cell Ranger software pipeline (version 4.0.0) was applied to conduct sample demultiplexing, barcode processing and mapping reads to the reference genome (human GRCh38). Different cell types were classified with markers with the "FindAllMarkers" function, and differential gene expression analysis was performed with Seurat software in R. The findings were confirmed by Reverse Transcription Real-Time PCR using samples from three AM patients.
RESULTS
We identified nine cell types: endothelial cells, epithelial cells, myoepithelial cells, smooth muscle cells, fibroblasts, lymphocytes, mast cells, macrophages and unknown cells. A number of differentially expressed genes, including and , were identified from all cell types. Functional enrichment showed that aberrant gene expression in fibroblasts and immune cells was related to fibrosis-associated terms, such as extracellular matrix dysregulation, focal adhesion and the PI3K-Akt signaling pathway. We also identified fibroblast subtypes and determined a potential developmental trajectory related to AM. In addition, we identified increased cell-cell communication patterns in EC, highlighting the imbalanced microenvironment in AM progression.
CONCLUSION
Our results support the theory of endometrial-myometrial interface disruption for AM, and repeated tissue injury and repair could lead to increased fibrosis in the endometrium. Therefore, the present study reveals the association between fibrosis, the microenvironment, and AM pathogenesis. This study provides insight into the molecular mechanisms regulating AM progression.
PubMed: 37179754
DOI: 10.2147/JIR.S402734 -
Biochimica Et Biophysica Acta.... Jan 2022Nearly all mammals rely on lactation to support their young and to ensure the continued survival of their species. Despite its importance, relatively little is known... (Review)
Review
Nearly all mammals rely on lactation to support their young and to ensure the continued survival of their species. Despite its importance, relatively little is known about how milk is produced and how it is ejected from the lumen of mammary alveoli and ducts. This review focuses on the latter. We discuss how a relatively small number of basal cells, wrapping around each alveolar unit, contract to forcibly expel milk from the alveolar lumen. We consider how individual basal cells coordinate their activity, the fate of these cells at the end of lactation and avenues for future deliberation and exploration.
Topics: Animals; Cell Plasticity; Epithelial Cells; Female; Humans; Lactation; Mammary Glands, Human
PubMed: 34653580
DOI: 10.1016/j.bbamcr.2021.119159 -
Cureus Jul 2023Pleomorphic adenomas (PA) are the most common benign salivary gland tumors. They arise from the major salivary glands, as well as the minor salivary glands. They may... (Review)
Review
Pleomorphic adenomas (PA) are the most common benign salivary gland tumors. They arise from the major salivary glands, as well as the minor salivary glands. They may arise rarely from the palate, oral cavity, neck, and nasal cavity also. Yet, the fourth, fifth, and sixth decades of life are the most common for them to manifest. Forty percent of them occur in males and 60% in females. It is a benign mixed tumor, which has three components: an epithelial component, a myoepithelial cell component, and a mesenchymal component. A fibrous capsule separates these cells from the surrounding tissues. It generally presents as a slowly progressing painless swelling, which is well-delineated, nonsymptomatic, and not involving the facial nerve. Salivary gland tumors can be accurately diagnosed before surgery using fine-needle aspiration (FNA), ultrasonography (USG), and computed tomography (CT) scan. Calponin, cluster of differentiation 9 (CD9), glial fibrillary acidic protein (GFAP), Mcl-2, metastasis suppressor gene (NM23), p63, S-100, smooth muscle actin (SMA), and SRY-box transcription factor 10 (SOX10) exhibit the majority of the positive reactions in pleomorphic adenomas. The diagnostic marker pleomorphic adenoma gene 1 (PLAG1) is frequently employed since it is specific for pleomorphic adenoma. Although benign, these epithelial tumors have a propensity to recur and undergo malignant transformation if incompletely excised, leading to increased morbidity in these patients. A review of the consensus guidelines and literature was conducted, and the online literature on the subject from 2002 was included. This article is not a complete review of all the available literature; rather, it is a comprehensive review of the topic.
PubMed: 37614271
DOI: 10.7759/cureus.42311 -
Journal of Dental Research Oct 2019Maintaining salivary gland function is critical for oral health. Loss of saliva is a common side effect of therapeutic irradiation for head and neck cancer or autoimmune... (Review)
Review
Maintaining salivary gland function is critical for oral health. Loss of saliva is a common side effect of therapeutic irradiation for head and neck cancer or autoimmune diseases such as Sjögren's syndrome. There is no curative treatment, and current strategies proposed for functional regeneration include gene therapy to reengineer surviving salivary gland tissue, cell-based transplant therapy, use of bioengineered glands, and development of drugs/biologics to stimulate in vivo regeneration or increase secretion. Understanding the genetic and cellular mechanisms required for development and homeostasis of adult glands is essential to the success of these proposed treatments. Recent advances in genetic lineage tracing provide insight into epithelial lineage relationships during murine salivary gland development. During early fetal gland development, epithelial cells expressing keratin 14 (K14) Sox2, Sox9, Sox10, and Trp63 give rise to all adult epithelium, but as development proceeds, lineage restriction occurs, resulting in separate lineages of myoepithelial, ductal, and acinar cells in postnatal glands. Several niche signals have been identified that regulate epithelial development and lineage restriction. Fibroblast growth factor signaling is essential for gland development, and other important factors that influence epithelial patterning and maturation include the Wnt, Hedgehog, retinoic acid, and Hippo signaling pathways. In addition, other cell types in the local microenvironment, such as endothelial and neuronal cells, can influence epithelial development. Emerging evidence also suggests that specific epithelial cells will respond to different types of salivary gland damage, depending on the cause and severity of damage and the resulting damaged microenvironment. Understanding how regeneration occurs and which cell types are affected, as well as which signaling factors drive cell lineage decisions, provides specific targets to manipulate cell fate and improve regeneration. Taken together, these recent advances in understanding cell lineages and the signaling factors that drive cell fate changes provide a guide to develop novel regenerative treatments.
Topics: Animals; Cell Lineage; Epithelial Cells; Keratins; Mice; SOX Transcription Factors; Salivary Glands; Signal Transduction; Trans-Activators
PubMed: 31331226
DOI: 10.1177/0022034519864592 -
The Journal of Cell Biology Aug 2019In epithelial cancers, cells must invade through basement membranes (BMs) to metastasize. The BM, a thin layer of extracellular matrix underlying epithelial and... (Review)
Review
In epithelial cancers, cells must invade through basement membranes (BMs) to metastasize. The BM, a thin layer of extracellular matrix underlying epithelial and endothelial tissues, is primarily composed of laminin and collagen IV and serves as a structural barrier to cancer cell invasion, intravasation, and extravasation. BM invasion has been thought to require protease degradation since cells, which are typically on the order of 10 µm in size, are too large to squeeze through the nanometer-scale pores of the BM. However, recent studies point toward a more complex picture, with physical forces generated by cancer cells facilitating protease-independent BM invasion. Moreover, collective cell interactions, proliferation, cancer-associated fibroblasts, myoepithelial cells, and immune cells are all implicated in regulating BM invasion through physical forces. A comprehensive understanding of BM structure and mechanics and diverse modes of BM invasion may yield new strategies for blocking cancer progression and metastasis.
Topics: Animals; Basement Membrane; Biomechanical Phenomena; Cell Communication; Humans; Neoplasm Invasiveness; Neoplasms; Peptide Hydrolases
PubMed: 31315943
DOI: 10.1083/jcb.201903066 -
NPJ Breast Cancer 2020The identification and molecular characterization of cellular hierarchies in complex tissues is key to understanding both normal cellular homeostasis and tumorigenesis.... (Review)
Review
The identification and molecular characterization of cellular hierarchies in complex tissues is key to understanding both normal cellular homeostasis and tumorigenesis. The mammary epithelium is a heterogeneous tissue consisting of two main cellular compartments, an outer basal layer containing myoepithelial cells and an inner luminal layer consisting of estrogen receptor-negative (ER) ductal cells and secretory alveolar cells (in the fully functional differentiated tissue) and hormone-responsive estrogen receptor-positive (ER) cells. Recent publications have used single-cell RNA-sequencing (scRNA-seq) analysis to decipher epithelial cell differentiation hierarchies in human and murine mammary glands, and reported the identification of new cell types and states based on the expression of the luminal progenitor cell marker KIT (c-Kit). These studies allow for comprehensive and unbiased analysis of the different cell types that constitute a heterogeneous tissue. Here we discuss scRNA-seq studies in the context of previous research in which mammary epithelial cell populations were molecularly and functionally characterized, and identified c-Kit progenitors and cell states analogous to those reported in the recent scRNA-seq studies.
PubMed: 32793804
DOI: 10.1038/s41523-020-00175-8 -
Head and Neck Pathology Mar 2023Optically clear cytoplasm may occur in neoplastic and non-neoplastic conditions, either as a characteristic feature of a disease entity or as a morphologic rarity,... (Review)
Review
BACKGROUND
Optically clear cytoplasm may occur in neoplastic and non-neoplastic conditions, either as a characteristic feature of a disease entity or as a morphologic rarity, potentially creating diagnostic dilemmas in various organ systems. In the head and neck, clear cell change can occur in lesions of salivary, odontogenic, thyroid, parathyroid, or sinonasal/skull base origin, as well as in metastases to these regions.
METHODS
This review elaborates the top ten clear cell lesions in the head and neck, emphasizing their distinguishing histologic, immunohistochemical, and molecular attributes, and presents a rational approach to arriving at an accurate classification.
RESULTS
Cytoplasmic pallor or clearing may be caused by accumulations of glycogen, lipid, mucin, mucopolysaccharides, water, foreign material, hydropic organelles, or immature zymogen granules. Overlapping morphologic features may present a diagnostic challenge to the surgical pathologist. Similarity in immunohistochemical profiles, often due to common cell type, as well as rare non-neoplastic mimics, furthers the diagnostic conundrum.
CONCLUSIONS
The top ten lesions reviewed in this article are as follows: (1) clear cell carcinoma (salivary and odontogenic), (2) mucoepidermoid carcinoma, (3) myoepithelial and epithelial-myoepithelial carcinoma, (4) oncocytic salivary gland lesions, (5) squamous cell carcinoma, (6) parathyroid water clear cell adenoma, (7) metastatic renal cell carcinoma (especially in comparison to clear cell thyroid neoplasms), (8) sinonasal renal cell-like adenocarcinoma, (9) chordoma, and (10) rhinoscleroma.
Topics: Humans; Carcinoma, Renal Cell; Kidney Neoplasms; Epithelial Cells; Carcinoma, Squamous Cell; Adenocarcinoma, Clear Cell; Salivary Gland Neoplasms
PubMed: 36928734
DOI: 10.1007/s12105-022-01518-6