A Guide to Epithelial Cell Markers

Epithelial cells are a diverse cell type in mammals, primarily known for forming protective layers and linings in organ systems such as the skin, digestive tract, respiratory tract, urinary tract, and central nervous system. Epithelial tissue, which is one of the four major types of tissue, fulfills many important functions, including absorption, transport, secretion, defense, and metabolism.

Epithelial cells are classified based on their shape—squamous, cuboidal, or columnar—as well as their layered structure, which includes simple, pseudostratified, stratified, and transitional. Beyond morphological classification, epithelial cell biomarkers provide a more precise understanding of cellular identity, function, and state, surpassing the limitations of traditional microscopy. These molecular markers are essential for distinguishing epithelial subtypes, tracking cell differentiation, and identifying pathological changes, particularly in the epithelial-mesenchymal transition, cancer diagnostics, and regenerative medicine. Here, we present common epithelial markers that have been identified in review literature.  

Cytokeratins as epithelial markers

Keratin proteins were initially thought to be exclusive to epithelial cells. These proteins form intermediate filaments that play a crucial role in protecting epithelial cells from both mechanical and non-mechanical stressors, as well as other functions like cell polarization and membrane protein targeting. While it is now known that keratins exist in other cell types, they remain widely used as markers for distinguishing subsets of epithelial cells, as specific keratin proteins are differentially expressed across various epithelial tissues. With the exception of the liver, which expresses only a single keratin pair, most epithelial types express approximately four to eight keratins.

Keratin expression varies across epithelial cell types, reflecting their specialized functions. K8 and K18 form the primary keratin pair in many simple epithelial cells, while K7 and K19 are found in duct-lining, intestinal, mesothelial, and pseudostratified epithelial cells, including the urothelium. Other examples of keratin expression include K6 and K16 (epidermis, nail epithelia, non-keratinizing stratified squamous epithelia), K5 and K14 (stratified squamous epithelium, myoepithelial cells of complex glandular tissues), K3 and K12 (corneal epithelium), K17 (skin injury), and K1, K2, K10, K15, K9 (keratinocytes).

The prevalence of keratins in epithelial cells has led to the widespread use of pan-cytokeratin (pan-CK) antibodies, which are broad-spectrum antibodies reactive to several keratin proteins. These include monoclonal antibody clones KL1, Lu-5, MAK-6, OSCAR, and antibody cocktails AE1/AE3 and CK22, which have been effective in routine immunohistochemical staining of various epithelial tumors.

Epithelial-mesenchymal transition markers

Epithelial-mesenchymal transition (EMT) is a biological process in which polarized epithelial cells, typically anchored to the basement membrane through their basal surface, undergo extensive biochemical changes to acquire a mesenchymal cell phenotype. This transition is characterized by enhanced migratory capacity, increased invasiveness, resistance to apoptosis, and elevated production of extracellular matrix (ECM) components.

This figure highlights general markers used in characterizing the spectrum of changes that occur during EMT. 

EMT has traditionally been classified into three types: type 1 occurs as a normal process during early development, type 2 is associated with tissue repair following trauma or injury, and type 3 drives the metastatic spread of epithelial tumors to distant tissues. EMT, along with its reversal, the mesenchymal-to-epithelial transition (MET), plays a pivotal role in the metastatic cascade across various tumor types. Patients whose tumors exhibit strong EMT signatures typically face poorer overall prognoses and higher rates of metastasis.

EMT involves a series of distinct molecular processes, many of which also serve as biomarkers for tracking a cell's progression through EMT. Key events include the loss of adherens junctions, cytoskeletal reorganization, production of ECM components, and resistance to anoikis, a form of apoptosis triggered by cell detachment.

Epithelial markers such as cytokeratins are downregulated followed by an increased expression of mesenchymal markers like fibronectin and vimentin. E-cadherin expression is notably switched to N-cadherin, accompanied by the activation of transcription factors (such as Snail, Slug, Twist, FOXC2, ZEB1) and altered expression of cell-surface proteins (CD24, DDR2, ITGB4, OCLN), ECM components (fibronectin, collagen I, laminin, MMPs, entactin), cytoskeletal proteins (α-SMA, desmin), and other intracellular proteins (β-catenin, S100A4, LEF1).

Table of epithelial cell markers

The table below highlights key protein markers used to characterize epithelial cells and the epithelial-mesnchymal transition (EMT), as identified in recent literature. Each marker is linked to relevant antibody and ELISA kit products, commonly employed for immunodetection in research and clinical settings. These products, sourced from various manufacturers, provide a valuable reference for identifying or isolating epithelial cell populations when used alongside other established epithelial markers.

References

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Karantza V. Keratins in health and cancer: more than mere epithelial cell markers. Oncogene. 2011;30(2):127-138. doi:10.1038/onc.2010.456

Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2010;120(5):1786. doi:10.1172/JCI39104C1

Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119(6):1429-1437. doi:10.1172/JCI36183

Ribatti D, Tamma R, Annese T. Epithelial-Mesenchymal Transition in Cancer: A Historical Overview. Transl Oncol. 2020;13(6):100773. doi:10.1016/j.tranon.2020.100773

Brown MS, Muller KE, Pattabiraman DR. Quantifying the Epithelial-to-Mesenchymal Transition (EMT) from Bench to Bedside. Cancers (Basel). 2022;14(5):1138. Published 2022 Feb 23. doi:10.3390/cancers14051138

Zhao H, Adler KB, Bai C, Tang F, Wang X. Epithelial proteomics in multiple organs and tissues: similarities and variations between cells, organs, and diseases. J Proteome Res. 2006;5(4):743-755. doi:10.1021/pr050389v

Franzén O, Gan L, Björkegren J. PanglaoDB: a web server for exploration of mouse and human single-cell RNA sequencing data. Database, Volume 2019, 2019, baz046, https://doi.org/10.1093/database/baz046