Fact-checked by Grok 2 weeks ago

Epithelial cell adhesion molecule

The epithelial cell adhesion molecule (EpCAM), also known as CD326, is a type I transmembrane glycoprotein that mediates calcium-independent homophilic cell-cell adhesion, primarily in epithelial tissues, and plays essential roles in maintaining epithelial integrity, cell proliferation, and signaling pathways.^[1] Encoded by the EPCAM gene on chromosome 2p21, it consists of 314 amino acids, including a large extracellular domain of 242 amino acids with three N-glycosylation sites, a 23-amino-acid transmembrane domain, and a short 26-amino-acid cytoplasmic tail that enables intracellular signaling.^[1] EpCAM forms homodimers and potentially higher-order structures like trans-tetramers to facilitate adhesion, while also modulating interactions with cadherins and tight junction proteins such as claudins.^[2] Through regulated intramembrane proteolysis, the extracellular domain (EpEX) can be shed, releasing the intracellular domain (EpICD), which translocates to the nucleus to act as a transcriptional co-activator, influencing genes involved in cell cycle progression (e.g., via cyclin D1 upregulation), stemness, and epithelial-to-mesenchymal transition (EMT).^[3] In normal physiology, EpCAM is highly expressed in simple epithelia, proliferating cells like intestinal stem cells, and pluripotent embryonic stem cells, where it supports tissue morphogenesis, wound healing, and pluripotency maintenance alongside factors such as OCT4 and SOX2.^[1] It also promotes motility in non-epithelial cells, such as epidermal Langerhans cells, by reducing adhesion to keratinocytes, facilitating immune surveillance.^[4] Mutations or deletions in EPCAM are linked to congenital tufting enteropathy (CTE), a severe diarrheal disorder caused by loss of surface expression leading to intestinal villus abnormalities, and to Lynch syndrome, where promoter hypermethylation of adjacent MSH2 increases colorectal cancer risk.^[1] In cancer, EpCAM is frequently overexpressed in epithelial-derived carcinomas, including breast, colorectal, ovarian, and pancreatic types, serving as a marker for cancer stem cells (CSCs) and circulating tumor cells (CTCs) that drive metastasis.^[3] Its functions in tumors are context-dependent: it promotes proliferation, invasion, and immune evasion via pathways like Wnt/β-catenin, PI3K/AKT/mTOR, and PTEN suppression, often correlating with poor prognosis and advanced disease stages, though high expression predicts better outcomes in some cases like ovarian cancer.^[2] EpCAM's role in EMT and stemness enhancement makes it a key prognostic biomarker and therapeutic target, with approved therapies like catumaxomab (a bispecific antibody; EMA approval as Korjuny in 2025) and ongoing developments in antibody-drug conjugates, CAR-T cells, and vaccines showing promise in clinical trials for solid tumors.^[3]^[5]

Discovery and nomenclature

Historical discovery

The epithelial cell adhesion molecule (EpCAM), initially identified as the 17-1A antigen, was first discovered in 1979 through the use of monoclonal antibody technology. Researchers led by Dorothee Herlyn immunized mice with human colon carcinoma cells and generated hybridoma clones, one of which produced the monoclonal antibody 1083-17-1A (also known as CO17-1A or mAb 17-1A) that specifically recognized a cell surface antigen on colorectal carcinoma cells.^[6] This antigen was detected on various epithelial tumor cell lines but not on most non-epithelial cells or normal colon mucosa, marking it as a potential tumor-specific marker.^[6] In the 1980s and 1990s, subsequent studies characterized the 17-1A antigen as a prominent surface marker for epithelial tumors, with investigations focusing on its expression and functional implications in cancer models. Early work demonstrated that the antigen was expressed on a wide range of adenocarcinomas, including those of the colon, stomach, and pancreas, and played a role in tumor progression.^[7] Notably, monoclonal antibodies targeting 17-1A, such as CO17-1A and GA733, were shown to mediate antibody-dependent cellular cytotoxicity and inhibit tumor growth in nude mouse xenograft models of human colorectal carcinoma, providing evidence for its potential in immunotherapy. These findings established EpCAM as a key epithelial tumor antigen during this period.^[8] Key publications advanced the molecular understanding of EpCAM, including the seminal 1979 report by Herlyn et al. on its isolation from colon cancer cells using monoclonal antibodies.^[6] In 1989, Linnenbach et al. purified the 40 kDa GA733-2 antigen from the human colorectal carcinoma cell line SW948 using immunoaffinity chromatography with monoclonal antibody GA733 and determined its partial N-terminal amino acid sequence (27 of 35 residues), identifying it as a novel glycoprotein associated with gastrointestinal tumors.^[9] Subsequently, in 1990, Szala et al. isolated the cDNA clone encoding GA733-2 from a human colorectal carcinoma expression library, determining the full-length sequence of 1,122 nucleotides predicting a 314-amino-acid type I transmembrane glycoprotein.^[10] These efforts laid the groundwork for recognizing EpCAM's overexpression in various carcinomas.

Gene and protein nomenclature

The official symbol for the gene encoding the epithelial cell adhesion molecule is EPCAM, which is an abbreviation for epithelial cell adhesion molecule, and it is located on the short arm of human chromosome 2 at position 2p21.^[11] The EPCAM gene has the NCBI Gene ID 4072.^[11] The corresponding protein is designated EpCAM, with the UniProt accession number P16422.^[12] EpCAM has several aliases, including CD326 (from the Cluster of Differentiation nomenclature), TACSTD1 (tumor-associated calcium signal transducer 1), and historical designations such as 17-1A (originally from a monoclonal antibody targeting the antigen) and GA733-2.^[13]^[11] EpCAM is classified as a type I transmembrane glycoprotein and is the founding member of the EPCAM family of adhesion molecules.^[13]^[11] The term "epithelial cell adhesion molecule" (EpCAM) was proposed in 1994 by Litvinov et al. to describe its role in calcium-independent homophilic cell-cell adhesion.^[14] In 2007, nomenclature was harmonized to standardize the gene and protein as EPCAM and EpCAM, respectively, across scientific literature.^[13]

Gene and expression

Genomic organization

The EPCAM gene is located on the short arm of chromosome 2 at position 2p21 and spans approximately 42 kb of genomic DNA on the forward strand. It consists of 9 exons, which together encode a precursor protein of 314 amino acids.^[11]^[15]^[12] The promoter region upstream of the EPCAM gene features binding sites for key transcription factors, including Sp1 and AP-2, which drive its basal transcriptional activity predominantly in epithelial cells. These elements ensure tissue-appropriate regulation of gene expression during development and homeostasis.^[16] Introns within the EPCAM gene primarily support standard splicing processes to produce mature mRNA, with limited characterization of additional regulatory functions in these regions. The gene exhibits strong evolutionary conservation across mammals, sharing about 80% amino acid sequence identity with its mouse ortholog.^[17]

Tissue-specific expression

EpCAM exhibits basolateral membrane localization in most simple epithelia, with particularly high expression levels in the colonic crypt germinal regions, pancreatic ducts, and lung alveolar epithelium. Moderate expression is observed in renal tubules and mammary gland progenitors.^[18]^[3] Expression of EpCAM is notably absent or minimal in non-epithelial tissues, such as skeletal muscle, neuronal cells, and hematopoietic lineages, underscoring its epithelial specificity. During embryonic development and tissue morphogenesis, EpCAM is dynamically upregulated in epithelial progenitors, including embryonic stem cells, the inner cell mass, and during intestinal epithelial formation, where it supports cell adhesion and differentiation.^[18]^[3]^[2]

Molecular structure

Domain architecture

The epithelial cell adhesion molecule (EpCAM) is a type I transmembrane glycoprotein composed of 314 amino acids, with the mature protein exhibiting an apparent molecular weight of approximately 30-40 kDa due to glycosylation.^[1]^[19] The protein's domain architecture is characterized by an N-terminal signal peptide spanning amino acids 1-23, which is cleaved during processing to direct the protein to the secretory pathway.^[1] Following cleavage, the mature extracellular domain extends from residues 24 to 265 and encompasses key structural motifs essential for intermolecular interactions.^[20] Within the extracellular domain, two EGF-like repeats are present at positions 47-85 and 125-163, flanking a central thyroglobulin type-1 domain located at amino acids 89-120; these motifs contribute to the protein's compact, heart-shaped dimeric structure observed in crystallographic studies.^[21] The transmembrane helix spans residues 266-288, anchoring EpCAM in the plasma membrane as a single-pass domain.^[1] The C-terminal cytoplasmic tail is short, comprising amino acids 289-314, and includes a dileucine motif that facilitates endocytic trafficking and lysosomal degradation.^[22] EpCAM undergoes regulated intramembrane proteolysis mediated by presenilin-2/γ-secretase complex at intramembrane sites within the transmembrane domain, including the ε-cleavage between Val284 and Val285 (and alternatively Leu286/Val287), and γ-cleavages at Val273/Val274, Val274/Val275, and Val275/Val276, resulting in the release of the extracellular fragment EpEX and the intracellular domain fragment EpICD.^[3] This cleavage occurs within the transmembrane region and is crucial for generating soluble and nuclear-translocating fragments, though the precise structural implications remain tied to the overall topology.^[23]

Post-translational modifications

EpCAM undergoes several post-translational modifications that regulate its stability, membrane trafficking, and functional activity. The protein features three N-linked glycosylation sites at Asn74, Asn111, and Asn198, located in the extracellular domain.^[24] These modifications add mass to the core polypeptide of approximately 35 kDa, resulting in a mature glycosylated form observed at 35-40 kDa on SDS-PAGE, with glycosylation contributing to this apparent mass.^[12]^[21] The glycans include both complex-type and high-mannose forms, which influence EpCAM's solubility and proper folding; for instance, glycosylation at Asn198 is particularly critical for protein stability and plasma membrane half-life.^[24] Hyperglycosylation at these sites has been noted in carcinoma tissues compared to normal epithelia, potentially affecting trafficking efficiency.^[3] O-linked glycosylation occurs at Thr171 and Thr172 within the thyroglobulin-like (TY) domain, which shares structural similarities with EGF-like motifs.^[24] These modifications, identified through proteomic analysis in select human cell lines, are thought to modulate interactions in the extracellular region, including potential ligand binding in the EGF-like domains, though their precise functional impact remains under investigation.^[25] Phosphorylation events primarily target tyrosine residues in the cytoplasmic tail, with Tyr297 identified as a key site via phosphoproteomic studies.^[26] This modification stabilizes the tail's structure and may influence protein-protein interactions, contributing to regulated trafficking and internalization dynamics.^[27] Additional phosphorylations at Tyr214 and Tyr215 in the extracellular domain have been detected but are less characterized in terms of functional outcomes.^[24] EpCAM is also subject to proteolytic processing through regulated intramembrane proteolysis (RIP). The metalloprotease ADAM17 (TACE) initiates ectodomain shedding near the plasma membrane, releasing the extracellular fragment (EpEX).^[24] This is followed by intramembrane cleavage of the C-terminal fragment by γ-secretase (via presenilin 2), liberating the intracellular domain (EpICD).^[28] These sequential cleavages are essential for EpCAM's processing and subsequent intracellular handling, with the events modulated by cellular context to control membrane residency.^[29]

Biological functions

Cell adhesion mechanisms

EpCAM mediates Ca²⁺-independent homotypic cell-cell adhesion primarily through interactions involving its extracellular domain, enabling the aggregation of EpCAM-expressing epithelial cells without the calcium dependency characteristic of classical cadherins.^[30] This adhesion occurs via cis-dimerization on the same cell surface, forming a heart-shaped structure stabilized by the N-terminal domain, thyroglobulin type-1 domain, and C-terminal domain, followed by potential trans-interactions between adjacent cells.^[21] The binding affinity for these trans-interactions, estimated at approximately 10 μM for tetramer formation, is notably weaker than that of cadherin-mediated adhesions, resulting in slower cell aggregation rates (e.g., around 40% aggregation in 120 minutes compared to 50-80% in 30 minutes for E-cadherin-expressing cells).^[21]^[30] In addition to its direct adhesive role, EpCAM modulates classical cadherin junctions, such as those formed by E-cadherin, by interfering with the linkage between adherens junctions and the actin cytoskeleton, thereby shifting adhesions from a strong, stable state to a weaker, more dynamic one.^[31] This modulation reduces the detergent-insoluble fraction of E-cadherin complexes and decreases the association with α-catenin, without altering total E-cadherin levels, which promotes epithelial plasticity during tissue remodeling.^[30]^[31] EpCAM also contributes to tight junction formation and stabilization in epithelial tissues, particularly by interacting with claudin family proteins, such as claudin-7, to regulate their localization and dynamics at apical cell-cell contacts.^[32] This interaction helps maintain paracellular barrier integrity and supports epithelial morphogenesis, as demonstrated in zebrafish models where EpCAM deficiency leads to disrupted tight junction assembly and impaired tissue integrity during epiboly and skin development.^[33]^[34]

Signaling and regulatory roles

Beyond its role in cell adhesion, EpCAM exerts significant influence through intracellular signaling pathways, particularly via the regulated intramembrane proteolysis that releases its intracellular domain (EpICD). Following cleavage by TACE and presenilin-2/γ-secretase, EpICD translocates to the nucleus where it interacts with the adaptor protein FHL2, forming a multiprotein complex with β-catenin and LEF-1/TCF-4 that binds to LEF-1 consensus sites on DNA.^[35] This nuclear complex activates transcription of key genes involved in cell cycle progression, including c-myc, cyclin A, and cyclin E, as well as E-cadherin, thereby promoting epithelial proliferation and maintaining tissue integrity.^[35] Experimental evidence from cell lines and mouse models demonstrates that disrupting this cleavage or complex formation impairs transcriptional activation and cell growth.^[35] EpCAM also indirectly modulates the Wnt/β-catenin pathway through its effects on cell surface interactions, such as blocking the association between Kremen-1 and Dickkopf-2, which stabilizes LRP6 co-receptors and enhances Wnt signaling to support epithelial homeostasis.^[36] In stem cell contexts, particularly embryonic stem cells (ESCs), EpCAM promotes proliferation and survival by enhancing AKT phosphorylation via direct interaction with the Ras-like protein ERas, fostering self-renewal without oncogenic transformation.^[36] These functions underscore EpCAM's role in maintaining stem cell pools during tissue regeneration, as observed in endodermal progenitors where Wnt-mediated EpCAM activity drives differentiation.^[36] Furthermore, EpCAM contributes to epithelial differentiation and migration by integrating with survival pathways, notably activating the PI3K/Akt axis. This occurs through competitive binding of the p85 regulatory subunit of PI3K to EpCAM rather than N-cadherin, leading to downstream Akt phosphorylation that inhibits apoptosis and supports cytoskeletal dynamics essential for cell movement.^[36] In ESCs, this signaling maintains endodermal identity and facilitates transitions to mesodermal lineages, such as cardiomyocytes, highlighting EpCAM's broader regulatory impact on epithelial morphogenesis.^[36]

Role in pathology

Involvement in cancer

EpCAM is overexpressed in the majority of epithelial-derived cancers, including approximately 90% of colorectal, breast, and prostate carcinomas, where its upregulation correlates with advanced tumor stages and poor patient prognosis.^[3]^[37]^[38] A 2023 meta-analysis of 57 studies involving over 14,000 patients across solid tumors showed that high EpCAM expression is associated with a hazard ratio of 1.30 (95% CI: 1.08–1.58) for shorter overall survival.^[39] This overexpression contributes to tumorigenesis by enhancing cell proliferation, with studies demonstrating that EpCAM-transfected cells exhibit prolonged proliferative capacity and upregulated cell cycle genes in model systems.^[40]^[13] Recent analyses as of 2025 have characterized the landscape of cancer-associated EpCAM mutations, revealing their prevalence (up to 5%) and impacts on signaling pathways like AP-1, NF-κB, Wnt/β-catenin, PI3K/AKT, and MAPK/ERK, which further promote tumor progression and invasion.^[41] In cancer progression, EpCAM promotes epithelial-to-mesenchymal transition (EMT) and tumor invasion, particularly through mechanisms that disrupt E-cadherin-mediated cell adhesion. Overexpression of EpCAM interferes with the interaction between E-cadherin and the actin cytoskeleton via α-catenin, resulting in reduced E-cadherin function and enhanced migratory potential in carcinoma cells.^[42]^[43] This abrogation of adherens junctions facilitates metastatic dissemination, as evidenced in nasopharyngeal and breast cancer models where EpCAM signaling activates pathways like PTEN/AKT/mTOR to drive EMT and invasion.^[44]^[45] EpCAM also plays a key role in enriching cancer stem cell (CSC) populations, particularly in breast and colorectal cancers, where EpCAM^high cells exhibit enhanced self-renewal and resistance to chemotherapy. In colorectal cancer, EpCAM combined with CD44 identifies CSCs with tumor-initiating properties and increased tumorigenicity in xenografts.^[13]^[46] Similarly, in breast cancer, EpCAM-positive subsets demonstrate stem-like traits, including sphere formation and chemoresistance, contributing to relapse and metastasis.^[24]^[42] Somatic mutations in EpCAM occur in 1-10% of tumors across various cancers, with missense variants often affecting structural domains such as the thyroglobulin type-1 or EGF-like regions, leading to altered protein localization and dysregulated signaling.^[47] For instance, mutations like C66Y in the thyroglobulin domain disrupt disulfide bonds, impair surface expression, and enhance invasion by failing to inhibit cathepsin-L activity. These genetic alterations further support oncogenic signaling, amplifying EpCAM's pro-tumorigenic effects in affected carcinomas.^[47]

Association with genetic disorders

Germline deletions in the 3' end of the EPCAM gene, particularly affecting exons 8 and 9, account for approximately 1-3% of Lynch syndrome cases, an autosomal dominant condition also known as hereditary nonpolyposis colorectal cancer.^[48] These deletions lead to transcriptional read-through and subsequent hypermethylation of the adjacent MSH2 promoter, resulting in tissue-specific silencing of MSH2 expression in EPCAM-expressing epithelia and DNA mismatch repair deficiency.^[49] Carriers face a substantially elevated lifetime risk of colorectal cancer, with a cumulative incidence of 75% by age 70 years, alongside a modestly increased risk of endometrial cancer at 12% by age 70 years in women.^[50] Such mutations often arise from Alu-mediated recombination and are recurrent in certain populations, such as Dutch and Spanish founder variants.^[48] In contrast, biallelic loss-of-function mutations in EPCAM cause congenital tufting enteropathy (CTE), a rare autosomal recessive disorder with an estimated incidence of 1 in 50,000 to 100,000 live births.^[48] These mutations, including nonsense, frameshift, and missense variants, abolish or severely impair EpCAM protein function, disrupting cell-cell adhesion, tight junction integrity, and epithelial barrier formation in the intestinal mucosa.^[48] Clinically, CTE manifests as severe, intractable watery diarrhea starting in the neonatal period, often accompanied by failure to thrive, villous atrophy with tufting of enterocytes, and dependence on total parenteral nutrition; certain variants, such as c.499dupC, are associated with particularly poor prognosis and higher mortality.^[48] The disorder was first linked to EPCAM through identification of homozygous and compound heterozygous mutations in affected families, confirming its role in maintaining intestinal epithelial polarity and cohesion.^[51] A 2024 study reported a case of biallelic EPCAM deletions causing germline mismatch repair deficiency with tissue-specific loss of MSH2, highlighting expanded mechanisms in Lynch syndrome-like phenotypes.^[52] Beyond Lynch syndrome and CTE, no other major genetic disorders are directly attributed to EPCAM mutations; identified variants typically reduce protein stability and adhesive function without conferring oncogenic gain-of-function effects.^[48]

Clinical applications

Diagnostic uses

EpCAM serves as a valuable biomarker in immunohistochemistry (IHC) for identifying epithelial tumors, particularly through the use of the BerEP4 monoclonal antibody, which targets its extracellular domain. In serous effusions, BerEP4 exhibits a mean sensitivity of 80% (95% CI: 0.78–0.82) and specificity of 94% (95% CI: 0.93–0.96) for detecting metastatic adenocarcinoma, aiding in the differentiation from malignant mesothelioma or reactive mesothelial cells.^[53] This high diagnostic accuracy, with an area under the summary receiver operating characteristic curve of 0.96, makes it a standard tool in pathology panels for distinguishing epithelial malignancies such as lung adenocarcinoma from epithelioid mesothelioma, where BerEP4 positivity is observed in 90–100% of adenocarcinomas and rarely in mesotheliomas.^[53]^[54] In the detection of circulating tumor cells (CTCs), EpCAM-based methods enable non-invasive monitoring of cancer metastasis, with the CellSearch system representing a clinically validated approach. This FDA-cleared platform uses anti-EpCAM antibodies for immunomagnetic enrichment of CTCs from peripheral blood, identifying epithelial-origin cells via additional markers like cytokeratins and excluding leukocytes with CD45. In metastatic breast cancer, ≥5 CTCs per 7.5 mL blood correlates with unfavorable prognosis (median overall survival of 10.9 months versus 21.9 months for <5 CTCs), while in prostate cancer, ≥5 CTCs predicts shorter survival (11.5 months versus 21.7 months).^[55] Similarly, in metastatic prostate and breast cancers, EpCAM-dependent CTC capture facilitates real-time assessment of disease progression and therapeutic response, with CTC levels serving as a dynamic biomarker for metastatic burden.^[55] High EpCAM expression also holds prognostic significance, particularly in colorectal cancer, where it is associated with aggressive disease and increased risk of recurrence. Meta-analyses indicate that elevated EpCAM levels in gastrointestinal tumors, including colorectal carcinoma, confer a hazard ratio of 1.50 (95% CI: 1.15–1.95) for poorer overall survival and 1.84 (95% CI: 1.52–2.33) for disease-free survival, reflecting its role in tumor progression beyond mere overexpression in carcinomas.^[56] This prognostic utility underscores EpCAM's value in risk stratification, guiding post-treatment surveillance in patients with epithelial-derived malignancies.^[56]

Therapeutic targeting

Therapeutic targeting of EpCAM has primarily focused on its overexpression in epithelial-derived cancers, such as colorectal and ovarian carcinomas, where it serves as a tumor-associated antigen to direct immunotherapeutic interventions.^[3] Early strategies employed monoclonal antibodies to engage immune effector functions against EpCAM-positive tumor cells, while more advanced approaches include bispecific antibodies, cytokine fusions, and engineered T-cell therapies to enhance antitumor efficacy.^[57] Edrecolomab, also known as 17-1A or Panorex, is a murine IgG2a monoclonal antibody that binds the EpCAM antigen on the surface of colorectal cancer cells, promoting antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).^[57] It received approval in Germany in 1995 for adjuvant therapy in stage III colorectal cancer following surgical resection, based on phase III trial data showing a modest improvement in disease-free survival.^[58] However, subsequent larger randomized trials, including a 2003 Lancet study, demonstrated no significant overall survival benefit compared to observation alone, leading to its market withdrawal by the manufacturer in the late 1990s for lack of efficacy.12147-2/fulltext)^[3] Catumaxomab (Removab) represents a bispecific antibody approach, engineered as a trifunctional construct that simultaneously binds EpCAM on tumor cells and CD3 on T cells, while also recruiting Fcγ receptor-bearing immune cells like macrophages to form immune synapses and trigger tumor lysis.^[59] It was conditionally approved by the European Medicines Agency in April 2009 for intraperitoneal treatment of malignant ascites in patients with EpCAM-positive cancers, such as those originating from ovarian, gastric, or breast primaries, following demonstration of reduced ascites accumulation and puncture frequency in a phase II/III trial.^[60] The therapy was associated with significant cytokine release syndrome and other toxicities, including abdominal pain and fever, which limited its broader adoption.^[59] In 2017, its marketing authorization was voluntarily withdrawn in the European Union for commercial reasons, despite its innovative mechanism.^[60] Antibody-drug conjugates and immunocytokine fusions have explored EpCAM for targeted delivery of cytotoxic payloads or immunomodulators. Tucotuzumab celmoleukin (EMD 273066 or huKS-IL2) is a fusion protein comprising a humanized anti-EpCAM monoclonal antibody linked to two interleukin-2 (IL-2) molecules at the Fc region, designed to selectively activate T cells and natural killer cells at EpCAM-expressing tumor sites while minimizing systemic IL-2 toxicity.^[61] It has been evaluated in phase II clinical trials for recurrent EpCAM-positive ovarian cancer, including a randomized study (NCT00408967) comparing it to best supportive care as maintenance therapy post-chemotherapy, though the trial was ultimately withdrawn without published efficacy results.^[62] Preclinical models indicated enhanced antitumor immune responses in ovarian and other epithelial tumors.^[61] Chimeric antigen receptor (CAR) T-cell therapies targeting EpCAM have shown promise in preclinical studies for solid tumors, where EpCAM CAR-T cells demonstrated potent cytotoxicity against EpCAM-overexpressing cell lines and xenograft models of ovarian and colorectal cancers, with reduced tumor burden and prolonged survival in mice.^[63] These constructs typically incorporate a single-chain variable fragment (scFv) derived from anti-EpCAM antibodies, coupled with CD3ζ and costimulatory domains like 4-1BB or CD28 to drive T-cell activation upon EpCAM binding.^[63] Phase I clinical trials for EpCAM-specific CAR-T cells in solid tumors, such as advanced gastric cancer with peritoneal metastases, initiated around 2018, focusing on safety and feasibility via intraperitoneal infusion to improve tumor access and mitigate on-target/off-tumor effects on normal epithelia. Early data from these trials reported manageable toxicities and preliminary signs of antitumor activity, paving the way for further optimization.

Recent developments

Recent research has advanced the targeting of EpCAM using single-domain antibodies (sdAbs), which offer advantages in tumor penetration and efficacy over traditional antibodies. A 2025 study isolated five fully human anti-EpCAM sdAbs that specifically bind to EpCAM peptides and demonstrate selective binding to various cancer cell lines, exhibiting potent anti-tumor activity in preclinical models through enhanced penetration into solid tumors.^[64] These sdAbs induced significant tumor regression in xenograft models without notable off-target effects, highlighting their potential as next-generation therapeutics building on earlier EpCAM-targeted approaches like catumaxomab.^[65] In nuclear medicine, EpCAM-targeted radioligands have emerged as precise tools for imaging and therapy in epithelial cancers. A 2025 review details advancements in these probes for positron emission tomography (PET) and single-photon emission computed tomography (SPECT), which provide superior specificity compared to immunohistochemistry by enabling non-invasive, real-time visualization of EpCAM expression in vivo.^[66] These radioligands, often conjugated to antibodies or peptides, facilitate targeted radionuclide therapy, delivering therapeutic isotopes directly to EpCAM-positive tumors while minimizing exposure to healthy tissues, with preclinical data showing improved diagnostic accuracy in colorectal and breast cancers.^[66] Genomic analyses have expanded understanding of EpCAM's mutational landscape in cancer. A 2025 study analyzed multiple cancer cohorts from genomic datasets, identifying over 150 cancer-associated EpCAM variants, with mutations in the epidermal growth factor (EGF)-like domain particularly linked to increased metastasis through disrupted protein stability and signaling.^[41] These findings correlate specific variants with poorer patient survival, informing personalized therapeutic strategies. Updates from 2022 research further refine EpCAM's role in tight junction regulation, showing that its proteolysis releases complexed claudin-7 to dynamically repair epithelial barriers under stress, a mechanism altered in mutant forms.^[67]

References

[1]
EpCAM: Structure and function in health and disease - ScienceDirect
These findings and the cancer cell invasion and metastasis promoting role of EpCAM in tumors suggest that EpCAM acts as a negative regulator of adhesion [63].
[2]
Understanding the versatile roles and applications of EpCAM in ...
Nov 11, 2022 · Epithelial cell adhesion molecule (EpCAM) functions not only in physiological processes but also participates in the development and progression of cancer.
[3]
Expression and function of epithelial cell adhesion molecule EpCAM
Jun 7, 2020 · Owing to its frequent and high expression on carcinomas and their metastases, EpCAM serves as a prognostic marker, a therapeutic target, and an ...
[4]
Cancer-associated epithelial cell adhesion molecule (EpCAM - PNAS
EpCAM has been reported both to enhance and to attenuate intercellular adhesion and, more recently, to transmit extracellular signals to the nucleus as well.
[5]
https://www.ema.europa.eu/en/medicines/human/EPAR/korjuny
[6]
https://doi.org/10.1073/pnas.76.3.1438
[7]
https://doi.org/10.1002/ijc.2910380109
[8]
EPCAM epithelial cell adhesion molecule [ (human)] - NCBI
Sep 13, 2025 · This gene encodes a carcinoma-associated antigen and is a member of a family that includes at least two type I membrane proteins.Missing: nomenclature | Show results with:nomenclature
[9]
EPCAM - Epithelial cell adhesion molecule - Homo sapiens (Human)
Names & Taxonomy. Protein names. Recommended name. Epithelial cell adhesion molecule. Short names. Ep-CAM. Alternative names. Adenocarcinoma-associated antigen ...Missing: aliases | Show results with:aliases
[10]
Biology and clinical relevance of EpCAM - PMC - PubMed Central
The EpCAM protein was discovered almost 40 years ago as a major epithelial carcinoma antigen by M. Herlyn and colleagues, as a result of its property to ...<|control11|><|separator|>
[11]
https://www.ncbi.nlm.nih.gov/gene/4072
[12]
[PDF] Regulation and epigenetic modulation of EpCAM gene expression ...
AP-2. PEA3. -377.CCCGCACCCTTCCCCCCAGG CCCCATTCTT ... DNA sequence in the EpCAM promoter (manuscript in press). ... the presence of Sp1 increases promoter activity20 ...
[13]
Functional consequences of EpCam mutation in mice and men - NIH
Murine EpCAM has 81% identity and 89% similarity to the human protein, with only one additional amino acid for a total 315 amino acids and the same predicted ...Epcam Mice Show Pathological... · Epcam Mice Show Intestinal... · Mutation Of Epcam Causes...Missing: percentage | Show results with:percentage
[14]
Epithelial Cell Adhesion Molecule: More than a Carcinoma ... - PMC
The epithelial cell adhesion molecule (EpCAM, CD326) is a glycoprotein of ∼40 kd that was originally identified as a marker for carcinoma.Expression Patterns Of Epcam · The Pleiotropic Nature Of... · The Double Face Of Epcam...
[15]
EpCAM an immunotherapeutic target for gastrointestinal malignancy
Feb 27, 2007 · 90% of Colorectal carcinoma cells express EpCAM but in a differential form. Modifications include variable glycosylation analogous to tumour ...Epcam Biology · Epcam Targeted Immunotherapy · Mechanism Of Tumour...
[16]
https://pure.rug.nl/ws/portalfiles/portal/2611288/12_thesis.pdf
[17]
The role of epithelial-mesenchymal transition and autophagy in ...
Aug 7, 2023 · PDAC cells lose EPCAM (EPCAM—) when initiating the EMT program, at which point the cancer cells transform into EMT-PDAC cells. In PDAC cells, ...
[18]
EpCAM and its potential role in tumor-initiating cells - PMC
... EpCAM as a glycosylated protein with an apparent molecular weight of 33–40 kDa., Early on, anti-EpCAM antibodies were assessed for the capacity to serve ...
[19]
https://pmc.ncbi.nlm.nih.gov/articles/PMC3364135/
[20]
Crystal structure and its bearing towards an understanding of key ...
Aug 28, 2014 · Here we present the crystal structure of a heart-shaped dimer of the extracellular part of human EpCAM.
[21]
Harnessing the Membrane Translocation Properties of AB Toxins for ...
Jan 6, 2021 · A long-lasting effect was due to the presence of a dileucine motif ... (EpCAM) at the surface of cells. These engineered constructs were ...
[22]
EpCAM proteolysis: new fragments with distinct functions?
It has been suggested that EpCAM might be able to affect certain cysteine proteases, the cathepsins, via its conserved TY domain [5]. TY type-1A domains have ...
[23]
Revisiting the Roles of Pro-Metastatic EpCAM in Cancer - PMC - NIH
Therefore, the amino acid sequence for a mature EpCAM protein starts only at Gln24. ... Previously, an EGF-like motif was assigned to aa 66-135 of EpCAM.2. Epcam Structure And Its... · 3. Epcam Post-Translational... · 5. Epcam Downstream Targets...
[24]
Revisiting the Roles of Pro-Metastatic EpCAM in Cancer - MDPI
(B) The presence of three N-glycosylation sites located on Asn74, Asn111 and Asn198 of EpCAM have been confirmed by numerous reports. Other post-translational ...2. Epcam Structure And Its... · 3. Epcam Post-Translational... · 5. Epcam Downstream Targets...
[25]
In Silico Identification of Potential Phosphorylation in the ...
Nov 23, 2020 · The epithelial cell adhesion molecule (EpCAM) is a transmembrane cell adhesion glycoprotein, which primarily contributes to stemness, ...
[26]
In Silico Identification of Potential Phosphorylation in the ... - NIH
Nov 23, 2020 · The study identified a putative phosphorylation site at Tyr297 in the cytoplasmic domain of EpCAM, which stabilizes its structure and affects ...
[27]
EpCAM: Another Surface-to-Nucleus Missile - ScienceDirect.com
The authors demonstrate that ADAM17 (TACE) and γ-secretase sequentially cleave EpCAM, producing a soluble ectodomain fragment and a 5 kDa ICD fragment, ...
[28]
EpCAM proteolysis: new fragments with distinct functions? - PMC - NIH
We report on four new peptides, but also discuss the previously described cleavage products to provide a comprehensive picture of EpCAM cleavage at multiple ...Missing: Thr175 | Show results with:Thr175
[29]
Epithelial Cell Adhesion Molecule (Ep-CAM) Modulates Cell ... - NIH
A homophilic, epithelial Ca 2+ -independent adhesion molecule (Ep-CAM) is expressed in most epithelia, benign or malignant proliferative lesions, or during ...Missing: EpCAM | Show results with:EpCAM
[30]
[PDF] Biology and clinical relevance of EpCAM - Cell Stress
May 21, 2019 · ABSTRACT Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein primarily known to mediate homotypic cell contacts in ...
[31]
Epithelial Cell Adhesion Molecule (EpCAM) Regulates Claudin ...
Herein, we report that EpCAM regulates the composition and function of tight junctions (TJ). EpCAM accumulated on the lateral interfaces of human colon ...
[32]
EpCAM contributes to formation of functional tight junction in the ...
Nov 15, 2012 · The epithelial cell adhesion molecule EpCAM is required for epithelial morphogenesis and integrity during zebrafish epiboly and skin development.
[33]
The Epithelial Cell Adhesion Molecule EpCAM Is Required for ...
Our data suggest that EpCAM acts as a partner of E-cadherin to control adhesiveness and integrity as well as plasticity and morphogenesis within simple ...
[34]
Nuclear signalling by tumour-associated antigen EpCAM - Nature Cell Biology
### Summary of EpCAM Nuclear Signaling (Nature Cell Biology, 2009)
[35]
Expression and function of epithelial cell adhesion molecule EpCAM
Jun 7, 2020 · EpCAM is reckoned as a multi-functional transmembrane protein involved in the regulation of cell adhesion, proliferation, migration, stemness, and epithelial- ...<|control11|><|separator|>
[36]
Breast Cancer Aptamers: Current Sensing Targets, Available ...
Overexpressed in 90% of breast cancers. ... EpApt-siEp appears to eliminate EpCAM-positive cancer cells while leaving healthy EpCAM-negative cells.
[37]
Antibodies targeting cancer stem cells - PubMed Central - NIH
In studies on colon cancer tumorigenicity, EpCAMhighCD44+ was seen as a ... It is a potential oncogene, overexpressed in 90% of colon cancers. An ...
[38]
The EpCAM overexpression is associated with clinicopathological ...
As a result, the pooled HR of 1.634 indicated that higher EpCAM expression was significantly associated with the shorter overall survival (OS) periods (95%CIs: ...
[39]
EpCAM overexpression prolongs proliferative capacity of primary ...
Jun 10, 2013 · Furthermore, it has been shown that EpCAM overexpression in cancer cells can support proliferation by enhancing Wnt signaling [11]. In breast ...
[40]
Understanding the versatile roles and applications of EpCAM ... - NIH
Nov 11, 2022 · ... sites. Four cleavage sites (α, β, γ, ε-sites) locate on EpCAM molecule, in which can be cleaved into soluble EpEX, TM and free EpICD. Human ...
[41]
EpCAM expression negatively regulates E-cadherin function in ... - NIH
Jul 6, 2023 · Also, EpCAM overexpression was significantly associated with reduced E-cadherin (p < 0.035) expression in tumour cells. Tumour extent within ...
[42]
Epithelial cell adhesion molecule overexpression regulates ... - NIH
EpCAM overexpression is correlated with distant metastasis and poor prognosis in NPC patients. To explore the clinical significance of EpCAM expression in ...
[43]
EpCAM in carcinogenesis: the good, the bad or the ugly - PubMed
On the other hand, EpCAM abrogates E-cadherin mediated cell-cell adhesion thereby promoting metastasis. Also, upon cleavage of EpCAM, the intracellular ...Missing: reduces | Show results with:reduces
[44]
Epithelial Cell Adhesion Molecule Regulates Tumor Initiation ... - NIH
EpCAM induces reprogramming factor and EMT gene expression, which regulates tumor self-renewal and tumorigenesis.
[45]
Cancer-associated mutations reveal a novel role for EpCAM ... - PMC
May 12, 2021 · We identified 115 unique somatic/missense coding EpCAM mutations (Fig. 1). Depending on the dataset and cancer type, EpCAM mutations are ...
[46]
EPCAM mutation update: Variants associated with congenital tufting ...
The epithelial cell adhesion molecule gene (EPCAM, previously known as TACSTD1 or TROP1) encodes a membrane‐bound protein that is localized to the basolateral ...<|control11|><|separator|>
[47]
Germline deletions in the EPCAM gene as a cause of Lynch syndrome
Aug 12, 2013 · EPCAM deletions cause MSH2 gene silencing by a mechanism known as promoter hypermethylation. Additional methyl groups attached to the MSH2 ...
[48]
https://pmc.ncbi.nlm.nih.gov/articles/PMC6328345/
[49]
https://pmc.ncbi.nlm.nih.gov/articles/PMC3765447/
[50]
Evaluation of 12 antibodies for distinguishing epithelioid ... - Nature
Mar 16, 2006 · The specificity of the nonmesothelial antigens for AdCA was 98% for BG8 and CEA, 97% for CD15, 95% for BerEp4, and 87% for MOC-31.<|control11|><|separator|>
[51]
https://www.sciencedirect.com/science/article/pii/S2352304218308561
[52]
https://www.nature.com/articles/s41698-024-00537-6
[53]
Edrecolomab - an overview | ScienceDirect Topics
Edrecolomab is a murine IgG2A monoclonal antibody that targets the human tumor-associated antigen Ep-CAM (17-1A). Edrecolomab has been approved in Europe ( ...
[54]
Monoclonal Antibodies: Edrecolomab and Abciximab
Edrecolomab This medication was never approved by the FDA, but was the first monoclonal antibody approved for a cancer indication, in Germany (1995).
[55]
Development and approval of the trifunctional antibody ... - PubMed
Mar 27, 2010 · Catumaxomab has been approved in the European Union since April 2009 for the i.p. treatment of malignant ascites (MA) in patients with EpCAM- ...Missing: withdrawal 2017
[56]
Removab | European Medicines Agency (EMA)
On 2 June 2017, the European Commission withdrew the marketing authorisation for Removab (catumaxomab) in the European Union (EU). ... commercial reasons. Removab ...
[57]
Stimulating the Antitumor Immune Response Using Immunocytokines
Tucotuzumab celmoleukin (EMD 273066/huKS–IL-2) consists of two IL-2 molecules fused to the Fc part of a humanized IgG mAb-targeting epithelial cell adhesion ...
[58]
https://www.kauveryhospital.com/kauverian-scientific-journal/monoclonal-antibodies-edrecolomab-and-abciximab/
[59]
Preclinical Evaluation of Chimeric Antigen Receptor–Modified T ...
This preclinical study of EpCAM CAR-T suggests that adoptive transfer of CAR-T cells targeting EpCAM is safe and efficacious and is a promising therapeutic ...
[60]
Novel human single-domain antibodies exert potent anti-tumor ...
Feb 12, 2025 · This study provides compelling evidence that targeting EpCAM with sdAbs is a promising approach for cancer treatment.
[61]
Novel human single-domain antibodies exert potent anti-tumor ... - NIH
Feb 13, 2025 · Five fully human anti-EpCAM sdAbs were isolated, all of which specifically bound to the EpCAM peptide and showed selective binding to various cancer cell lines.
[62]
Emerging Applications of EpCAM-Targeted Nuclear Medicine Probes
Sep 4, 2025 · This paper provides a comprehensive review of recent advancements in EpCAM-targeted radionuclide probes, focusing specifically on a range of ...
[63]
Landscape of cancer associated EpCAM mutations - PubMed Central
Jul 1, 2025 · The N-terminal domain of EpCAM, a critical region containing functional domains such as the EGF-like domain, RCD and TY-1 domain. Our ...
[64]
EpCAM proteolysis and release of complexed claudin-7 repair and ...
Nov 15, 2022 · Our results reveal a novel mechanism of TJ maintenance through the localized proteolysis of EpCAM at TJ leaks, and provide a better understanding of the ...