Epithelial cell adhesion molecule (EpCAM) functions not only in physiological processes but also participates in the development and progression of cancer. In recent decades, extensive efforts have been made to decipher the role of EpCAM in cancers. Great advances have been achieved in elucidating its structure, molecular functions, pathophysiological mechanisms, and clinical applications. Beyond its well-recognized role as a biomarker of cancer stem cells (CSCs) or circulating tumor cells (CTCs), EpCAM exhibits novel and promising value in targeted therapy. At the same time, the roles of EpCAM in cancer progression are found to be highly context-dependent and even contradictory in some cases. The versatile functional modules of EpCAM and its communication with other signaling pathways complicate the study of this molecule. In this review, we start from the structure of EpCAM and focus on communication with other signaling pathways. The impacts on the biology of cancers and the up-to-date clinical applications of EpCAM are also introduced and summarized, aiming to shed light on the translational prospects of EpCAM. 

/pdf/understanding-the-versatile-roles-and-applications-of-epcam-68rfo4ea.pdf

Understanding the versatile roles and applications of EpCAM in cancers: from bench to bedside

Tufting enteropathy (TE) is caused by recessive EPCAM mutations, and is characterized by intractable diarrhea of congenital onset and disorganization of enterocytes. TE generally requires parenteral nutrition (PN) during childhood or intestinal bowel transplantation. We report three unrelated families with six children with TE. We highlight the high rate of disease-related mortality. We observe adequate weight gain with PN, but low to normal and stunted body length, supporting the recent notion that a short stature might be intrinsic to TE. The diagnosis of TE in the index patients from each family was delayed for months to years, even when clinical data, duodenal biopsies, or exome sequencing data were obtained early on. We identified three novel pathogenic EPCAM variants: a deletion of exon 1 that removes the ATG initiation codon, a missense variant c.326A > G (p.Gln109Arg), and nonsense mutation c.429G > A (p.Trp143*) in a compound heterozygous state with the Mediterranean splice site variant c.556-14A > G (Tyr186Phefs*6). Homozygosity for p.Gln109Arg was associated with absent EPCAM staining, and compound heterozygosity for p.Trp143*/Tyr186Phefs*6 was associated with reduced EPCAM staining in duodenal biopsies; such observations might contribute to a genotype-phenotype correlation in larger cohorts of TE patients. This study extends the clinical and molecular spectrum of TE.

Three Novel EPCAM Variants Causing Tufting Enteropathy in Three Families

ABSTRACT Epithelial cell adhesion molecule (EPCAM) is a transmembrane glycoprotein expressed on the surface of most epithelial and epithelium-derived tumor cells and reported to regulate stability of epithelial tight junction proteins, claudins. Despite its widespread expression, loss of EPCAM function has so far only been reported to prominently affect intestinal development, resulting in severe early onset enteropathy associated with impaired growth and decreased survival in both humans and mice. In this study, we show that the critical role of EPCAM is not limited to intestinal tissues and that it shares its essential function with its only known homolog, Trophoblast cell surface antigen 2 (TROP2). EPCAM-deficient mice show significant growth retardation and die within 4 weeks after birth. In addition to changes in small and large intestines, loss of EPCAM results in hyperkeratosis in the skin and forestomach, hair follicle atrophy leading to alopecia, nephron hypoplasia in the kidney, proteinuria, and altered production of digestive enzymes by the pancreas. Expression of TROP2 partially, but not completely, overlaps with EPCAM in a number developing epithelia. Although loss of TROP2 had no gross impact on mouse development and survival, TROP2 deficiency generally compounded developmental defects observed in EPCAM-deficient mice, led to an approximately 60% decrease in embryonic viability, and further shortened postnatal lifespan of born pups. Importantly, TROP2 was able to compensate for the loss of EPCAM in stabilizing claudin-7 expression and cell membrane localization in tissues that co-express both proteins. These findings identify overlapping functions of EPCAM and TROP2 as regulators of epithelial development in both intestinal and extraintestinal tissues.

/pdf/epcam-and-trop2-share-a-role-in-claudin-stabilization-and-2g7mtxov.pdf

EPCAM and TROP2 share a role in claudin stabilization and development of intestinal and extraintestinal epithelia in mice

Cellular and transcriptional heterogeneity in the intrahepatic biliary epithelium.

Background & aims Tufting enteropathy (TE) is a rare congenital disorder often caused by mutations in the gene encoding epithelial cell adhesion molecule (EpCam) The disease leads to diarrhea, intestinal failure and dependence on total parenteral nutrition (TPN) These patients often have liver impairments, but the pathology and mechanism of the damage are not well understood We evaluated liver biopsies from TE patients to understand the pathophysiology Methods We identified three patients with TE who underwent liver biopsy Two normal controls and 45 patients on TPN secondary to short gut syndrome were selected for comparison (5 were age- and TPN duration-matched to the TE patients) Results We found that all TE patients showed a complete loss of EpCam expression in enterocytes and biliary epithelial cells, while the normal and TPN groups show basolateral expression Histologically TE patients showed ductopenia, which was not seen in control groups E-cadherin and β-catenin are normally located along the lateral membrane of biliary epithelial cells However, they were relocated to the apical membrane in TE patients, indicating a defect in the apical-basal polarity of cholangiocytes We examined hepatic reparative cells and found near absence of hepatic progenitor cells and intermediate hepatobiliary cells with mild reactive ductular cells in TE patients Conclusion Our findings show that TE is associated with disrupted polarity of cholangiocyte and ductopenia We demonstrate for the first time a role of EpCam in the maintenance of integrity of biliary epithelium We also provided evidence for a disrupted development of hepatic reparative cells

Yougen Zhan

Papers

EpCam is required for maintaining the integrity of the biliary epithelium.