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

Abstract

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.

Keywords: Cancer; Cell signaling; EpCAM; Extracellular vesicles; Immune; Therapy.

Fig. 1

Schematic illustration of EpCAM structure. The premature EpCAM molecule is comprised of 314 amino acids (AA), including a signal peptide, which is cleaved during maturation. The mature membrane-bound EpCAM protein consists of an extracellular domain (EpEX), a transmembrane domain (TM) and an intracellular domain (EpICD). EpEX contains an N-terminal domain (ND), thyroglobulin-domain (TY) and C-terminal domain (CD), including three N-glycosylation 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 EpCAM contains two α-sites for ADAM protases, a β-site for BACE1 cleavage, and γ-secretase mediated cleavage on γ-sites and ε-sites

Fig. 2

Roles of EpCAM in cancer development and progression. a EpCAM on CSCs membrane surface was cleaved by ADAM17 and γ-secretase, generating EpICD. Most of the EpICD is degraded by proteasome, while the remaining EpICD can bind with FHL2, β-catenin and Lef-1, forming the trans-nuclear complex to activate proliferation and pluripotency related genes. b EpEX/EGFR pathway and EpICD trans-nuclear complex can promote cell proliferation. EGF and TGF-β pathway can regulate EMT markers and EpCAM expression. c In hypoxic condition, EpCAM is upregulated in ATP-high state, whereas in ATP-low situation, HIF-1α is upregulated. CAIX is overexpressed mediated by HIF-1α. CAIX⁺, together with higher EpCAM and K19 expression HCC subgroup exhibited with high resistance to chemoembolization. Additionally, N-glycosylated EpCAM can regulate HIF-1α and promote EMT and stemness related properties. d MHC-I/TCR interaction serves as T cell activation signals. While activated EpEX/EGFR/ERK pathway results in reduction of PD-L1 ubiquitination degradation. PD-L1 on tumor surface hampers activation of CD8⁺ T cells and leading to immune escape. CAIX carbonic anhydrase-IX, ECM extracellular matrix, FHL2 four and a half LIM domain protein 2, HIF-1α hypoxia inducible factor 1α, K19 keratin 19, Lef-1 lymphoid enhancer factor 1

Fig. 3

Changes and developments of EpCAM in metastasis, detection and immunotherapy. a Dynamic expression of EpCAM in EMT process of cancer cells. b EpCAM related CTC detection methods, advantages and their limitations. c Development of EpCAM mediated immunotherapies. ADC antibody–drug conjugate, ADCC antibody-dependent cell-mediated cytotoxicity, CDC complement-dependent cytotoxicity, CRS cytokine release syndrome

Fig. 4

Functions and applications of EpCAM. EpCAM participates in aspects of cancer pathological processes and leads to various cancerous properties, including EMT, hypoxic metabolism, stemness, angiogenesis and immune evasion. Due to its versatile functions in cancer development, diverse clinical applications are displayed and come into use. EpCAM-targeting immunotherapy and modified microparticles have shown clinical prospects for cancer therapy. In addition, EpCAM is used for CTC detection, as well as a CSC marker for diagnosis and prognosis values