To investigate whether elevated urinary HAI-1, EpCAM and EGFR are independent prognostic biomarkers within non-muscle-invasive bladder cancer (NMIBC) patients, and have utility for risk ...stratification to facilitate treatment decisions.
After accounting for EAU risk group in NMIBC patients, the risk of BC-specific death was 2.14 times higher (95% CI: 1.08 to 4.24) if HAI-1 was elevated and 2.04 times higher (95% CI: 1.02 to 4.07) if EpCAM was elevated. The majority of events occurred in the high-risk NMIBC group and this is where the biggest difference is seen in the survival curves when plotted for EAU risk groups separately. In MIBC patients, being elevated for any of the three biomarkers was significantly associated with BC-specific mortality after accounting for other risk factors, HR = 4.30 (95% CI: 1.85 to 10.03).
Urinary levels of HAI-1, EpCAM and EGFR were measured by ELISA in 683 and 175 patients with newly-diagnosed NMIBC and MIBC, respectively, recruited to the Bladder Cancer Prognosis Programme. Associations between biomarkers and progression, BC-specific mortality and all-cause mortality were evaluated using univariable and multivariable Cox regression models, adjusted for European Association of Urology (EAU) NMIBC risk groups. The upper 25% of values for each biomarker within NMIBC patients were considered as elevated. Exploratory analyses in urine from MIBC patients were also undertaken.
Urinary HAI-1 and EpCAM are prognostic biomarkers for NMIBC patients. These biomarkers have potential to guide treatment decisions for high-risk NMIBC patients. Further analyses are required to define the roles of HAI-1, EpCAM and EGFR in MIBC patients.
Epidermal cell adhesion molecule (EpCAM) is a tumor-associated antigen (TAA), which has been considered as a cancer vaccine candidate. The EpCAM protein fused to the fragment crystallizable region of ...immunoglobulin G (IgG) tagged with KDEL endoplasmic reticulum (ER) retention signal (EpCAM-Fc K ) has been successfully expressed in transgenic tobacco (Nicotiana tabacum cv. Xanthi) and purified from the plant leaf. In this study, we investigated the ability of the plant-derived EpCAM-FcK (EpCAM-FcK P ) to elicit an immune response in vivo. The animal group injected with the EpCAM-FcK P showed a higher differentiated germinal center (GC) B cell population (~9%) compared with the animal group injected with the recombinant rhEpCAM-Fc chimera (EpCAM-Fc M ). The animal group injected with EpCAM-FcK P (~42%) had more differentiated T follicular helper cells (Tfh) than the animal group injected with EpCAM-FcM (~7%). This study demonstrated that the plant-derived EpCAM-FcK fusion antigenic protein induced a humoral immune response in mice.
The major issue associated with chemotherapeutics is the non-specific distribution, extended range of toxicity, and low intratumoral accumulation. Targeted therapy using aptamers could be a ...ground-breaking approach in cancer treatment. Poly(amidoamine) PAMAM dendrimers are a type of nanocarriers with a well-defined structure, higher encapsulation efficiency and modification surface groups. However, the toxicity of cationic dendrimers and non-targetability poses a great risk to patients' health. Considering this, we developed a EpCAM aptamer-functionalized, red blood cell (RBC) membrane-camouflaged PAMAM dendrimer loaded with doxorubicin to selectively target EpCAM-positive triple-negative breast cancer (TNBC) cells. An increase in size of doxorubicin (Dox) loaded PAMAM was observed from 11.34 nm to 108.4 nm post coating with RBC membrane and aptamer, respectively. The biocompatibility and blood circulation time were enhanced by the coating of the RBC membrane on the surface of the dendrimers while functionalization with aptamers improved its cancer cell internalization. The results obtained suggested that the coating with RBC provided controlled and sustained release during the 140 h of study. In vitro cell viability study showed enhanced apoptosis and significantly elevated uptake by the cancer cells as compared with the non-targeted preparation. Furthermore, the volume of the tumor was significantly reduced in groups treated with aptamer-modified, cell membrane-coated dendrimer due to selective internalization in the cancer cells only. This novel, personalized, and targeted therapy could be a potent platform for TNBC therapy.
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Injection of tumor cells in mice more than 30years ago resulted in the discovery of an epithelial antigen, later defined as a cell adhesion molecule (EpCAM). Although EpCAM has since evoked ...significant interest as a target in cancer therapy, mechanistic insights on the functions of this glycoprotein have been emerging only very recently. This may have been caused by the multitude of functions attributed to the glycoprotein, its localization at different subcellular sites and complex posttranslational modifications. Here, we review how EpCAM modifies cell–cell contact adhesion strength and tissue plasticity, and how it regulates cell proliferation and differentiation. Major knowledge derived from human diseases will be highlighted: Mutant EpCAM that is absent from the cell surface leads to fatal intestinal abnormalities (congenital tufting enteropathy). EpCAM-mediated cell proliferation in cancer may result from signaling (i) via regulated intramembrane proteolysis and/or (ii) the localization and association with binding partners in specialized membrane microdomains. New insight in EpCAM signaling will help to develop optimized cancer therapies and open new avenues in the field of regenerative medicine.
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•EpCAM structure/ function under (patho)physiological conditions reviewed•EpCAM is a target for tumor therapy and diagnosis, as well as regenerative medicine•EpCAM signals in tetraspanin-enriched microdomains and via regulated proteolysis•These models emerge as generic signaling mechanisms by cell surface molecules•Mutant EpCAM absent from the cell surface leads to intestinal abnormalities
•IMT030122 exhibited differential affinity with EpCAM, CD3and 4-1BB, ensuring its targeted effect on tumors.•The mechanism of IMT030122 was dependent on EpCAM for the activation of the CD3 and 4-1BB ...signaling pathways. This activation initiated conditional killing while ensuring safety.•IMT030122 recruited peripheral blood lymphocytes to the colorectal cancer tissue, primarily exerting anti-tumor effects through the stimulation of activation, proliferation, and differentiation of CD8 + T cells.•Even when the lymphocyte count in colorectal cancer tissue was extremely low, IMT030122 still demonstrated anti-tumor effects.
Colorectal cancer is a major global health burden, with limited efficacy of traditional treatment modalities in improving survival rates. However, recently advances in immunotherapy has improved treatment outcomes for patients with this cancer. To address the continuing need for improved treatment efficacy, this study introduced a novel tri-specific antibody, IMT030122, that targets EpCAM, 4-1BB, and CD3. We evaluated the pharmacological efficacy and mechanism of action of IMT030122 in vitro and in vivo. In in vitro studies, IMT030122 exhibited differential binding to antigens and cells expressing EpCAM, 4-1BB, and CD3. Moreover, IMT030122 relied on EpCAM-targeted activation of intracellular CD3 and 4-1BB signaling and mediated T cell cytotoxicity specific to HCT116 colorectal cancer cells. In vivo, IMT030122 demonstrated potent anti-tumor activity, significantly inhibiting the growth of colon cancer HCT116 and MC38-hEpCAM subcutaneous grafts. Further pharmacological analysis revealed that IMT030122 recruited lymphocytes from peripheral blood into colorectal cancer tissue and exerted durable anti-tumor activity, predominantly by promoting the activation, proliferation, and differentiation of CD8T cells. Notably, IMT030122 still exhibited anti-tumor efficacy even in the presence of significantly depleted lymphocytes in colorectal cancer tissue. The potent pharmacological activity and anti-tumor effects of IMT030122 suggest it may enhance treatment efficacy and substantially extend the survival of patients with colorectal cancer in the future.
Breast cancer is one of the leading causes of cancer-related death. An effective diagnostic system that enables early cancer detection is required for timely diagnosis and better treatment outcomes. ...Here, we developed an ultrasensitive electrochemical aptasensor for the multiplex detection of exosome biomarkers based on the electrochemical signals of metal ions. Specifically, a screen-printed carbon electrode (SPCE) was first modified with a multi-walled carbon nanotube (MWCNT), ionic liquid (IL), and chitosan (CHT) composite, and then gold nanoparticles (GNPs) were deposited via electrodeposition (GNPs/MWCNT-IL-CHT). To capture target exosomes, an aptamer specific for CD63, the universal exosome surface protein, was immobilized on the GNPs/MWCNT-IL-CHT/SPCE. When EpCAM or HER-2 positive exosomes were present in the sample, they could bind to EpCAM or HER-2 aptamers with primer sequences that acted as a rolling circle amplification reaction initiator, thereby generating numerous poly-guanine and poly-thymine repeats of a metal ion binding sequence, which produced strong electrochemical signals upon complexation with copper and lead ions. Using the proposed, multiplex exosome analysis system, EpCAM- and HER-2-positive exosomes were simultaneously detected with high specificity and a detection limit of 1 particle mL−1. In addition, its clinical applicability was validated via spike-and-recovery experiments using human serum samples.
Ultrasensitive electrochemical aptasensor was developed for multiplex detection of exosome biomarkers, which relies on different electrochemical signals of metal ions. Display omitted
•An aptasensor was developed for multiplex detection of EpCAM and HER-2 positive exosomes.•Lead and copper ions were employed as electrochemical signal reporters.•Electrode surface modification in combination with dual RCA significantly enhanced the detection sensitivity.•EpCAM and HER2 positive exosomes were detected with a detection limit of 1 particle/mL.
Epithelial cell adhesion molecule (EpCAM) is a surface marker which is frequently overexpressed in hepatocellular carcinoma (HCC) but minimally expressed on mature hepatocytes. We developed a ...specific aptamer against EpCAM (EpCAM-apt) and tested its potential as a drug delivery agent for HCC. The targeting ability of EpCAM-apt was confirmed in vitro and in vivo after which the complex was conjugated with doxorubicin (Dox) to form EpCAM-apt-Dox. The targeting efficacy of the drug-loaded complex against liver cancer stem-like cells (LCSCs) and therapeutic effects in HCC were evaluated. EpCAM-expressing (EpCAM+) HCC cells showed characteristics of stem like cells including greater proliferative capacity and tumour sphere formation. EpCAM-apt-Dox selectively delivered Dox to EpCAM+ HCC cells with high drug retention and accumulation versus control. EpCAM-apt-Dox reduced the self-renewal capacity and stem-like cell frequency in vitro. Elimination of cancer stem-like cells (CSCs) with EpCAM-apt-Dox significantly inhibited the growth of HCC cells and patient-derived HCC organoids but exerted minimal cytotoxicity to normal liver organoids. Moreover, EpCAM-apt-Dox suppressed the growth of xenograft tumours derived from HCC organoids in vivo and prolonged mouse survival without inducing adverse effects to major organs. Thus, aptamer-based drug delivery to the stem-like cell population is a promising strategy for HCC treatment.
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The causes of intractable diarrhoea in infancy are varied, and can be classified into enteropathic and non-enteropathic groups. Congenital tufting enteropathy (CTE) is a rare cause of enteropathic ...form of intractable diarrhoea in infants requiring nutritional supplementation. We herein report a case of CTE in a one-year-old female child who presented with recurrent abdominal distension, frequent watery diarrhoea and marked stunted growth soon after birth. A systematic clinical, laboratory and pathological evaluation brought out the etiology, followed by genotypic confirmation. Histological examination revealed mild villous abnormality with presence of epithelial tufts both in the villous and crypt surface, in the duodenum and rectal biopsies supported by complete loss of MOC31 staining. Deep sequencing revealed homozygous 3' splice mutation at intron 5 of the EPCAM gene (c.556-14A>G). She was given TPN support and discharged with weight gain under home-based parenteral nutrition supplement. This case brings out the need for a multidisciplinary team approach to reveal underlying the cause of infantile intractable diarrhoea and report a favorable outcome with nutritional supplementation.
This paper presents a “turn-on” fluorescence biosensor based on graphene quantum dots (GQDs) and molybdenum disulfide (MoS2) nanosheets for rapid and sensitive detection of epithelial cell adhesion ...molecule (EpCAM). PEGylated GQDs were used as donor molecules, which could not only largely increase emission intensity but also prevent non-specific adsorption of PEGylated GQD on MoS2 surface. The sensing platform was realized by adsorption of PEGylated GQD labelled EpCAM aptamer onto MoS2 surface via van der Waals force. The fluorescence signal of GQD was then quenched by MoS2 nanosheets via fluorescence resonance energy transfer (FRET) mechanism. In the presence of EpCAM protein, the stronger specific affinity interaction between aptamer and EpCAM protein could detach GQD labelled EpCAM aptamer from MoS2 nanosheets, leading to the restoration of fluorescence intensity. By monitoring the change of fluorescence signal, the target EpCAM protein could be detected sensitively and selectively with a linear detection range from 3nM to 54nM and limit of detection (LOD) around 450pM. In addition, this nanobiosensor has been successfully used for EpCAM-expressed breast cancer MCF-7 cell detection.
•A novel fluorescence turn-on apatamer was developed for EpCAM protein detection.•This FRET sensor used GQD as donor and MoS2 nanosheets as acceptor.•A detection limit of 450 was achieved for EpCAM protein.•This FRET sensor was successfully used for MCF-7 cell detection.
The circulating tumor cells (CTCs, the root cause of cancer metastasis and poor cancer prognosis) are very difficult to culture for scale-up
, which has hampered their use in cancer ...research/prognosis and patient-specific therapeutic development. Herein, we report a robust electromicrofluidic chip for not only efficient capture of heterogeneous (EpCAM+ and CD44+) CTCs with high purity but also glutathione-controlled gentle release of the CTCs with high efficiency and viability. This is enabled by coating the polydimethylsiloxane (PDMS) surface in the device with a 10 nm gold layer through a 4 nm titanium coupling layer, for convenient PEGylation and linkage of capture antibodies via the thiol-gold chemistry. Surprisingly, the percentage of EpCAM+ mammary CTCs can be as low as ∼35% (∼70% on average), showing that the commonly used approach of capturing CTCs with EpCAM alone may miss many EpCAM- CTCs. Furthermore, the CD44+ CTCs can be cultured to form 3D spheroids efficiently for scale-up. In contrast, the CTCs captured with EpCAM alone are poor in proliferation
, consistent with the literature. By capture of the CTC heterogeneity, the percentage of stage IV patients whose CTCs can be successfully cultured/scaled up is improved from 12.5% to 68.8%. These findings demonstrate that the common practice of CTC capture with EpCAM alone misses the CTC heterogeneity including the critical CD44+ CTCs. This study may be valuable to the procurement and scale-up of heterogeneous CTCs, to facilitate the understanding of cancer metastasis and the development of cancer metastasis-targeted personalized cancer therapies conveniently via the minimally invasive liquid/blood biopsy.
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