• Exosomes
• Glioma
• Small extracellular vesicles

• 2208085MH220 Natural Science Foundation of Anhui Province
• 2208085MH220 Natural Science Foundation of Anhui Province
• 2208085MH220 Natural Science Foundation of Anhui Province
• 2208085MH220 Natural Science Foundation of Anhui Province
• 2208085MH220 Natural Science Foundation of Anhui Province
• Anhui Medical University Foundation (2023xkj034)

• Antibody Fragment
• Breast Cancer
• EpCAM
• Receptor Tyrosine Kinase
• Recombinant
• scFv

• Humans
• Animals
• Mice
• Female
• Cell Adhesion Molecules/metabolism
• Antigens, Neoplasm
• Cell Line, Tumor
• Antibodies, Monoclonal/therapeutic use
• MCF-7 Cells
• Recombinant Proteins/therapeutic use
• Breast Neoplasms

• Humans
• Cell Line, Tumor
• Cytosol/metabolism
• Epithelial Cell Adhesion Molecule/genetics
• Epithelial Cell Adhesion Molecule/metabolism
• Epithelial-Mesenchymal Transition/genetics
• Signal Transduction
• Zinc Finger E-box-Binding Homeobox 1/genetics
• Zinc Finger E-box-Binding Homeobox 1/metabolism

• Startup Foundation

• EpCAM-binding
• Non-invasive procedure
• Oral administration
• Protein engineering
• Targeted cancer therapy

• EpCAM
• antibody-dependent cellular cytotoxicity
• antitumor activities
• breast cancer
• pancreatic cancer

• Cancer stem cells
• Tumor heterogeneity
• Tumor microenvironment

• Angiogenesis inhibitors
• growth factors
• hypoxia
• radiation
• therapy
• tumor microenvironment

The high mortality rate of breast cancer is mainly caused by the metastatic ability of cancer cells, resistance to chemotherapy and radiotherapy, and tumor regression capacity. In recent years, it has been shown that the presence of breast cancer stem cells is closely associated with the migration and metastatic ability of cancer cells, as well as with their resistance to chemotherapy and radiotherapy. The tumor microenvironment is one of the main molecular factors involved in cancer and metastatic processes development, in this sense it is interesting to study the role of platelets, one of the main communicator cells in the human body which are activated by the signals they receive from the microenvironment and can generate more than one response. Platelets can ingest and release RNA, proteins, cytokines and growth factors. After the platelets interact with the tumor microenvironment, they are called "tumor-educated platelets." Tumor-educated platelets transport material from the tumor microenvironment to sites adjacent to the tumor, thus helping to create microenvironments conducive for the development of primary and metastatic tumors. It has been observed that the clone capable of carrying out the metastatic process is a cancer cell with stem cell characteristics. Cancer stem cells go through a series of processes, including epithelial-mesenchymal transition, intravasation into blood vessels, movement through blood vessels, extravasation at the site of the establishment of a metastatic focus, and site colonization. Tumor-educated platelets support all these processes. 

• Breast cancer stem cells
• Platelets
• Metastasis
• Tumor microenvironment
• Epithelial-mesenchymal transition

Development of chemo−/radioresistance is a major challenge for the current prostate cancer (CaP) therapy. We have previously demonstrated that epithelial cell adhesion molecule (EpCAM) is associated with CaP growth and therapeutic resistance in vitro, however, the role of EpCAM in CaP in vivo is not fully elucidated. Here, we aimed to investigate how expression of EpCAM is involved in CaP growth and chemo−/radiotherapy response in NOD/SCID mouse models in vivo and to validate its role as a therapeutic target for CaP therapy.

EpCAM was knocked down in PC-3 CaP cell line using short hairpin RNA (shRNA). The effect of EpCAM-knockdown (KD) on tumour growth, chemo−/radiotherapy response and animal survival was evaluated on subcutaneous (s.c) and orthotopic mouse models.

We found that KD of EpCAM significantly inhibited tumour growth, increased xenograft sensitivity to chemotherapy/radiotherapy, and prolonged the survival of tumour-bearing mice. In addition, we demonstrated that KD of EpCAM is associated with downregulation of the PI3K/Akt/mTOR pathway.

In conclusion, our data confirms that CaP growth and chemo−/radioresistance in vivo is associated with over-expression of EpCAM, which serves both a functional biomarker and promising therapeutic target.

The online version of this article (10.1186/s12885-018-5010-5) contains supplementary material, which is available to authorized users.

• Animal model
• Chemoresistance
• EpCAM
• PI3K/Akt/mTOR signaling pathway
• Prostate cancer
• Radioresistance

• Adenoid cystic carcinoma
• Ber-EP4
• EpCAM
• biomarker
• non-salivary gland

Despite a growing body of evidence, the role of the gut microbiome in cardiovascular diseases (CVDs) is still unclear. Here we present a systems-genome-wide and metagenome-wide association study on plasma concentrations of 92 CVD-related proteins in the population cohort Lifelines-DEEP. We identified genetic components for 73 proteins and microbial associations for 41 proteins, of which 31 were associated to both. The genetic and microbial factors identified mostly exert additive effects and collectively explain up to 76.6% of inter-individual variation (17.5% on average). Genetics contributes most to concentrations of immune-related proteins, while the gut microbiome contributes most to proteins involved in metabolism and intestinal health. We found several host-microbe interactions that impact proteins involved in epithelial function, lipid metabolism and central nervous system function. This study reveals important evidence for a joint genetic and microbial effect in cardiovascular disease and provides directions for future applications in personalized medicine.

Epithelial ovarian cancer is a highly lethal malignancy; moreover, overcoming chemoresistance is the major challenging in treating ovarian cancer patients. The cancer stem cell (CSC) hypothesis considers CSCs to be the main culprits in driving tumor initiation, metastasis, and resistance to conventional therapy. Although growing evidence suggest that CSCs are responsible for chemoresistance, the contribution of CSC marker EpCAM to resistance to chemotherapy remains unresolved.

Here we have demonstrated that ovarian cancers containing high levels of EpCAM have a significantly much lower probability of achieving overall responsive rates after first-line chemotherapy. In addition, multivariate analysis revealed that EpCAM expression is an independent risk factor for chemoresistance, indicating that EpCAM expression is a predictive biomarker of chemotherapeutic response. Consistent with these clinical observations, in vitro assays, we found that the subpopulation of EpCAM-positive ovarian cancer cells shows a significantly higher viability compared with EpCAM-negative cells in response to cisplatin treatment by preventing chemotherapy-induced apoptosis, which is regulated by EpCAM-Bcl-2 axis. Furthermore, in an in vivo mouse model, platinum agents preferentially eliminated EpCAM-negative cells in comparison with EpCAM-positive cells, suggesting that the remaining subpopulation of EpCAM-positive cells contributes to tumor recurrence after chemotherapy. Finally, we also found that an increased expression of EpCAM is associated with poor prognosis in ovarian cancer patients.

Our findings highlight the clinical significance of EpCAM in the resistance to chemotherapy and provide a rationale for EpCAM-targeted therapy to improve chemoresistance. Targeting EpCAM should be a promising approach to effectively extirpate the CSCs as the putative root of ovarian cancer.

• EpCAM
• cancer stem cell
• chemoresistance
• ovarian cancer
• prognosis

• CTCs
• DTCs
• EpCAM
• MICs
• metastases

The standard of treatment for botulism, equine antitoxin, is a foreign protein with associated safety issues and a short serum half-life which excludes its use as a prophylactic antitoxin and makes it a less-than-optimal therapeutic. Due to these limitations, a recombinant monoclonal antibody (mAb) product is preferable. It has been shown that combining three mAbs that bind non-overlapping epitopes leads to highly potent botulinum neurotoxin (BoNT) neutralization. Recently, a triple human antibody combination for BoNT/A has demonstrated potent toxin neutralization in mouse models with no serious adverse events when tested in a Phase I clinical trial. However, a triple antibody therapeutic poses unique development and manufacturing challenges. Thus, potentially to streamline development of BoNT antitoxins, we sought to achieve the potency of multiple mAb combinations in a single IgG-based molecule that has a long serum half-life. The design, production, and testing of a single tri-epitopic IgG1-based mAb (TeAb) containing the binding sites of each of the three parental BoNT/A mAbs yielded an antibody of nearly equal potency to the combination. The approach taken here could be applied to the design and creation of other multivalent antibodies that could be used for a variety of applications, including toxin elimination.

• antitoxin
• bi-epitopic
• botulinum neurotoxin
• botulism
• kinetic-exclusion analysis
• mouse neutralization assay
• multivalent antibody
• negative-stain electron microscopy
• recombinant monoclonal antibody
• tri-epitopic

• biomarkers
• cancer therapy
• liver cancer
• molecular targeting
• stem cells

• Cancer stem cell markers
• Cancer stem cells
• Hepatocellular carcinoma
• Metastasis
• Tumor heterogeneity
• Tumor recurrence

Epithelial cell adhesion molecule (EpCAM) is known to be overexpressed in epithelial cancers associated with enhanced malignant potential, particularly colorectal carcinoma (CRC) and head and neck squamous cell carcinoma (HNSCC). However, it is unknown whether progression of malignance can be directly inhibited by targeting EpCAM. Here, we have generated five novel monoclonal antibodies (mAbs) against EpCAM. One of these anti-EpCAM mAbs, EpAb2-6, was found to induce cancer cell apoptosis in vitro, inhibit tumor growth, and prolong the overall survival of both a pancreatic cancer metastatic mouse model and mice with human colon carcinoma xenografts. EpAb2-6 also increases the therapeutic efficacy of irinotecan, fluorouracil, and leucovorin (IFL) therapy in a colon cancer animal model and gemcitabine therapy in a pancreatic cancer animal model. Furthermore, EpAb2-6, which binds to positions Y95 and D96 of the EGF-II/TY domain of EpCAM, inhibits production of EpICD, thereby decreasing its translocation and subsequent signal activation. Collectively, our results indicate that the novel anti-EpCAM mAb can potentially be used for cancer-targeted therapy.

• EpCAM
• cancer therapy
• colorectal carcinoma
• targeting imaging
• therapeutic antibody

Cancer stem cells (CSCs) are a small subpopulation in cancer, have been proposed to be cancer-initiating cells, and have been shown to be responsible for chemotherapy resistance and cancer recurrence. The identification of CSC subpopulations inside a tumor presents a new understanding of cancer development because it implies that tumors can only be eradicated by targeting CSCs. Although advances in liver cancer detection and treatment have increased the possibility of curing the disease at early stages, unfortunately, most patients will relapse and succumb to their disease. Strategies aimed at efficiently targeting liver CSCs are becoming important for monitoring the progress of liver cancer therapy and for evaluating new therapeutic approaches. Herein, we provide a critical discussion of biological markers described in the literature regarding liver cancer stem cells and the potential of these markers to serve as therapeutic targets.

• Liver cancer
• Cancer recurrence
• Liver cancer stem cells
• Cancer stem cell markers
• Targeted therapy

• Animals
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/metabolism
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Molecular Targeted Therapy
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Phenotype

• Cancer stem cell (CSC)
• immunoresistance
• immunotherapy

• combined hepatocellular-cholangiocarcinoma
• epithelial cell adhesion molecule
• hepatic stem/progenitor cell

• cancer stem cell
• tumorigenicity
• signalling pathways
• cancer stem cell markers
• cancer therapy

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Humans
• Molecular Targeted Therapy/methods
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Signal Transduction/drug effects

Molecularly targeted drugs promise a safer and more effective treatment modality than conventional chemotherapy for cancer patients. However, tumors are dynamic systems that readily adapt to these agents activating alternative survival pathways as they evolve resistant phenotypes. Combination therapies can overcome resistance but finding the optimal combinations efficiently presents a formidable challenge. Here we introduce a new paradigm for the design of combination therapy treatment strategies that exploits the tumor adaptive process to identify context-dependent essential genes as druggable targets.

We have developed a framework to mine high-throughput transcriptomic data, based on differential coexpression and Pareto optimization, to investigate drug-induced tumor adaptation. We use this approach to identify tumor-essential genes as druggable candidates. We apply our method to a set of ER⁺ breast tumor samples, collected before (n = 58) and after (n = 60) neoadjuvant treatment with the aromatase inhibitor letrozole, to prioritize genes as targets for combination therapy with letrozole treatment. We validate letrozole-induced tumor adaptation through coexpression and pathway analyses in an independent data set (n = 18).

We find pervasive differential coexpression between the untreated and letrozole-treated tumor samples as evidence of letrozole-induced tumor adaptation. Based on patterns of coexpression, we identify ten genes as potential candidates for combination therapy with letrozole including EPCAM, a letrozole-induced essential gene and a target to which drugs have already been developed as cancer therapeutics. Through replication, we validate six letrozole-induced coexpression relationships and confirm the epithelial-to-mesenchymal transition as a process that is upregulated in the residual tumor samples following letrozole treatment.

To derive the greatest benefit from molecularly targeted drugs it is critical to design combination treatment strategies rationally. Incorporating knowledge of the tumor adaptation process into the design provides an opportunity to match targeted drugs to the evolving tumor phenotype and surmount resistance.

Accumulating evidence has indicated the importance of cancer stem cells in carcinogenesis. The goal of the present study was to determine the effect of low-dose cisplatin on enriched liver cancer stem cells (LCSCs). Human hepatoblastoma HepG2 cells were treated with concentrations of cisplatin ranging from 1 to 5 μg/mL. Cell survival and proliferation were evaluated using a tetrazolium dye (MTT) assay. LCSCs were identified using specific markers, namely aldehyde dehydrogenase-1 (ALDH1) and CD133. The percentage of ALDH1+ or CD133+ cells was examined by flow cytometric analysis. The expression of ALDH1 and/or CD133 in HepG2 cells was determined by immunocytochemical analysis. Low-dose cisplatin treatment significantly decreased cell survival in HepG2 cells after 24 or 72 h. However, the percentage of LCSCs in the surviving cells was greatly increased. The percentage of ALDH1+ or CD133+ cells was increased in a time- and dose-dependent manner after treatment with 1-4 μg/mL cisplatin, whereas 5 μg/mL cisplatin exposure slightly reduced the number of positive cells. These findings indicate that low-dose cisplatin treatment may efficiently enrich the LCSC population in HepG2 cells.

• Adenocarcinoma, Clear Cell/metabolism
• Adenocarcinoma, Clear Cell/pathology
• Adenocarcinoma, Clear Cell/therapy
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Carcinoma in Situ/metabolism
• Carcinoma in Situ/pathology
• Carcinoma in Situ/therapy
• Carcinoma, Ovarian Epithelial
• Cell Line, Tumor
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/metabolism
• Cystadenocarcinoma, Serous/metabolism
• Cystadenocarcinoma, Serous/pathology
• Cystadenocarcinoma, Serous/therapy
• Fallopian Tubes/drug effects
• Fallopian Tubes/metabolism
• Fallopian Tubes/pathology
• Female
• Humans
• Molecular Targeted Therapy
• Neoplasms, Glandular and Epithelial/metabolism
• Neoplasms, Glandular and Epithelial/pathology
• Neoplasms, Glandular and Epithelial/therapy
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Ovarian Neoplasms/therapy
• Ovary/drug effects
• Ovary/metabolism
• Ovary/pathology

• Antibodies, Monoclonal/chemistry
• Antibodies, Monoclonal/immunology
• Antigens, Neoplasm/chemistry
• Antigens, Neoplasm/immunology
• Cell Adhesion Molecules/chemistry
• Cell Adhesion Molecules/immunology
• Cell Line, Tumor
• Epithelial Cell Adhesion Molecule
• Gold/chemistry
• Humans
• Metal Nanoparticles/chemistry
• Particle Size
• Polyethylene Glycols/chemistry
• Solutions
• Surface Properties

The basic idea of displaying peptides on a phage, introduced by George P. Smith in 1985, was greatly developed and improved by McCafferty and colleagues at the MRC Laboratory of Molecular Biology and, later, by Barbas and colleagues at the Scripps Research Institute. Their approach was dedicated to building a system for the production of antibodies, similar to a naïve B cell repertoire, in order to by-pass the standard hybridoma technology that requires animal immunization. Both groups merged the phage display technology with an antibody library to obtain a huge number of phage variants, each of them carrying a specific antibody ready to bind its target molecule, allowing, later on, rare phage (one in a million) to be isolated by affinity chromatography. Here, we will briefly review the basis of the technology and the therapeutic application of phage-derived bioactive molecules when addressed against key players in tumor development and progression: growth factors and their tyrosine kinase receptors.

• anticancer therapy
• growth factors
• humanized antibody
• phage display
• tyrosine kinase receptors

• Antigens, Neoplasm/metabolism
• Cell Adhesion Molecules/metabolism
• Cell Line
• Epithelial Cell Adhesion Molecule
• Flow Cytometry
• Humans
• Hyaluronan Receptors/metabolism
• Integrin alpha6/metabolism
• Male
• Prostate/cytology
• Reverse Transcriptase Polymerase Chain Reaction

• P30 AI028697 NIAID NIH HHS
• P30 CA016042 NCI NIH HHS

The cancer stem cell (CSC) hypothesis was first proposed over 40 years ago. Advances in CSC isolation were first achieved in hematological malignancies, with the first CSC demonstrated in acute myeloid leukemia. However, using similar strategies and technologies, and taking advantage of available surface markers, CSCs have been more recently demonstrated in a growing range of epithelial and other solid organ malignancies, suggesting that the majority of malignancies are dependent on such a compartment.

Primary liver cancer consists predominantly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). It is believed that hepatic progenitor cells (HPCs) could be the origin of some HCCs and ICCs. Furthermore, stem cell activators such as Wnt/β-catenin, TGF-β, Notch and Hedgehog signaling pathways also expedite tumorigenesis, and these pathways could serve as molecular targets to assist in designing cancer prevention strategies. Recent studies indicate that additional factors such as EpCAM, Lin28 or miR-181 may also contribute to HCC progression by targeting HCC CSCs. Various therapeutic drugs that directly modulate CSCs have been examined in vivo and in vitro. However, CSCs clearly have a complex pathogenesis, with a considerable crosstalk and redundancy in signaling pathways, and hence targeting single molecules or pathways may have a limited benefit for treatment. Many of the key signaling molecules are shared by both CSCs and normal stem cells, which add further challenges for designing molecularly targeted strategies specific to CSCs but sparing normal stem cells to avoid side effects. In addition to the direct control of CSCs, many other factors that are needed for the maintenance of CSCs, such as angiogenesis, vasculogenesis, invasion and migration, hypoxia, immune evasion, multiple drug resistance, and radioresistance, should be taken into consideration when designing therapeutic strategies for HCC.

Here we provide a brief review of molecular signaling in liver CSCs and present insights into new therapeutic strategies for targeting liver CSCs.

• BMI-1 signaling
• Cholangiocellular carcinoma
• EpCAM
• Hedgehog signaling
• Hepatocellular carcinoma
• Lin-28
• Liver cancer stem cell
• Notch signaling
• Self-protection
• Self-renewal
• TGF-β signaling
• Wnt/β-catenin signaling
• miR-181

• Adult
• Aged
• Aged, 80 and over
• Antigens, Neoplasm/metabolism
• Cell Adhesion Molecules/metabolism
• Disease Progression
• Epithelial Cell Adhesion Molecule
• Female
• Humans
• Male
• Middle Aged
• Neoplastic Cells, Circulating/metabolism
• Neuroendocrine Tumors/blood
• Neuroendocrine Tumors/diagnostic imaging
• Neuroendocrine Tumors/metabolism
• Paraffin Embedding
• Radiography

• Cancer Research UK
• Department of Health

We previously demonstrated that nuclear and cytoplasmic accumulation of the intracellular domain (Ep-ICD) of epithelial cell adhesion molecule (EpCAM) accompanied by a reciprocal reduction of its extracellular domain (EpEx), occurs in aggressive thyroid cancers. This study was designed to determine whether similar accumulation of Ep-ICD is a common event in other epithelial cancers.

Ten epithelial cancers were immunohistochemically analyzed using Ep-ICD and EpEx domain-specific antibodies. The subcellular localization of EpEx and Ep-ICD in the human colon adenocarcinoma cell line CX-1 was observed using immunofluorescence. Nuclear and cytoplasmic Ep-ICD expression was increased in cancers of the breast (31 of 38 tissues, 82%), prostate (40 of 49 tissues, 82%), head and neck (37 of 57 tissues, 65%) and esophagus (17 of 46 tissues, 37%) compared to their corresponding normal tissues that showed membrane localization of the protein. Importantly, Ep-ICD was not detected in the nuclei of epithelial cells in most normal tissues. High nuclear and cytoplasmic Ep-ICD accumulation also occurred in the other six epithelial cancer types analyzed - lung, colon, liver, bladder, pancreatic, and ovarian. A concomitant reduction in membrane EpEx expression was observed in a subset of all cancer types. Receiver operating characteristic curve analysis revealed nuclear Ep-ICD distinguished breast cancers with 82% sensitivity and 100% specificity and prostate cancers with 82% sensitivity and 78% specificity. Similar findings were observed for cytoplasmic accumulation of Ep-ICD in these cancers. We provide clinical evidence of increased nuclear and cytoplasmic Ep-ICD accumulation and a reduction in membranous EpEx in these cancers.

Increased nuclear and cytoplasmic Ep-ICD was observed in all epithelial cancers analyzed and distinguished them from normal tissues with high-sensitivity, specificity, and AUC. Development of a robust high throughput assay for Ep-ICD will facilitate the determination of its diagnostic, prognostic and therapeutic relevance in epithelial cancers.

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antigens, Neoplasm/metabolism
• Binding Sites
• Cell Adhesion Molecules/metabolism
• Cell Line, Tumor
• Cell Nucleus/metabolism
• Cytoplasm/metabolism
• Epithelial Cell Adhesion Molecule
• Epithelial Cells/pathology
• Female
• Fluorescent Antibody Technique
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Neoplasm Staging
• Neoplasms/diagnosis
• Neoplasms/metabolism
• ROC Curve