Development of palliative medicine in the United Kingdom and Ireland
Eduardo Bruera, Irene Higginson, Charles F von Gunten, Tatsuya Morita in Textbook of Palliative Medicine and Supportive Care, 2015
Epithelial cell adhesion molecule (EpCAM) is a cell surface glycoprotein that mediates epithelial cell to cell adhesion. It is found to be expressed in the majority of epithelial carcinomas, including those responsible for most incidences of malignant ascites, and is a tempting target for immunotherapy. The normal peritoneal cavity is lined by mesothelial cells that do not express EpCAM. Catumaxomab is a trifunctional monoclonal antibody that binds to EpCAM, and the T-lymphocyte surface antigen, CD3 and is designed to recruit not only T cells but also cytokine-producing accessory cells. Â 58 A phase II/III clinical trial of intraperitoneal infusions of catumaxomab in individuals with malignant ascites and EpCAM positive tumors resulted in an increase in puncture-free survival and a delayed deterioration in the quality of life when compared with a standard approach of serial paracenteses alone. Â 59**,60** However, side effects were common, and the protocol called for four repeat intraperitoneal infusions over a 10 -day period.
Antibody-Based Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
The Human Epithelial Cell Adhesion Molecule (EpCAM) is a Type I transmembrane glycoprotein consisting of two epidermal growth factor-like domains, one cysteine-poor region, one transmembrane domain and one short cytoplasmic tail. In normal cells and tissues, EpCAM expression is limited and the glycoprotein is shielded by tight junctions which limit its accessibility. In contrast, in tumor cells EpCAM is expressed on the whole cell surface, and thus becomes more accessible for binding. It is one of the most frequently and strongly expressed tumor-associated antigens in a number of tumor types including ovarian, gastric, colon, pancreatic, prostate, lung, and endometrial carcinoma. In particular, EpCAM is expressed on the vast majority of the main epithelial cancers that cause malignant ascites.
Immunotherapy of peritoneal carcinomatosis
Wim P. Ceelen, Edward A. Levine in Intraperitoneal Cancer Therapy, 2015
The human epithelial cell adhesion molecule (EpCAM, CD326) represents a membrane-embedded protein that mediates epithelium-specific cell-to-cell adhesion [13]. Investigations on the expression of EpCAM on normal human tissue showed that the protein could primarily be detected on epithelial tissue including pancreas, colon, lung, bile ducts, and breast, whereas EpCAM-negative tissue includes bone marrow, lymphocytes, endothelium, heart, ovary, muscle, and mesenchymal tissue [14,15]. The high frequency of its overexpression on epithelial tumors qualifies EpCAM as a smart target for anticancer therapy. High-level EpCAM expression was found in gastric cancer, colon cancer, prostate cancer, and lung cancer [16]. Treatment of head and neck cancer and breast cancer cell lines with EpCAM-specific antisense or siRNAs resulted in the partial or complete reduction of cell migration, proliferation and invasive capacity [17,18].
Potential lung attack and lethality generated by EpCAM-specific CAR-T cells in immunocompetent mouse models
Published in OncoImmunology, 2020
Diyuan Qin, Dan Li, Benxia Zhang, Yue Chen, Xuelian Liao, Xiaoyu Li, Peter B. Alexander, Yongsheng Wang, Qi-Jing Li
Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein which is mainly expressed on certain luminal epithelial cells in an ordered and oriented manner. Upon malignant transformation, EpCAM becomes overexpressed on some carcinomas cells in an unrestricted pattern,18–20 leading to increased accessibility for EpCAM-specific CAR-T cells and heightened CAR-T activation. Apparently, EpCAM has been proposed as an ideal target for CAR-T therapy and existing data demonstrate that human EpCAM targeted CAR-T cells can eradicate established tumor xenografts without toxicities in mouse models.21–23 Based on these results, several CAR-T clinical trials targeting EpCAM have already been initiated.24–28 However, although the efficacy evaluation of these pioneer studies in mice may indeed reflect their anti-tumor potential in human, the safety assessment might be problematic: first, the induction of CRS relies on the interaction between exogenous CAR-T cells and an intact mouse immune system; and second, the human EpCAM-specific scFv within these CAR constructs does not recognize mouse autologous EpCAM. Previous clinical trials suggest that the latter is a prominent issue for any CAR targeting a tumor-associated antigen: on-target/off-tumor side effects undetectable in xenograft mouse models may induce patient lethality.10,29
Role and molecular mechanism of stem cells in colorectal cancer initiation
Published in Journal of Drug Targeting, 2020
Meng-Yan Wang, Yu-Han Qiu, Mei-Lian Cai, Cong-Hui Zhang, Xiao-Wei Wang, Hong Liu, Yi- Chen, Wu-Li Zhao, Jing-Bo Liu, Rong-Guang Shao
The epithelial cell adhesion molecule (EpCAM) is a single transmembrane protein with a molecular weight of 30–40 kDa. EpCAM consists of three parts: the extracellular domain, a single transmembrane domain and an intracellular domain with 26 amino acids called EpICD [40]. EpCAM is found to be highly expressed in a variety of epithelial cell-derived tumour tissues and is regarded as a stem cell-specific marker for colorectal cancer [41,42]. EpCAM can release proliferative signals to tumour stem cells and can play a role in tumourigenesis and the maintenance of stem cell characteristics. Studies have shown that EpCAM could play a role similar to that of the Wnt signal pathway in CSCs. EpCAM was a direct target gene downstream of the Wnt pathway, and scientists have used GSK-3β inhibitors to activate the Wnt pathway to find that the proportion of EpCAM + HuH1 and HuH7 increased [43]. In addition, scientists have analysed the samples from patients with advanced liver cancer and concluded that EpCAM + liver cancer cells have stem cell-like characteristics, and the Wnt pathway activation level was higher than that of the control group, which was characterised by autocrine Wnt pathway activators such as Wnt3a [40].
HOTAIR knockdown impairs metastasis of cervical cancer cells by down-regulating metastasis-related genes
Published in Journal of Obstetrics and Gynaecology, 2023
Lei Shi, Dehui Zhang, Huijuan Han, Liangyu Zhang, Sirui Li, Fang Yang, Caijun He
Epithelial cell adhesion molecule (EpCAM) is known to be strongly associated with poor clinical outcomes in cancer patients (Park et al. 2020). It is regarded as a pro-metastatic gene and the presence of circulating cancer cells expressing EpCAM in the blood of cancer patients is strongly associated with poor prognosis (de Wit et al. 2018). This gene is upregulated in many tumours, such as squamous cell carcinoma (Stoecklein et al.2006) and breast cancer (Osta et al.2004). The expression of EpCAM also was downregulated in the cervical cell lines after HOTAIR knockdown. Previously, downregulation of EpCAM was shown to suppress the proliferation of gastric cancer and arrest cell cycle of AGS and SGC7901 cells (Wenqi et al.2009). In addition, silencing of EpCAM with siRNA was found to efficiently inhibits the proliferation of MCF-7 and WERI-Rb1 cells (Subramanian et al.2015). These data are consistent with our results.