{"doi":"10.18632/oncotarget.27454","title":"Carcinogenetic initiation contributed by EpCAM+ cancer cells in orthotopic HCC models of immunocompetent and athymic mice","abstract":"// Harshul Pandit 1 , 5 , Yan Li 1 , 5 , Qianqian Zheng 2 , Wei Guo 3 , Youxi Yu 4 , Suping Li 1 and Robert C.G. Martin 1 , 5 1 Division of Surgical Oncology, Hiram C. Polk Jr. M.D. Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA 2 Department of Pathophysiology, Basic Medicine College, China Medical University, Shenyang 110122, China 3 Department of Hematology, The First Hospital of Jilin University, Changchun 130021, China 4 Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun 130021, China 5 Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA Correspondence to: Robert C.G. Martin, email: robert.martin@louisville.edu Keywords: hepatocellular carcinoma; Wnt/β-catenin signaling; cancer stem cells; epithelial cell adhesion molecule (EpCAM); tumor-initiating cells Received: October 30, 2019     Accepted: December 26, 2019     Published: June 02, 2020 ABSTRACT Purpose: Overexpression of epithelial cell adhesion molecule (EpCAM) correlates with poor prognosis, therapeutic failure and early tumor recurrence in hepatocellular carcinoma (HCC) patients. The tumor microenvironment dictates the fate of tumor-initiating cancer stem cells (CSCs); however, very limited studies were attempted to evaluate CSC tumorigenesis in the liver microenvironment. Here, we have systemically investigated the role of EpCAM+ cancer cells in tumor initiation in orthotopic HCC models. Results: Control mice and the mice with bland steatosis failed to develop tumors. In the mice with steatohepatitis, EpCAM+ CSCs have shown significantly increased ability in terms of tumor initiation and growth, compared to that with EpCAM- non-CSCs inoculation ( p < 0.005). For Hep3B inoculation, EpCAM-High group has shown significantly higher tumor growth compared with EpCAM-Low ( p < 0.005). For HepG2 inoculation, both EpCAM-High and EpCAM-Low groups confirmed similar tumor incidence and growth. Methods: Diet-induced compromised microenvironments were established to mimic clinical fatty liver and non-alcoholic steatohepatitis (NASH) patients and the tumorigenic capabilities of Hepa1-6 cells were evaluated. CSCs were enriched by spheroid culture and labeled with copGFP for EpCAM+ CSCs and with mCherry for non-CSCs. FACS-sorted cells were inoculated into left liver lobes, and tumor growth was monitored by high-frequency ultrasound. The subpopulations of Hep3B and HepG2 cells in terms of EpCAM-Low and EpCAM-High were evaluated in the orthotopic model of athymic mice. Conclusions: NASH microenvironment promotes the EpCAM+ CSCs initiated tumorigenesis in immunocompetent mouse model. Differential EpCAM expression demonstrates distinct tumor biology in athymic mouse models.","journal":"Oncotarget","year":2020,"id":89078,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9591,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":451028,"name":"Yán Li","orcid":"0000-0003-4537-7672","position":1,"is_corresponding":false},{"id":451029,"name":"Qianqian Zheng","orcid":"0000-0001-5906-148X","position":2,"is_corresponding":false},{"id":253879,"name":"Wei Guo","orcid":"0009-0009-9725-0092","position":3,"is_corresponding":false},{"id":452090,"name":"Youxi Yu","orcid":null,"position":4,"is_corresponding":false},{"id":451030,"name":"Suping Li","orcid":"0000-0002-0294-8861","position":5,"is_corresponding":false},{"id":445524,"name":"Robert C.G. Martin","orcid":"0000-0002-5537-3387","position":6,"is_corresponding":false},{"id":451027,"name":"Harshul Pandit","orcid":"0000-0002-0198-9303","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-18T22:01:50.225871Z","pmid":"32547703","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}