EpCAM- and/or NCAM-Expressing Hepatocellular Carcinoma in Which Behavior of Hepatic Progenitor Cell Marker-Positive Cells Are Followed

Abstract

Hepatic progenitor cell (HPC) marker-positive hepatocellular carcinomas (HCCs) have recently been extensively analyzed, and their prognosis has been reported as poor compared to HPC marker-negative HCCs. However, previous studies have analyzed the existence of HPC marker-positive cancer cells only in primary lesions, as well as the recurrence rate and prognosis of such tumors. Here, we are the first to report the behavior of HPC marker-positive cancer cells during vascular invasion and metastasis of an HCC. We concurrently analyzed EpCAM- and/or NCAM-expressing cancer cells in the primary, vascular invasion, and metastatic lesions of an HCC. An HCC which includes EpCAM- and/or NCAM-expressing cancer cells has not been previously reported. EpCAM- and/or NCAM-positive cancer cells invaded the vessels and formed heterogeneous populations of these HPC marker-positive cancer cells with HPC marker-negative cancer cells. The frequency of HPC marker-positive cancer colonies and cells in vessels was higher than that in the primary HCC. In the metastatic lesions, EpCAM-positive cancer cells were more frequently detected than NCAM-positive cancer cells, indicating that EpCAM may be more important than NCAM for cancer cell settlement in the metastatic lesions. Furthermore, bigger metastatic tumors tended to include HPC marker-positive cancer cells, suggesting that HPC marker-positive cancer cells have a growth advantage in the metastatic lesions. These results showed that HPC marker-positive cancer cells would be important for vascular invasion and metastasis and suggested that HPC marker-positive cancer cells are an important target in HCC treatment.

GITR/GITRL reverse signalling modulates the proliferation of hepatic progenitor cells by recruiting ANXA2 to phosphorylate ERK1/2 and Akt

“…Our overexpression and silencing data support the growth stimulatory effect of GITRL on hepatic progenitor cells, which is similar to the effect of GITRL on macrophages [ 38 ]. As a cell compartment involved in HCC carcinogenesis [ 8 , 9 ], hepatic progenitor cells expressing GITRL activate pathways of cancer, MAPK, PI3K/Akt and epithelial–mesenchymal transition by binding to ANXA2, which could enhance the progression of HCC [ 39 – 41 ] and many other tumours, including colorectal cancer [ 42 ], pancreatic cancer [ 43 ], breast cancer [ 44 , 45 ] and prostate cancer [ 46 ], suggesting that GITRL may contribute to the abnormal transformation of hepatic progenitor cells.…”

“…The number of hepatic stem/progenitor cells is increased as chronic disease progresses, and the extent of hepatocytes derived from hepatic stem/progenitor cells is correlated with disease severity [ 4 , 5 ]. However, given that severe chronic liver diseases enhance the incidence of hepatocellular carcinoma (HCC) [ 6 , 7 ] and that HCC shares many common markers with hepatic stem/progenitor cells [ 8 , 9 ], it has been postulated that hepatic stem/progenitor cells are a possible cellular origin of HCC. Therefore, modulating the expansion or proliferation of hepatic stem/progenitor cells and preventing their abnormal transformation are essential for balancing regeneration and carcinogenesis.…”

Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer

“…These data suggest that EpCAM could be a potential target for the diagnosis and therapy of hepatic cancers. Yamashita et al demonstrated that activation of the Wnt/β-catenin signaling pathway stimulates EpCAM expression which, in turn, negatively affects the prognosis of HCC patients [ 103 , 104 ]. Wang et al [ 105 ] and Arzumanyan et al [ 106 ] demonstrated that hepatitis B antigen HBx promotes the self-renewal and tumorigenicity of EpCAM + hepatic progenitor cells by stimulating β-catenin signaling and miR-181 expression.…”

Hepatocellular carcinoma risk-stratification based on ASGR1 in circulating epithelial cells for cancer interception

“…With respect to HCC, several meta-analyses demonstrated the diagnostic and prognostic utility of detecting CTCs ( Fan et al, 2015 ), ( Sun et al, 2017 ), ( Cui et al, 2020 ), although different isolation and detection technologies may undermine their clinical utility. Isolation methodologies based on EpCAM such as CellSearch ® are widely used, although elevated EpCAM expression levels were only found in metastatic HCC lesions compared to primary and vascular invaded tumor ( Tsuchiya et al, 2019 ). Furthermore, elevated EpCAM expression levels were also linked to poor prognosis ( Shimada et al, 2019 ).…”