Recent advances in cancer stem cell research for cholangiocarcinoma

Abstract

Cancer stem cells have been identified as cells with the capacity to self‐renew and differentiate into multiple lineages of human malignancies. Cholangiocarcinoma is one of the most difficult intra‐abdominal malignancies that can be treated using a surgical approach. Chemotherapy in addition to surgery is necessary to improve patient survival. However, its clinical benefit is limited, and, to date, no other effective anticancer drug is available for this disease. Several reports have shown the existence of cholangiocarcinoma stem cells. Cell surface antigens such as CD133, CD24, EpCAM, CD44, and others have been used to isolate cholangiocarcinoma stem cells. In general, enhanced expression of these markers in resected specimens of cholangiocarcinoma was associated with malignant potential. Distinct and specific pathways are expected to be present in cancer stem cells compared to other cancer cells that have no stem cell properties. To date, reports showing possible signaling pathways in cholangiocarcinoma stem cells are limited. More research is anticipated. Targeting therapies for surface molecular markers or specific signaling pathways of cholangiocarcinoma stem cells may be important in order to change the clinical outcome of patients with this disease. However, no clinical trial has been performed so far. This review will focus on the markers and signaling pathways used to define cholangiocarcinoma stem cells. A novel therapeutic approach of targeting cholangiocarcinoma stem cells will also be discussed.

Participation of peribiliary glands in biliary tract pathophysiologies

“…Our previous study showed that PDX1 expressed in preneoplastic and neoplastic biliary epithelia was related to their proliferative activities; therefore, it also seems likely that PDX1 expression in the peribiliary glands of hepatolithiasis may be related to their proliferation and neoplastic process [6,7,14] . The increased expression of pancreatic and endodermal S/P cell markers in the lining epithelium and peribiliary glands may be also related to the unique features of the neoplastic processes of the biliary tract [28] . Our recent study showed that hilar cholangiocarcinomas shared features with pancreatic duct adenocarcinomas (PDAC) [29] .…”

Impact of microenvironment and stem-like plasticity in cholangiocarcinoma: Molecular networks and biological concepts

“…Notably, the cell-of-origin represents a stem-like cell that has acquired a cancer-promoting genetic or epigenetic alteration, and is not necessarily associated with the CSC-concept. Although, it has already been shown that HCC progression is driven by CSCs [37][38][39][40] very few studies have indicated that CCAs harbour phenotypic features of stem/progenitor cells (reviewed in [41]). Consistently, CSC-surface markers were recently proposed in CCA and include the expression of CD133 [42], CD24 [43], EpCAM [44], CD44 [45], and CD117 [46].…”

“…In mammals, Notch receptors (Notch 1-4) are activated by five ligands (Jagged1, Jagged2, and Delta-like ligands 1, 3, and 4), responsible for the switch-on of downstream target genes, such as Hes1 and Hey1. The expression of Notch receptors 1 and 3 correlates with cancer progression and poor survival in CCA [41], whereas the overexpression of Notch receptors 1 and 4 in HCC may exert tumourigenic effects [50].…”

“…The Notch canonical signalling pathway is a highly conserved pathway controlling cell differentiation, proliferation and apoptosis, as well as maintenance of stem cells (including hepatic progenitor cells) ( [41,47], reviewed in [48]) and morphogenesis of bile ducts (reviewed in [49]). In mammals, Notch receptors (Notch 1-4) are activated by five ligands (Jagged1, Jagged2, and Delta-like ligands 1, 3, and 4), responsible for the switch-on of downstream target genes, such as Hes1 and Hey1.…”

“…Notably, b-catenin is expressed in 58% of CCAs. In 8% of cases, b-catenin is mutated, which likely promotes the HPC compartment and is considered an early determinant in CCA-progression [41]. Additionally, Wnt expression is stimulated by commonly used progenitor markers, such as CD133 and EpCAM [54].…”