Cell of origin in biliary tract cancers and clinical implications

Abstract

Biliary tract cancers (BTCs) are aggressive epithelial malignancies that can arise at any point of the biliary tree. Albeit rare, their incidence and mortality rates have been rising steadily over the past 40 years, highlighting the need to improve current diagnostic and therapeutic strategies. BTCs show high inter- and intra-tumour heterogeneity both at the morphological and molecular level. Such complex heterogeneity poses a substantial obstacle to effective interventions. It is widely accepted that the observed heterogeneity may be the result of a complex interplay of different elements, including risk factors, distinct molecular alterations and multiple potential cells of origin. The use of genetic lineage tracing systems in experimental models has identified cholangiocytes, hepatocytes and/or progenitor-like cells as the cells of origin of BTCs. Genomic evidence in support of the distinct cell of origin hypotheses is growing. In this review, we focus on recent advances in the histopathological subtyping of BTCs, discuss current genomic evidence and outline lineage tracing studies that have contributed to the current knowledge surrounding the cell of origin of these tumours.

Keywords: ARID1A, AT-rich interactive domain-containing protein 1A; BAP1, BRCA1-associated protein 1; BRAF, v-Raf murine sarcoma viral oncogene homolog B; BTC, biliary tract cancer; Biliary tract cancers; CCA, cholangiocarcinoma; CDKN2A/B, cyclin-dependent kinase inhibitor 2A/B; CK, cytokeratin; CLC, cholangiolocarcinoma; Cell of origin; Cholangiocarcinoma; CoH, Canal of Hering; DCR, disease control rate; ER, estrogen receptor; ERBB2/3, Erb-B2 Receptor Tyrosine Kinase 2/3; FGFR, fibroblast growth factor receptor; FGFR2, Fibroblast Growth Factor Receptor 2; GBC, gallbladder cancer; GEMM, genetically engineered mouse models; Genomics; HCC, hepatocellular carcinoma; HPCs, hepatic progenitor cells; IDH, isocitrate dehydrogenase; KRAS, Kirsten Rat Sarcoma Viral Oncogene Homolog; Lineage tracing; MET, Hepatocyte Growth Factor Receptor; MST1, Macrophage Stimulating 1; NA, not applicable; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NGS, next-generation sequencing; NR, not reported; NTRK, Neurotrophic Receptor Tyrosine Kinase 1; ORR, objective response rate; OS, overall survival; PBG, peribiliary gland; PFS, progression- free survival; PIK3CA, Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha; PLC, primary liver cancer; PRKACA/B, Protein Kinase CAMP-Activated Catalytic Subunit Alpha/Beta; PROM1, Prominin 1; PSC, primary sclerosing cholangitis; Personalized therapy; RNF43, Ring Finger Protein 43; SMAD4, SMAD Family Member 4; TBG, thyroid binding globulin; TP53, Tumor Protein P53; WHO, World Health Organization; dCCA, distal cholangiocarcinoma; eCCA, extrahepatic cholangiocarcinoma; iCCA, intrahepatic cholangiocarcinoma; mo, months; pCCA, perihilar cholangiocarcinoma.

Fig. 1

Biliary tract cancer classification, anatomical location and histopathological traits. Based on the anatomical site of origin, BTCs are classified into iCCA, pCCA, dCCA, and GBC. iCCA is defined as tumours located in the periphery of intrahepatic bile ductules and segmental ducts. iCCA together with HCC and mixed HCC-CCA represent the main types of primary liver cancers arising in the liver parenchyma. Mixed HCC-CCAs are a group of histologically heterogeneous tumours sharing unequivocal phenotypical characteristics of both HCC and iCCA. Multiple subtypes of mixed HCC-CCA have been identified, including classical HCC-CCA and CLC among others. Classical mixed HCC-CCA presents hepatocytic and cholangiocytic components, either admixed or as separate areas within the same tumour (displayed in the fig.); CLC presents malignant ductular-like structures embedded in a dense stroma (displayed in the figure). Among the extrahepatic CCA subtypes, pCCA arises in the right and/or left hepatic duct and/or at their junction, and dCCA involves the common bile duct. Representative histopathological images of different BTCs subtypes are included to ultimately highlight the heterogeneity in cellular phenotypes. BTCs, biliary tract cancers; CCA, cholangiocarcinoma; CLC, cholangiolocarcinoma; dCCA, distal cholangiocarcinoma; eCCA, extrahepatic cholangiocarcinoma; GBC, gallbladder cancer; HCC, hepatocellular carcinoma; iCCA, intrahepatic cholangiocarcinoma; pCCA, perihilar cholangiocarcinoma.

Fig. 2

Hepatobiliary stem cell niches. Schematic representation of the biliary system anatomy with emphasis on the location and structure of stem cell niches. In the adult liver, HPCs are postulated to be located within the CoH (purple circles) near the portal triads. HPCs are thought to have the potential to differentiate into hepatocytes and cholangiocytes. Mature hepatocytes and cholangiocytes have high self-renewal capability and are responsible for normal tissue turnover upon injury or oncogenic insult (represented as highlighted cells with red hallow). Biliary tree stem cell niches containing biliary-committed progenitor cells are located in the PBGs (pink circles). PBGs are occasionally observed as small evaginations of the bile duct epithelium at the level of the septal intrahepatic bile ducts and along the extrahepatic duct, containing less differentiated (in blue) to fully differentiated biliary cells (in green). CoH, canal of Hering; HPCs, hepatic progenitor cells; PBGs, peribiliary glands.

Fig. 3

Potential cells of origin of hepatobiliary cancers. Current evidence from histopathological, genomic and preclinical models suggest multiple potential cells of origin. HPCs or dedifferentiated hepatocytes can potentially generate liver tumours with biliary features. In addition, intermediate states of HPCs, such as biliary-committed precursors, may represent the cell of origin of CLC or iCCA with stem cell features. Furthermore, recent evidence supports the hypothesis that mature hepatocytes can transdifferentiate into biliary-like cells, leading to the development of iCCA. Finally, cholangiocyte lineage cells (precursor and/or mature cholangiocyte) are considered to be the common cell of origin of all anatomical subtypes of BTCs. BTCs, biliary tract cancers; CLC, cholangiolocarcinoma; dCCA, distal cholangiocarcinoma; HPCs, hepatic progenitor cells; iCCA, intrahepatic cholangiocarcinoma; GBC, gallbladder cancer; HCC, hepatocellular carcinoma; iCCA, intrahepatic cholangiocarcinoma; pCCA, perihilar cholangiocarcinoma.

Fig. 4

Lineage tracing promoter systems and related pathways involved in the onset of BTCs. Depending on the experimental setting and developmental stage, the Cre system may recombine floxed alleles in different cell types. The Cre^ERT system, a fusion of Cre and the tamoxifen-inducible domain of the estrogen receptor, enables spatiotemporal control, which has been crucial for manipulating genes in the adult liver. Induction of alterations in signalling pathways (black continuous arrows), for example activation of NOTCH and YAP signalling, together with oncogenic insults (i.e. Tp53 or Kras mutations) or liver injury, result in the malignant transformation of potential cells of origin (highlighted with red hallow). KRAS, Kirsten Rat Sarcoma Viral Oncogene Homolog; TP53, Tumor Protein P53.