Current Advances in Basic and Translational Research of Cholangiocarcinoma.

Keisaku Sato,Shannon Glaser,Gianfranco Alpini,Wenjun Zhang,Burcin Ekser,Leonardo Baiocchi,Heather Francis,Lindsey Kennedy

doi:10.3390/cancers13133307

Abstract

Simple SummaryCholangiocarcinoma (CCA) is highly malignant biliary tract cancer, which is characterized by limited treatment options and poor prognosis. Basic science studies to seek therapies for CCA are also limited due to lack of gold-standard experimental models and heterogeneity of CCA resulting in various genetic alterations and origins of tumor cells. Recent studies have developed new experimental models and techniques that may facilitate CCA studies leading to the development of novel treatments. This review summarizes the update in current basic studies of CCA.Cholangiocarcinoma (CCA) is a type of biliary tract cancer emerging from the biliary tree. CCA is the second most common primary liver cancer after hepatocellular carcinoma and is highly aggressive resulting in poor prognosis and patient survival. Treatment options for CCA patients are limited since early diagnosis is challenging, and the efficacy of chemotherapy or radiotherapy is also limited because CCA is a heterogeneous malignancy. Basic research is important for CCA to establish novel diagnostic testing and more effective therapies. Previous studies have introduced new techniques and methodologies for animal models, in vitro models, and biomarkers. Recent experimental strategies include patient-derived xenograft, syngeneic mouse models, and CCA organoids to mimic heterogeneous CCA characteristics of each patient or three-dimensional cellular architecture in vitro. Recent studies have identified various novel CCA biomarkers, especially non-coding RNAs that were associated with poor prognosis or metastases in CCA patients. This review summarizes current advances and limitations in basic and translational studies of CCA.

Highlights

Cholangiocarcinoma (CCA) emerges from the biliary epithelium and is the second most common primary liver cancer after hepatocellular carcinoma (HCC) [1]
Xenograft mouse models established by transplantation of human CCA cell lines usually do not generate the tumor microenvironment, which is often observed in CCA patients [33]
Syngeneic CCA models may be suitable as animal models for studies of CCA tumor microenvironment

Summary

Introduction

Cholangiocarcinoma (CCA) emerges from the biliary epithelium and is the second most common primary liver cancer after hepatocellular carcinoma (HCC) [1]. Whole-exome sequencing for 318 iCCA patients identified 32 mutated genes associated with poor survival rates, which included TP53 and KRAS [25]. This study showed that a high percentage of cHCC-CCA tumors expressed Nestin compared to HCC or iCCA, and positivity of Nestin expression was associated with poor survival rates, suggesting that Nestin could be useful as a novel biomarker for diagnosis testing of cHCC-CCA [27]. Analysis of gene expression and gene methylation for CCA samples using datasets obtained from Gene Expression Omnibus (GEO) database found 98 hypermethylated, downregulated genes and 93 hypomethylated, upregulated genes [29] Another analysis using GEO datasets showed that CCA patients with widespread hypermethylation of promoter-related CpG sites suffered unfavorable prognosis with poor survival rates [30]. These studies show that whole-genome screening and landscape of mutations, genome, transcriptome, and methylation may lead to identification of novel biomarkers and therapeutic targets of CCA; a genomewide association study for CCA is still not available to date, which may provide novel understandings of genetic variations associated with CCA

Animal Models

In Vitro Models

Biomarkers

Emerging Roles of Gut Microbiota in CCA

Findings

Conclusions and Future Perspectives