Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

Ahn, Daniel H.; Bekaii‐Saab, Tanios

doi:10.21037/jgo.2016.10.01

Cited by 57 publications

(45 citation statements)

References 83 publications

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“…At present, sorafenib is the reference drug used in the pharmacological treatment of HCC. The high proportion of genetic alterations in critical signaling pathways involved in cell proliferation in CCA has led to an interest in the development of clinical trials investigating targeted therapies including sorafenib . However, data on the effectiveness of sorafenib, and other TKIs, in patients with CCA are controversial, reporting both beneficial effect and poor activity against this type of liver cancer .…”

Section: Discussionmentioning

confidence: 99%

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Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy

et al. 2019

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Although the multi-tyrosine kinase inhibitor sorafenib is useful in the treatment of several cancers, cholangiocarcinoma (CCA) is refractory to this drug. Among other mechanisms of chemoresistance, impaired uptake through human organic cation transporter type 1 (hOCT1) (gene SLC22A1) has been suggested. Here we have investigated the events accounting for this phenotypic characteristic and have evaluated the interest of selective gene therapy strategies to overcome this limitation. Gene expression and DNA methylation of SLC22A1 were analyzed using intrahepatic (iCCA) and extrahepatic (eCCA) biopsies (Copenhagen and Salamanca cohorts; n = 132) and The Cancer Genome Atlas (TCGA)-CHOL (n = 36). Decreased hOCT1 mRNA correlated with hypermethylation status of the SLC22A1 promoter. Treatment of CCA cells with decitabine (demethylating agent) or butyrate (histone deacetylase inhibitor) restored hOCT1 expression and increased sorafenib uptake. MicroRNAs able to induce hOCT1 mRNA decay were analyzed in paired samples of TCGA-CHOL (n = 9) and Copenhagen (n = 57) cohorts. Consistent upregulation in tumor tissue was found for miR-141 and miR-330. High proportion of aberrant hOCT1 mRNA splicing in CCA was also seen. Lentiviral-mediated transduction of eCCA (EGI-1 and TFK-1) and iCCA (HuCCT1) cells with hOCT1 enhanced sorafenib uptake and cytotoxic effects. In chemically induced CCA in rats, reduced rOct1 expression was accompanied by impaired sorafenib uptake. In xenograft models of eCCA cells implanted in mouse liver, poor response to sorafenib was observed. However, tumor growth was markedly reduced by cotreatment with sorafenib and adenoviral vectors encoding hOCT1 under the control of the BIRC5 promoter, a gene highly up-regulated in CCA. Conclusion: The reason for impaired hOCT1-mediated sorafenib uptake by CCA is multifactorial. Gene therapy capable of selectively inducing hOCT1 in tumor cells can be considered a potentially useful chemosensitization strategy to improve the response of CCA to sorafenib. (Hepatology 2019;70:1246-1261).

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Section: Discussionmentioning

confidence: 99%

“…Biliary tract cancers are a type of heterogeneous tumors that include cholangiocarcinoma (CCA), both intrahepatic (iCCA) and extrahepatic (eCCA), and gallbladder cancer, with diverse phenotypic characteristics . CCA, whose incidence is increasing worldwide, is currently the second most frequent primary hepatic malignancy after hepatocellular carcinoma (HCC).…”

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confidence: 99%

Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy

et al. 2019

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“…Their results are inconsistent with ours for the following reasons. First, BTC is a heterogeneous group of diseases consisting of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer; each anatomic group within BTC behaves as a distinct disease, with different prognoses and outcomes . Second, Harder included only the advanced BTC (unresectable ICC patients), which is quite different from our study cohort (resectable ICC patients following hepatectomy).…”

Section: Discussionmentioning

confidence: 99%

ID3 Promotes Stem Cell Features and Predicts Chemotherapeutic Response of Intrahepatic Cholangiocarcinoma

et al. 2019

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Cancer stem cells contribute to a high rate of recurrence and chemotherapeutic resistance in many types of cancer, including intrahepatic cholangiocarcinoma (ICC). Inhibitor of differentiation 3 (ID3) has been reported to promote cancer stem cells, but its role in ICC is obscure. In this study, we identified that ID3 is highly expressed in human ICC tissues compared with matched normal tissues and correlates with poor prognosis. Functional studies demonstrate that ID3 is required for stemness maintenance in cholangiocarcinoma both in vitro and in vivo . Consistent with the regulation of cancer stem cell features by ID3, transgenic expression of ID3 enhances chemoresistance of cholangiocarcinoma cells. Moreover, we found that ICC patients with low ID3 levels benefited from postoperative transarterial chemoembolization, whereas patients with high ID3 levels did not, indicating the significance of ID3 in individualized ICC therapy. Mechanistically, ID3 could interact with E47 and block E47 recruitment to the promoter of β-catenin, which leads to activation of Wnt/β-catenin signaling. Conclusion: Our results show that ID3 could promote the stemness of ICC by increasing the transcriptional activity of β-catenin and could serve as a biomarker in predicting ICC patients' response to adjuvant chemotherapeutics.

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“…Compared with its counterpart occupied in the liver (roughly 5%‐10% of total cholangiocarcinomas), which is currently classified as primary liver cancer . EBDC is unique not only from the perspective of anatomy, but also from epidemiology, pathogenesis and its further development compared with other malignancies . Over 12 000 cases of extrahepatic biliary tract cancers are diagnosed annually in the United States, more than 60% are gallbladder cancers.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 EBDC is unique not only from the perspective of anatomy, but also from epidemiology, pathogenesis and its further development compared with other malignancies. 5,6 Over 12 000 cases of extrahepatic biliary tract cancers are diagnosed annually in the United States, more than 60% are gallbladder cancers. The rest, approximately 3000 cases per year, are extrahepatic cholangiocarcinomas.…”

Section: Introductionmentioning

confidence: 99%

Pattern of distant metastases in primary extrahepatic bile‐duct cancer: A SEER‐based study

Wang

Chen

et al. 2018

Cancer Medicine

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Extrahepatic bile duct cancer (EBDC) is a combined type of malignancy mainly consisting of extrahepatic cholangiocarcinoma and gallbladder cancer. Clinically, it is featured with latent symptoms and early metastasis, leading to a poor prognosis. Therefore, this cohort study aimed to depict the possible metastatic patterns of EBDC of diverse sub‐types and evaluate the prognostic significance of diverse metastatic destinations with data from the clinical database. Relevant data of total 4061 confirmed EBDC patients diagnosed between 2010 and 2013 from the Surveillance, Epidemiology and End Results (SEER) database was obtained. We applied t test to describe the baseline data of patients included and used chi‐square test to compare the distribution of distant metastatic sites. We further adopted odds ratio assess the combined metastatic patterns and compared survival difference of patients with different distal metastasis organ by Kaplan‐Meier analysis. We identified totally 4061 patients over 18 years old diagnosed with extrahepatic bile tract malignancies between 2010 and 2013, with clear metastatic status and follow‐up data, without primary malignancies. Liver and distant lymph (DL) are the two most common sites as a single metastasis organ. In combined metastasis patterns, bi‐organ is more frequent than the other types. Lung is the organ preferentially for bi‐organ metastasis, while bone and distant lymph similarly intend to co‐metastasize with brain. Distal metastasis in EBDC patients indicates an extremely poor prognosis. According to the final analysis results, malignancies in extrahepatic bile duct exhibit similar metastatic patterns, suggesting that we can regard them as a unity to assess its development. Profound differences exist in distribution of distant extrahepatic metastatic sites and their combinations. Results from our studies would provide some information for follow‐up strategies and future studies.

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Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

Cited by 57 publications

References 83 publications

Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy

Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy

ID3 Promotes Stem Cell Features and Predicts Chemotherapeutic Response of Intrahepatic Cholangiocarcinoma

Pattern of distant metastases in primary extrahepatic bile‐duct cancer: A SEER‐based study

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