Establishment and Characterization of Two Novel Cholangiocarcinoma Cell Lines

Zhang, Yanhua; Luo, Jingfeng; Dong, Xue; Yang, Fang; Zhang, Miaofeng; Zhao, Juanjuan; Wang, Qiangfeng; Zhou, Fei; Sun, Jihong; Yang, Xiaoming

doi:10.1245/s10434-019-07649-5

Cited by 10 publications

(8 citation statements)

References 41 publications

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“…Comparable to the HLA-ABC expression, CD29 was also enhanced on circulating EVs from CCA patients and markedly reduced by SIRT. Considering that CD29 is also expressed on CCA tumor cell lines [ 63 ] und can be used as a cancer stem cell marker [ 64 , 65 ], it has to be further investigated whether the CD29 expressing EVs originate from activated leukocytes or tumor cells. The fact that CD29 prior SIRT positively correlated with the administered activity dose might support rather the local deliberation of CD29 loaded EVs and post SIRT observed changes in CCA patients.…”

Section: Discussionmentioning

confidence: 99%

Selective Internal Radiotherapy Changes the Immune Profiles of Extracellular Vesicles and Their Immune Origin in Patients with Inoperable Cholangiocarcinoma

Haag

Manikkam

Kraft

et al. 2022

Cells

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The incidence of cholangiocellular carcinoma (CCA) is rising worldwide. As there are no specific early symptoms or specific markers of CCA, it is often diagnosed in later inoperable stages. Accumulating evidence underlines the importance of radiation therapy in the induction of antitumor immunity. The surface protein composition on extracellular vesicles (EVs) relates to originating cells and thus may play a role in vesicle function. We assessed immune profiles of EVs and their immune origin in patients with inoperable CCA prior and after selective internal radiotherapy (SIRT). A total of 47 CCA patients receiving SIRT and 12 healthy volunteers (HV) were included. Blood was withdrawn before therapy (pre T) and after T. EVs were purified from plasma by cluster of differentiation (CD)9-, CD63-, and CD81-immunobead isolation. To detect differently abundant surface markers, dynamic range and EVs input quality were assessed. A total of 37 EVs surface markers were measured by flow cytometry and correlated either with the administered activity dose (MBq) or with the interval until death (month). EVs phenotyping identified lymphocytes, B cells, NK cells, platelets, endothelial cells, leukocyte activation, B cell activation, T and B cell adhesion markers, stem/progenitor cells, and antigen-presenting cells (APC) as EVs-parenteral cells. CD4 and CD8 significantly declined, while other markers significantly increased in CCA patients pre T vs. HV. Platelets-deriving EVs significantly decreased, normalizing to levels of HV but still significantly increasing vs. HV post SIRT. B cells-deriving EVs significantly increased pre T vs. HV, positively correlating with administered activity dose. MHCII and CD40 EVs significantly increased pre SIRT and negatively correlated with administered activity dose, while EVs from antigen presenting cells and CD49e pre SIRT positively correlated with survival time after therapy. Increased levels of CD24 and CD44 in cancer pre T were significantly decreased post T. Among the heterogeneity of EVs that was demonstrated, in particular, B cells-deriving, MHCII, and CD40 positive or APC-deriving EVs need to be further studied for their diagnostic or prognostic relevance in clinical scenarios.

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Section: Discussionmentioning

confidence: 99%

Selective Internal Radiotherapy Changes the Immune Profiles of Extracellular Vesicles and Their Immune Origin in Patients with Inoperable Cholangiocarcinoma

Haag

Manikkam

Kraft

et al. 2022

Cells

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“…Furthermore, primary cholangiocytes possess the morphological and functional characteristics of the original tissue, but the primary sources are scarce and rapidly dedifferentiate in (two-dimensional) culture conditions, resulting in reduced FXR expression [ 33 ] that indicate the loss of specific functions including BA homeostasis [ 34 ]. Tumor-derived cell lines play an important role in studying cholangiocarcinoma biology and anticancer therapeutics [ 35 ]; however, without a defined function [ 36 ] they are not suitable to study drug toxicity. For this, the human iPSCs-derived cholangiocyte-like cells were used, but studies were hampered by time consuming and low efficiency processes [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Cholangiocyte organoids to study drug-induced injury

Wang,

Xing,

van der Laan

et al. 2024

Stem Cell Res Ther

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Background Drug induced bile duct injury is a frequently observed clinical problem leading to a wide range of pathological features. During the past decades, several agents have been identified with various postulated mechanisms of bile duct damage, however, mostly still poorly understood. Methods Here, we investigated the mechanisms of chlorpromazine (CPZ) induced bile duct injury using advanced in vitro cholangiocyte cultures. Intrahepatic cholangiocyte organoids (ICOs) were driven into mature cholangiocyte like cells (CLCs), which were exposed to CPZ under cholestatic or non-cholestatic conditions through the addition of a bile acid cocktail. Results CPZ caused loss of monolayer integrity by reducing expression levels of tight junction protein 1 (TJP1), E-cadherin 1 (CDH1) and lysyl oxidase homolog 2 (LOXL2). Loss of zonula occuludens-1 (ZO-1) and E-cadherin was confirmed by immunostaining after exposure to CPZ and rhodamine-123 leakage further confirmed disruption of the cholangiocyte barrier function. Furthermore, oxidative stress seemed to play a major role in the early damage response by CPZ. The drug also decreased expression of three main basolateral bile acid transporters, ABCC3 (ATP binding cassette subfamily C member 3), SLC51A/B (solute carrier family 51 subunit alpha/beta) and multidrug resistance transporter ABCB1 (ATP binding cassette subfamily B member 1), thereby contributing to bile acid accumulation. CPZ did not induce an inflammatory response by itself, but addition of TNFα revealed a synergistic effect. Conclusion These results show that ICOs present a model to identify toxic drugs affecting the bile ducts while providing mechanistic insights into hepatotoxicity.

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“…Furthermore, primary cholangiocytes possess the morphological and functional characteristics of the original tissue, but the primary sources are scarce and rapidly dedifferentiate in (two-dimensional) culture conditions, resulting in the shortage of FXR expression [32] that indicate the loss of speci c functions including BA homeostasis [33]. Tumor-derived cell lines play an important role in studying cholangiocarcinoma biology and anticancer therapeutics [34], however, without a de ned function [35] they are not suitable to study drug toxicity. For this, the human iPSCs-derived cholangiocyte-like cells were used, but studies were hampered by time consuming and low e ciency processes [36].…”

Section: Discussionmentioning

confidence: 99%

Cholangiocyte Organoids to Model Chlorpromazine-Induced Bile Duct Injury

Wang,

Xing,

Laan

et al. 2023

Preprint

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Background Drug induced bile duct injury is a frequently observed clinical problem leading to a wide range of pathological features. During the past decades, several agents have been identified with various postulated mechanisms of bile duct damage, however, mostly still poorly understood. Methods Here, we investigated the mechanisms of chlorpromazine(CPZ) induced bile duct injury using advanced in vitro cholangiocyte cultures. Intrahepatic cholangiocyte organoids (ICOs) were driven into mature cholangiocyte like cells (CLCs), which were exposed to CPZ under cholestatic or non-cholestatic conditions through the addition of a bile acid cocktail. Results CPZ caused loss of monolayer integrity by reducing expression levels of tight junction protein 1 (TJP1), E-cadherin 1 (CDH1) and lysyl oxidase homolog 2 (LOXL2). Loss of zonula occuludens-1 (ZO-1) and E-cadherin was confirmed by immunostaining after exposure to CPZ and rhodamine-123 leakage further confirmed disruption of the cholangiocyte barrier function. Furthermore, oxidative stress seemed to play a major role in the early damage response by CPZ. The drug also decreased expression of three main basolateral bile acid transporters, ABCC3 (ATP binding cassette subfamily C member 3), SLC51A/B (solute carrier family 51 subunit alpha/beta) and multidrug resistance transporter ABCB1 (ATP binding cassette subfamily B member 1), thereby contributing to bile acid accumulation. CPZ did not induce an inflammatory response by itself, but addition of TNFα revealed a synergistic effect. Conclusion These results show that ICOs present a model to identify toxic drugs affecting the bile ducts while providing mechanistic insights into hepatotoxicity.

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Establishment and Characterization of Two Novel Cholangiocarcinoma Cell Lines

Cited by 10 publications

References 41 publications

Selective Internal Radiotherapy Changes the Immune Profiles of Extracellular Vesicles and Their Immune Origin in Patients with Inoperable Cholangiocarcinoma

Selective Internal Radiotherapy Changes the Immune Profiles of Extracellular Vesicles and Their Immune Origin in Patients with Inoperable Cholangiocarcinoma

Cholangiocyte organoids to study drug-induced injury

Cholangiocyte Organoids to Model Chlorpromazine-Induced Bile Duct Injury

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