Cholangiocarcinoma: from molecular biology to treatment

Brito, Ana; Abrantes, Ana Margarida; Encarnação, João Crispim; Tralhão, José Guilherme; Botelho, Maria Filomena

doi:10.1007/s12032-015-0692-x

Cited by 41 publications

(38 citation statements)

References 62 publications

(135 reference statements)

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“…CCA accounts for 15–20% of the primary liver tumors, which are the second most common cause of cancer-related death worldwide, being responsible for around 9.1% of total deaths 1,2 . CCA still carries a dismal prognosis, with a median survival below 2 years, and a survival rate of less than 10% 3 . Furthermore, the incidence of iCCA is markedly increasing, especially in Western countries 4 .…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, several pathological conditions associated with chronic liver inflammation carry an increased risk to develop CCA, including infection with hepatobiliary flukes, hepatolithiasis, primary sclerosing cholangitis, and congenital malformations of the bile ducts (e.g., Caroli’s disease, choledochal cysts). It has now become clear that also patients with hepatitis B virus (HBV)- and HCV-related cirrhosis, as well as patients with metabolic syndrome, are at higher risk of developing iCCA 3,4,9 . Although CCA is commonly thought to originate from biliary epithelial cells (cholangiocytes), hepatic progenitor cells (HPCs) and mature hepatocytes have also been proposed as candidate cells of origin, particularly for the intrahepatic variant 4,8 .…”

Section: Introductionmentioning

confidence: 99%

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Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

et al. 2018

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The acquisition of invasive functions by tumor cells is a first and crucial step towards the development of metastasis, which nowadays represents the main cause of cancer-related death. Cholangiocarcinoma (CCA), a primary liver cancer originating from the biliary epithelium, typically develops intrahepatic or lymph node metastases at early stages, thus preventing the majority of patients from undergoing curative treatments, consistent with their very poor prognosis. As in most carcinomas, CCA cells gradually adopt a motile, mesenchymal-like phenotype, enabling them to cross the basement membrane, detach from the primary tumor, and invade the surrounding stroma. Unfortunately, little is known about the molecular mechanisms that synergistically orchestrate this pro-invasive phenotypic switch. Autocrine and paracrine signals (cyto/chemokines, growth factors, morphogens) permeating the tumor microenvironment undoubtedly play a prominent role in this context. Moreover, a number of recently identified signaling systems are currently drawing attention as putative mechanistic determinants of CCA cell invasion. They encompass transcription factors, protein kinases and phosphatases, ubiquitin ligases, adaptor proteins, and miRNAs, whose aberrant expression may result from either stochastic mutations or the abnormal activation of upstream pro-oncogenic pathways. Herein, we sought to summarize the most relevant molecules in this field, and to discuss their mechanism of action and potential prognostic relevance in CCA. Hopefully, a deeper knowledge of the molecular determinants of CCA invasiveness will help to identify clinically useful biomarkers and novel druggable targets, with the ultimate goal to develop innovative approaches to the management of this devastating malignancy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

et al. 2018

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“…3b). These chemokines are reportedly key cytokines in the pathogenesis of CCA and its proliferative effect [20][21][22]. These data suggested the critical role of cholangiocyte senescence and the subsequent secretion of SASP components in the progression of biliary tract cancers associated with PBM and intrahepatic cholelithiasis.…”

Section: Discussionmentioning

confidence: 97%

Protective effect of phosphatidylcholine on lysophosphatidylcholine‐induced cellular senescence in cholangiocyte

Ohigashi

Kanno

Sugiyama

et al. 2019

J Hepato Biliary Pancreat

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Background Pancreaticobiliary maljunction and intrahepatic gallstones are at a high risk for biliary malignancy. Lysophosphatidylcholine (LPC) is increased in the bile of these patients, and we have previously reported that LPC‐induced cytotoxicity causes senescence‐associated secretory phenotype (SASP) in cholangiocytes. We aimed to determine the protective effect of phosphatidylcholine (PC) on LPC‐induced cholangiocyte cytotoxicity. Methods MMNK‐1, a human immortalized cholangiocyte cell line was treated with LPC with or without PC. To assess the biological effects of SASP components on cholangiocarcinoma, HuH28 and HuCCT1 (human cholangiocarcinoma cell lines) were cultured in the conditioned media where MMNK‐1 cells treated with LPC. Results The presence of PC reduced reactive oxygen species generation and oxidative DNA damage in MMNK‐1 treated with LPC. Moreover, SA‐β‐gal activity was markedly downregulated by PC. The secretion of SASP components, including interleukin (IL)‐8, IL‐6, and C‐C motif chemokine ligand 2 was also substantially reduced in the presence of PC. Cellular proliferation and migration were enhanced in HuCCT1 and HuH28 cells when cultured in the conditioned media, and these observations were suppressed by simultaneous addition of PC. Conclusion PC protects cholangiocytes against LPC‐induced cytotoxicity and cellular senescence, suggesting its potential as a target for inhibiting LPC‐related carcinogenesis and its promotion.

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“…Non-surgical methods include systemic therapies with 5-fluorouracil, doxorubicin, cisplatin and mitomycin C (response rate of about 10-30%), combinations with gemcitabine or local radiotherapy (median survival=5-12 months), however, their benefit is very limited, a better result in survival is obtained with intra-arterial therapies (8,9,13).…”

Section: Discussionmentioning

confidence: 99%

Chemoembolization with Drug-eluting Microspheres Loaded with Doxorubicin for the Treatment of Cholangiocarcinoma

2017

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Abstract. Aim: To report clinical outcomes of transarterial chemoembolization (TACE) using drug-eluting beads (DEBs) loaded with doxorubicin for the treatment of unresectable intrahepatic cholangiocarcinoma (CCA). Patients and Methods: We treated 127 patients with doxorubicin via TACE. Inclusion criteria were: diagnosis of unresectable CCA; indication for TACE, performance status (PS) 0-2, >3 months of life expectancy, >18 years old, written consent. TACE was performed using DEBs for 109 (86%) patients and polythylene glycol drug-elutable microspheres (PEG) loaded with doxorubicin for 18 (14%) patients. Results: Tumor response of the whole sample of 127 patients was partial response (PR) in 19 (15%) patients, stable disease (SD) in 101 (80%) and progressive disease (PD) in seven (5%) 3 months after therapy, with no complete responses.There were differences between type of embolics: PR was 7% and 77%, SD was 88% and 8%, and PD was 5% and 15%, and the disease control rate was 95% and 85% in the DEB and PEG groups, respectively. Most frequent side-effects were: abdominal pain, fever, nausea, and transaminase rise. Conclusion: TACE was effective and safe for CCA treatment, with a high disease control rate. The best response of PEG-TACE was PR, whereas it was SD for DEB-TACE.About 10% of primary hepatic cancer is represented by cholangiocarcinoma (CCA), with a preferential distribution among men rather than women (1). CCA classification includes intrahepatic, perihilar and distal extrahepatic cancer (galbladder or coledocus). These groups have different biological characteristics, clinical diagnoses, and treatment management (2).Known risk factors for CCA include chronic inflammation, and injury of the bile tract, biliary lithiasis, and other novel risk factors such as obesity and hepatitis C virus infection (3). Over the past decades, CCA incidence and mortality has been increasing in Europe (4).Surgery is considered the only curative option for CCA, however, it is possible only for 27-30% of patients (5). Unresectable CCA has a poor prognosis, with a median survival of 3-6 months (6, 7). Systemic chemotherapy aims to reduce tumor growth and symptoms, and to improve the quality of life of patients with unresectable CCA, however, its benefits are poor, leading to an overall survival of about 1 year (8, 9). The combination of systemic chemotherapy with capecitabine and intra-arterial administration of toxic drugs is increasingly being used (10-12).Transarterial chemoembolization (TACE) allows the delivery of high concentration of chemotherapy selectively to the liver, in association with the embolization of the arteries afferent to the tumor (13-18). This method is achieving encouraging results in patients with CCA. Several studies with TACE for the therapy of unresectable CCA include mixed intrahepatic and extrahepatic CCA populations of only a small number of patients, for this reason it is difficult to have clear results on its efficacy. The purpose of this study was to report clinical outcomes of treatments of ...

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Cholangiocarcinoma: from molecular biology to treatment

Cited by 41 publications

References 62 publications

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

Protective effect of phosphatidylcholine on lysophosphatidylcholine‐induced cellular senescence in cholangiocyte

Chemoembolization with Drug-eluting Microspheres Loaded with Doxorubicin for the Treatment of Cholangiocarcinoma

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