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Liu B, Liu W, Xu M, Zhao T, Zhou B, Zhou R, Zhu Z, Chen X, Bao Z, Wang K, Li H. Drug delivery systems based on mesoporous silica nanoparticles for the management of hepatic diseases. Acta Pharm Sin B 2025; 15:809-833. [PMID: 40177563 PMCID: PMC11959912 DOI: 10.1016/j.apsb.2024.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 11/18/2024] [Accepted: 11/20/2024] [Indexed: 04/05/2025] Open
Abstract
The liver performs multiple life-sustaining functions. Hepatic diseases, including hepatitis, cirrhosis, and hepatoma, pose significant health and economic burdens globally. Along with the advances in nanotechnology, mesoporous silica nanoparticles (MSNs) exhibiting diversiform size and shape, distinct morphological properties, and favorable physico-chemical features have become an ideal choice for drug delivery systems and inspire alternative thinking for the management of hepatic diseases. Initially, we introduce the physiological structure of the liver and highlight its intrinsic cell types and correlative functions. Next, we detail the synthesis methods and physicochemical properties of MSNs and their capacity for controlled drug loading and release. Particularly, we discuss the interactions between liver and MSNs with respect to the passive targeting mechanisms of MSNs within the liver by adjusting their particle size, pore diameter, surface charge, hydrophobicity/hydrophilicity, and surface functionalization. Subsequently, we emphasize the role of MSNs in regulating liver pathophysiology, exploring their value in addressing liver pathological states, such as tumors and inflammation, combined with multi-functional designs and intelligent modes to enhance drug targeting and minimize side effects. Lastly, we put forward the problems, challenges, opportunities, as well as clinical translational issues faced by MSNs in the management of liver diseases.
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Affiliation(s)
- Boyan Liu
- School of Pharmacy, China Medical University, Shenyang 110122, China
- China Medical University and Queen University of Belfast Joint College, China Medical University, Shenyang 110122, China
| | - Wenshi Liu
- Department of Organ Transplantation and Hepatobiliary, the First Hospital of China Medical University, Shenyang 110001, China
| | - Miao Xu
- School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Tongyi Zhao
- School of Pharmacy, China Medical University, Shenyang 110122, China
- China Medical University and Queen University of Belfast Joint College, China Medical University, Shenyang 110122, China
| | - Bingxin Zhou
- School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Ruilin Zhou
- School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Ze Zhu
- School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Xuchun Chen
- Department of Organ Transplantation and Hepatobiliary, the First Hospital of China Medical University, Shenyang 110001, China
| | - Zhiye Bao
- Department of Organ Transplantation and Hepatobiliary, the First Hospital of China Medical University, Shenyang 110001, China
| | - Keke Wang
- Department of Pharmacy, the First Hospital of China Medical University, Shenyang 110001, China
| | - Heran Li
- School of Pharmacy, China Medical University, Shenyang 110122, China
- China Medical University and Queen University of Belfast Joint College, China Medical University, Shenyang 110122, China
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Liu H, Lan T, Cai YS, Lyu YH, Zhu J, Xie SN, Hu FJ, Liu C, Wu H. Predicting prognosis in intrahepatic cholangiocarcinoma by the histopathological features. Asian J Surg 2024; 47:2589-2597. [PMID: 38604849 DOI: 10.1016/j.asjsur.2024.03.085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 12/23/2023] [Accepted: 03/06/2024] [Indexed: 04/13/2024] Open
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is a highly heterogeneous liver tumor. The associations between histopathological feature and prognosis of ICC are limited. The present study aimed to investigate the prognostic significance of glandular structure and tumor budding in ICC. METHODS Patients received radical hepatectomy for ICC were included. Glandular structure and tumor budding were detected by Hematoxylin-eosin staining. The Kaplan-Meier method and the Cox proportional hazards regression model were used to calculate the survival and hazard ratio. Based on the results of multivariate analysis, nomograms of OS and DFS were constructed. C-index and Akaike information criterion (AIC) were used to assess accuracy of models. RESULTS A total of 323 ICC patients who underwent surgery were included in our study. Glandular structure was associated with worse overall survival (OS) [hazard ratio (HR): 2.033, 95% confidence interval (CI): 1.047 to 3.945] and disease-free survival (DFS) [HR: 1.854, 95% CI: 1.082 to 3.176]. High tumor budding was associated with worse DFS [HR: 1.636, 95%CI: 1.060 to 2.525]. Multivariate analysis suggested that glandular structure, tumor number, lymph node metastasis, and CA19-9 were independent risk factors for OS. Independent predictor factors for DFS were tumor budding, glandular structure, tumor number, and lymph node metastasis. The c-index (0.641 and 0.642) and AIC (957.69 and 1188.52) showed that nomograms of OS and DFS have good accuracy. CONCLUSION High tumor budding and glandular structure are two important histopathological features that serve as prognostic factors for ICC patients undergoing hepatectomy.
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Affiliation(s)
- Hu Liu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tian Lan
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yun-Shi Cai
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ying-Hao Lyu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiang Zhu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Si-Nan Xie
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Feng-Juan Hu
- The Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chang Liu
- Division of Liver, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Department of Minimal Invasive Surgery, Shangjin Nanfu Hospital, Chengdu, 610037, China.
| | - Hong Wu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China; Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Cheo FY, Chan KS, Shelat VG. Outcomes of liver resection in hepatitis C virus-related intrahepatic cholangiocarcinoma: A systematic review and meta-analysis. World J Virol 2024; 13:88946. [PMID: 38616852 PMCID: PMC11008402 DOI: 10.5501/wjv.v13.i1.88946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 11/10/2023] [Accepted: 12/28/2023] [Indexed: 03/11/2024] Open
Abstract
BACKGROUND Cholangiocarcinoma is the second most common primary liver malignancy. Its incidence and mortality rates have been increasing in recent years. Hepatitis C virus (HCV) infection is a risk factor for development of cirrhosis and cholangiocarcinoma. Currently, surgical resection remains the only curative treatment option for cholangiocarcinoma. We aim to study the impact of HCV infection on outcomes of liver resection (LR) in intrahepatic cholangiocarcinoma (ICC). AIM To study the outcomes of curative resection of ICC in patients with HCV (i.e., HCV+) compared to patients without HCV (i.e., HCV-). METHODS We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies to assess the outcomes of LR in ICC in HCV+ patients compared to HCV- patients in tertiary care hospitals. PubMed, EMBASE, The Cochrane Library and Scopus were systematically searched from inception till August 2023. Included studies were RCTs and non-RCTs on patients ≥ 18 years old with a diagnosis of ICC who underwent LR, and compared outcomes between patients with HCV+ vs HCV-. The primary outcomes were overall survival (OS) and recurrence-free survival. Secondary outcomes include perioperative mortality, operation duration, blood loss, intrahepatic and extrahepatic recurrence. RESULTS Seven articles, published between 2004 and 2021, fulfilled the selection criteria. All of the studies were retrospective studies. Age, incidence of male patients, albumin, bilirubin, platelets, tumor size, incidence of multiple tumors, vascular invasion, bile duct invasion, lymph node metastases, and stage 4 disease were comparable between HCV+ and HCV- group. Alanine transaminase [MD 22.20, 95%confidence interval (CI): 13.75, 30.65, P < 0.00001] and aspartate transaminase levels (MD 27.27, 95%CI: 20.20, 34.34, P < 0.00001) were significantly higher in HCV+ group compared to HCV- group. Incidence of cirrhosis was significantly higher in HCV+ group [odds ratio (OR) 5.78, 95%CI: 1.38, 24.14, P = 0.02] compared to HCV- group. Incidence of poorly differentiated disease was significantly higher in HCV+ group (OR 2.55, 95%CI: 1.34, 4.82, P = 0.004) compared to HCV- group. Incidence of simultaneous hepatocellular carcinoma lesions was significantly higher in HCV+ group (OR 8.31, 95%CI: 2.36, 29.26, P = 0.001) compared to HCV- group. OS was significantly worse in the HCV+ group (hazard ratio 2.05, 95%CI: 1.46, 2.88, P < 0.0001) compared to HCV- group. CONCLUSION This meta-analysis demonstrated significantly worse OS in HCV+ patients with ICC who underwent curative resection compared to HCV- patients.
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Affiliation(s)
- Feng Yi Cheo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Kai Siang Chan
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - Vishal G Shelat
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
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Li Z, Gao Q, Wu Y, Ma X, Wu F, Luan S, Chen S, Shao S, Shen Y, Zhang D, Feng F, Yuan L, Wei S. HBV infection effects prognosis and activates the immune response in intrahepatic cholangiocarcinoma. Hepatol Commun 2024; 8:e0360. [PMID: 38206204 PMCID: PMC10786594 DOI: 10.1097/hc9.0000000000000360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 11/08/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND The impact of HBV infection on the prognosis of patients with intrahepatic cholangiocarcinoma (ICC) remains uncertain, and the underlying mechanism has not been elucidated. This study aims to explore the potential mechanism via clinical perspectives and immune features. METHODS We retrospectively reviewed 1308 patients with ICC treated surgically from January 2007 to January 2015. Then, we compared immune-related markers using immunohistochemistry staining to obtain the gene expression profile GSE107943 and related literature for preliminary bioinformatics analysis. Subsequently, we conducted a drug sensitivity assay to validate the role of TNFSF9 in the ICC organoid-autologous immune cell coculture system and in the patient-derived organoids-based xenograft platform. RESULTS The analysis revealed that tumors in patients without HBV infection exhibited greater size and a higher likelihood of lymphatic metastasis, tumor invasion, and relapse. After resection, HBV-infected patients had longer survival time than uninfected patients (p<0.01). Interestingly, the expression of immune-related markers in HBV-positive patients with ICC was higher than that in uninfected patients (p<0.01). The percentage of CD8+ T cells in HBV-positive tissue was higher than that without HBV infection (p<0.05). We screened 21 differentially expressed genes and investigated the function of TNFSF9 through bioinformatics analyses. The expression of TNFSF9 in ICC organoids with HBV infection was lower than that in organoids without HBV infection. The growth of HBV-negative ICC organoids was significantly inhibited by inhibiting the expression of TNFSF9 with a neutralizing antibody. Additionally, the growth rate was faster in HbsAg (-) ICC patient-derived organoids-based xenograft model than in HbsAg (+) group. CONCLUSIONS The activation of the immune response induced by HBV infection makes the prognosis of HBV-positive patients with ICC differ from that of uninfected patients.
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Affiliation(s)
- Zhizhen Li
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Soochow University, Soochow, China
- Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Qingxiang Gao
- Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Yingjun Wu
- Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Xiaoming Ma
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Soochow University, Soochow, China
| | - Fangyan Wu
- Shanghai OneTar Biomedicine Co., Ltd., Shanghai, China
| | - Siyu Luan
- Shanghai OneTar Biomedicine Co., Ltd., Shanghai, China
| | - Sunrui Chen
- Shanghai OneTar Biomedicine Co., Ltd., Shanghai, China
| | - Siyuan Shao
- Shanghai OneTar Biomedicine Co., Ltd., Shanghai, China
| | - Yang Shen
- Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Ding Zhang
- Department of Medical, 3D Medicines Inc., Shanghai, China
| | - Feiling Feng
- Department of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Lei Yuan
- Department of Hepatobiliary Surgery, Quzhou People's Hospital, Quzhou, Zhejiang, China
| | - Shaohua Wei
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Soochow University, Soochow, China
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Chen Y, Chen J, Yang C, Wu Y, Wei H, Duan T, Zhang Z, Long L, Jiang H, Song B. Preoperative prediction of cholangiocyte phenotype hepatocellular carcinoma on contrast-enhanced MRI and the prognostic implication after hepatectomy. Insights Imaging 2023; 14:190. [PMID: 37962669 PMCID: PMC10645671 DOI: 10.1186/s13244-023-01539-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 10/13/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) expressing cytokeratin (CK) 7 or CK19 has a cholangiocyte phenotype that stimulates HCC proliferation, metastasis, and sorafenib therapy resistance This study aims to noninvasively predict cholangiocyte phenotype-positive HCC and assess its prognosis after hepatectomy. METHODS Between January 2010 and May 2022, preoperative contrast-enhanced MRI was performed on consecutive patients who underwent hepatectomy and had pathologically confirmed solitary HCC. Two abdominal radiologists separately assessed the MRI features. A predictive model for cholangiocyte phenotype HCC was created using logistic regression analysis and five-fold cross-validation. A receiver operating characteristic curve was used to calculate the model performance. Kaplan-Meier and log-rank methods were used to evaluate survival outcomes. RESULTS In total, 334 patients were included in this retrospective study. Four contrast-enhanced MRI features, including "rim arterial phase hyperenhancement" (OR = 5.9, 95% confidence interval [CI]: 2.9-12.0, 10 points), "nodule in nodule architecture" (OR = 3.5, 95% CI: 2.1-5.9, 7 points), "non-smooth tumor margin" (OR = 1.6, 95% CI: 0.8-2.9, 3 points), and "non-peripheral washout" (OR = 0.6, 95% CI: 0.3-1.0, - 3 points), were assigned to the cholangiocyte phenotype HCC prediction model. The area under the curves for the training and independent validation set were 0.76 and 0.73, respectively. Patients with model-predicted cholangiocyte phenotype HCC demonstrated lower rates of recurrence-free survival (RFS) and overall survival (OS) after hepatectomy, with an estimated median RFS and OS of 926 vs. 1565 days (p < 0.001) and 1504 vs. 2960 days (p < 0.001), respectively. CONCLUSIONS Contrast-enhanced MRI features can be used to predict cholangiocyte phenotype-positive HCC. Patients with pathologically confirmed or MRI model-predicted cholangiocyte phenotype HCC have a worse prognosis after hepatectomy. CRITICAL RELEVANCE STATEMENT Four contrast-enhanced MRI features were significantly associated with cholangiocyte phenotype HCC and a worse prognosis following hepatectomy; these features may assist in predicting prognosis after surgery and improve personalized treatment decision-making. KEY POINTS • Four contrast-enhanced MRI features were significantly associated with cholangiocyte phenotype HCC. • A noninvasive cholangiocyte phenotype HCC predictive model was established based on MRI features. • Patients with cholangiocyte phenotype HCC demonstrated a worse prognosis following hepatic resection.
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Affiliation(s)
- Yidi Chen
- Department of Radiology, West China Hospital, Sichuan University, Guoxue Road No. 37, Chengdu, 610041, Sichuan, China
| | - Jie Chen
- Department of Radiology, West China Hospital, Sichuan University, Guoxue Road No. 37, Chengdu, 610041, Sichuan, China
| | - Chongtu Yang
- Department of Radiology, West China Hospital, Sichuan University, Guoxue Road No. 37, Chengdu, 610041, Sichuan, China
| | - Yuanan Wu
- Big Data Research Center, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Hong Wei
- Department of Radiology, West China Hospital, Sichuan University, Guoxue Road No. 37, Chengdu, 610041, Sichuan, China
| | - Ting Duan
- Department of Radiology, West China Hospital, Sichuan University, Guoxue Road No. 37, Chengdu, 610041, Sichuan, China
| | - Zhen Zhang
- Department of Radiology, West China Hospital, Sichuan University, Guoxue Road No. 37, Chengdu, 610041, Sichuan, China
| | - Liling Long
- Department of Radiology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Hanyu Jiang
- Department of Radiology, West China Hospital, Sichuan University, Guoxue Road No. 37, Chengdu, 610041, Sichuan, China.
| | - Bin Song
- Department of Radiology, West China Hospital, Sichuan University, Guoxue Road No. 37, Chengdu, 610041, Sichuan, China.
- Department of Radiology, Sanya People's Hospital, Sanya, Hainan, China.
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d'Abrigeon C, McNamara MG, Le Sourd S, Lamarca A, Lièvre A, Bourien H, Peinoit A, Uguen T, Hubner RA, Valle JW, Edeline J. Influence of cirrhosis on outcomes of patients with advanced intrahepatic cholangiocarcinoma receiving chemotherapy. Br J Cancer 2023; 129:1766-1772. [PMID: 37813958 PMCID: PMC10667219 DOI: 10.1038/s41416-023-02460-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 09/18/2023] [Accepted: 09/29/2023] [Indexed: 10/11/2023] Open
Abstract
BACKGROUND Cirrhosis is a risk factor for intrahepatic cholangiocarcinoma (iCC). However, its exact prevalence is uncertain and its impact on the management of advanced disease is not established. METHODS Retrospective analysis of patients treated with systemic chemotherapy for advanced iCC in the 1st-line setting at 2 tertiary cancer referral centres. Cirrhosis was diagnosed based on at least one element prior to any treatment: pathological diagnosis, baseline platelets <150 × 109/L, portal hypertension and/or dysmorphic liver on imaging. RESULTS In the cohort of patients (n = 287), 82 (28.6%) had cirrhosis (45 based on pathological diagnosis). Patients with cirrhosis experienced more grade 3/4 haematologic toxicity (44% vs 22%, respectively, P = 0.001), and more grade 3/4 non-haematologic toxicity (34% vs 14%, respectively, P = 0.001) than those without. The overall survival (OS) was significantly shorter in patients with cirrhosis: median 9.1 vs 13.1 months for those without (HR = 1.56 [95% CI: 1.19-2.05]); P = 0.002), confirmed on multivariable analysis (HR = 1.48 [95% CI: 1.04-2.60]; P = 0.028). CONCLUSION Cirrhosis was relatively common in patients with advanced iCC and was associated with increased chemotherapy-induced toxicity and shorter OS. Formal assessment and consideration of cirrhosis in therapeutic management is recommended.
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Affiliation(s)
| | - Mairéad G McNamara
- Division of Cancer Sciences, University of Manchester/Department of Medical Oncology, The Christie NHS Foundation, Manchester, UK
| | - Samuel Le Sourd
- Department of Medical Oncology, Centre Eugène Marquis, Rennes, France
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation, Manchester/Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Astrid Lièvre
- Department of Gastroenterology, CHU Pontchaillou, Inserm U1242, COSS (Chemistry Oncogenesis Stress Signaling), Rennes 1 University, Rennes, France
| | - Héloïse Bourien
- Department of Medical Oncology, Centre Eugène Marquis, Rennes, France
| | - Alexandre Peinoit
- Department of Medical Oncology, Centre Eugène Marquis, Rennes, France
| | - Thomas Uguen
- Department of Hepatology, CHU Pontchaillou, Rennes, France
| | - Richard A Hubner
- Department of Medical Oncology, The Christie NHS Foundation, Manchester/Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Juan W Valle
- Division of Cancer Sciences, University of Manchester/Department of Medical Oncology, The Christie NHS Foundation, Manchester, UK
| | - Julien Edeline
- Department of Medical Oncology, Centre Eugène Marquis, Rennes, France.
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Liu JQ, Wang J, Huang XL, Liang TY, Zhou X, Mo ST, Xie HX, Yang KJ, Zhu GZ, Su H, Liao XW, Long LL, Peng T. A radiomics model based on magnetic resonance imaging to predict cytokeratin 7/19 expression and liver fluke infection of hepatocellular carcinoma. Sci Rep 2023; 13:17553. [PMID: 37845287 PMCID: PMC10579381 DOI: 10.1038/s41598-023-44773-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/12/2023] [Indexed: 10/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC with liver fluke infection could harbor unique biological behaviors. This study was aimed at investigating radiomics features of HCC with liver fluke infection and establishing a model to predict the expression of cytokeratin 7 (CK7) and cytokeratin 19 (CK19) as well as prognosis at the same time. A total of 134 HCC patients were included. Gadoxetic acid-enhanced magnetic resonance imaging (MRI) images of all patients were acquired. Radiomics features of the tumor were extracted and then data dimensionality was reduced. The radiomics model was established to predict liver fluke infection and the radiomics score (Radscore) was calculated. There were 11 features in the four-phase combined model. The efficiency of the combined model increased significantly compared to each single-phase MRI model. Radscore was an independent predictor of liver fluke infection. It was also significantly different between different expression of CK7/ CK19. Meanwhile, liver fluke infection was associated with CK7/CK19 expression. A cut-off value was set up and all patients were divided into high risk and low risk groups of CK7/CK19 positive expression. Radscore was also an independent predictor of these two biomarkers. Overall survival (OS) and recurrence free survival (RFS) of negative liver fluke infection group were significantly better than the positive group. OS and RFS of negative CK7 and CK19 expression were also better, though not significantly. Positive liver fluke infection and CK19 expression prediction groups harbored significantly worse OS and RFS, survival of positive CK7 expression prediction was unsatisfying as well. A radiomics model was established to predict liver fluke infection among HCC patients. This model could also predict CK7 and CK19 expression. OS and RFS could be foreseen by this model at the same time.
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Affiliation(s)
- Jun-Qi Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Rd. 6#, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Jing Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Rd. 6#, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xia-Ling Huang
- Department of Radiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Tian-Yi Liang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Rd. 6#, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Rd. 6#, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Shu-Tian Mo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Rd. 6#, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Hai-Xiang Xie
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Rd. 6#, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Ke-Jian Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Rd. 6#, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Guang-Zhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Rd. 6#, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Hao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Rd. 6#, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xi-Wen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Rd. 6#, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Li-Ling Long
- Department of Radiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Rd. 6#, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China.
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China.
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Ariño S, Aguilar-Bravo B, Coll M, Lee WY, Peiseler M, Cantallops-Vilà P, Sererols-Viñas L, Martínez-García de la Torre RA, Martínez-Sánchez C, Pedragosa J, Zanatto L, Gratacós-Ginès J, Pose E, Blaya D, Almodóvar X, Fernández-Fernández M, Ruiz-Blázquez P, Lozano JJ, Affo S, Planas AM, Ginès P, Moles A, Kubes P, Sancho-Bru P. Ductular reaction-associated neutrophils promote biliary epithelium proliferation in chronic liver disease. J Hepatol 2023; 79:1025-1036. [PMID: 37348790 PMCID: PMC10585421 DOI: 10.1016/j.jhep.2023.05.045] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 05/22/2023] [Accepted: 05/30/2023] [Indexed: 06/24/2023]
Abstract
BACKGROUND & AIMS Ductular reaction expansion is associated with poor prognosis in patients with advanced liver disease. However, the mechanisms promoting biliary cell proliferation are largely unknown. Here, we identify neutrophils as drivers of biliary cell proliferation and the defective wound-healing response. METHODS The intrahepatic localization of neutrophils was evaluated in patients with chronic liver disease. Neutrophil dynamics were analyzed by intravital microscopy and neutrophil-labeling assays in DDC-treated mice. Neutrophil depletion or inhibition of recruitment was achieved using a Ly6g antibody or a CXCR1/2 inhibitor, respectively. Mice deficient in PAD4 (peptidyl arginine deiminase 4) and ELANE/NE (neutrophil elastase) were used to investigate the mechanisms underlying ductular reaction expansion. RESULTS In this study we describe a population of ductular reaction-associated neutrophils (DRANs), which are in direct contact with biliary epithelial cells in chronic liver diseases and whose numbers increased in parallel with disease progression. We show that DRANs are immobilized at the site of ductular reaction for a prolonged period of time. In addition, liver neutrophils display a unique phenotypic and transcriptomic profile, showing a decreased phagocytic capacity and increased oxidative burst. Depletion of neutrophils or inhibition of their recruitment reduces DRANs and the expansion of ductular reaction, while mitigating liver fibrosis and angiogenesis. Mechanistically, neutrophils deficient in PAD4 and ELANE abrogate neutrophil-induced biliary cell proliferation, thus indicating the role of neutrophil extracellular traps and elastase release in ductular reaction expansion. CONCLUSIONS Overall, our study reveals the accumulation of DRANs as a hallmark of advanced liver disease and a potential therapeutic target to mitigate ductular reaction and the maladaptive wound-healing response. IMPACT AND IMPLICATIONS Our results indicate that neutrophils are highly plastic and can have an extended lifespan. Moreover, we identify a new role of neutrophils as triggers of expansion of the biliary epithelium. Overall, the results of this study indicate that ductular reaction-associated neutrophils (or DRANs) are new players in the maladaptive tissue-healing response in chronic liver injury and may be a potential target for therapeutic interventions to reduce ductular reaction expansion and promote tissue repair in advanced liver disease.
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Affiliation(s)
- Silvia Ariño
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Beatriz Aguilar-Bravo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Mar Coll
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Medicine Department, Faculty of Medicine, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
| | - Woo-Yong Lee
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
| | - Moritz Peiseler
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
| | - Paula Cantallops-Vilà
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Laura Sererols-Viñas
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | | | - Celia Martínez-Sánchez
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Jordi Pedragosa
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Neuroscience and Experimental Therapeutics, Institute of Biomedical Research of Barcelona, Spanish National Research Council (CSIC), Barcelona, Spain
| | - Laura Zanatto
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Jordi Gratacós-Ginès
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Liver Unit, Hospital Clínic, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Elisa Pose
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Medicine Department, Faculty of Medicine, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Liver Unit, Hospital Clínic, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Delia Blaya
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Xènia Almodóvar
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - María Fernández-Fernández
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Department of Experimental Pathology, Institute of Biomedical Research of Barcelona, Spanish National Research Council (CSIC), Barcelona, Spain
| | - Paloma Ruiz-Blázquez
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Department of Experimental Pathology, Institute of Biomedical Research of Barcelona, Spanish National Research Council (CSIC), Barcelona, Spain
| | - Juan José Lozano
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Silvia Affo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Anna M Planas
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Neuroscience and Experimental Therapeutics, Institute of Biomedical Research of Barcelona, Spanish National Research Council (CSIC), Barcelona, Spain
| | - Pere Ginès
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Medicine Department, Faculty of Medicine, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Liver Unit, Hospital Clínic, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Anna Moles
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Department of Experimental Pathology, Institute of Biomedical Research of Barcelona, Spanish National Research Council (CSIC), Barcelona, Spain
| | - Paul Kubes
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
| | - Pau Sancho-Bru
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Medicine Department, Faculty of Medicine, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
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Thakral N, Gonzalez T, Nano O, Shin SH, Samuels S, Hussein A. Cirrhosis in intrahepatic cholangiocarcinoma: prognostic importance and impact on survival. BMC Gastroenterol 2023; 23:151. [PMID: 37179301 PMCID: PMC10183123 DOI: 10.1186/s12876-023-02710-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 03/03/2023] [Indexed: 05/15/2023] Open
Abstract
CONTEXT Cholangiocarcinoma (CCA), a malignancy of the biliary tract epithelium is of increasing importance due to its rising incidence worldwide. There is a lack of data on cirrhosis in intrahepatic CCA (iCCA) and how it affects overall survival and prognosis. OBJECTIVES The primary objective of this study was to examine if there were differences in survival outcomes between iCCA patients with concomitant cirrhosis and those without cirrhosis. METHODS The National Cancer Database (NCDB) was used to identify and study patients with iCCA from 2004 to 2017. The presence of cirrhosis was defined using CS Site-Specific Factor 2 where 000 indicated no cirrhosis and 001 indicated the presence of cirrhosis. Descriptive statistics were utilized for patient demographics, disease staging, tumor, and treatment characteristics. Kaplan-Meier (KM) method with log-rank test and a multivariate logistic regression model was used to assess if the presence of cirrhosis in iCCA was associated with survival status and long-term survival (60 or more months after diagnosis). RESULTS There were 33,160 patients with CCA in NCDB (2004-2017), of which 3644 patients were diagnosed with iCCA. One thousand fifty-two patients (28.9%) had cirrhosis as defined by Ishak Fibrosis score 5-6 on biopsy and 2592 patients (71.1%) did not meet the definition for cirrhosis. Although in univariate analyses using KM/log-rank tests showed a survival advantage for non-cirrhotic patients, there was no statistically significant association found between cirrhosis and survival status (OR = 0.82, p = 0.405) or long-term survival (OR = 0.98, p = 0.933) when multivariate analysis was used. iCCA patients with cirrhosis and Stage 1 tumor had the highest median OS (132 months) vs 73.7 months in the non-cirrhotic arm, while patients with stage IV disease who had cirrhosis had half the survival time of those without. Our data thus indicates that the presence of cirrhosis is not an independent prognostic factor for survival.
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Affiliation(s)
- Nimish Thakral
- Department of Hepatology, University of Kentucky, 740 S. Limestone, Medicine Specialties, Kentucky Clinic Wing C, Room 211, Floor, 2, Lexington, KY 40536 USA
| | | | - Olger Nano
- Memorial Healthcare System, Hollywood, USA
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10
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Otsuka K, Iwasaki T. Insights into radiation carcinogenesis based on dose-rate effects in tissue stem cells. Int J Radiat Biol 2023; 99:1503-1521. [PMID: 36971595 DOI: 10.1080/09553002.2023.2194398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 03/16/2023] [Indexed: 03/29/2023]
Abstract
PURPOSE Increasing epidemiological and biological evidence suggests that radiation exposure enhances cancer risk in a dose-dependent manner. This can be attributed to the 'dose-rate effect,' where the biological effect of low dose-rate radiation is lower than that of the same dose at a high dose-rate. This effect has been reported in epidemiological studies and experimental biology, although the underlying biological mechanisms are not completely understood. In this review, we aim to propose a suitable model for radiation carcinogenesis based on the dose-rate effect in tissue stem cells. METHODS We surveyed and summarized the latest studies on the mechanisms of carcinogenesis. Next, we summarized the radiosensitivity of intestinal stem cells and the role of dose-rate in the modulation of stem-cell dynamics after irradiation. RESULTS Consistently, driver mutations can be detected in most cancers from past to present, supporting the hypothesis that cancer progression is initiated by the accumulation of driver mutations. Recent reports demonstrated that driver mutations can be observed even in normal tissues, which suggests that the accumulation of mutations is a necessary condition for cancer progression. In addition, driver mutations in tissue stem cells can cause tumors, whereas they are not sufficient when they occur in non-stem cells. For non-stem cells, tissue remodeling induced by marked inflammation after the loss of tissue cells is important in addition to the accumulation of mutations. Therefore, the mechanism of carcinogenesis differs according to the cell type and magnitude of stress. In addition, our results indicated that non-irradiated stem cells tend to be eliminated from three-dimensional cultures of intestinal stem cells (organoids) composed of irradiated and non-irradiated stem cells, supporting the stem-cell competition. CONCLUSIONS We propose a unique scheme in which the dose-rate dependent response of intestinal stem cells incorporates the concept of the threshold of stem-cell competition and context-dependent target shift from stem cells to whole tissue. The concept highlights four key issues that should be considered in radiation carcinogenesis: i.e. accumulation of mutations; tissue reconstitution; stem-cell competition; and environmental factors like epigenetic modifications.
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Affiliation(s)
- Kensuke Otsuka
- Biology and Environmental Chemistry Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry, Tokyo, Japan
| | - Toshiyasu Iwasaki
- Strategy and Planning Division, Sustainable System Research Laboratory, Central Research Institute of Electric Power Industry, Tokyo, Japan
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11
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Hernandez JC, Chen CL, Machida T, Uthaya Kumar DB, Tahara SM, Montana J, Sher L, Liang J, Jung JU, Tsukamoto H, Machida K. LIN28 and histone H3K4 methylase induce TLR4 to generate tumor-initiating stem-like cells. iScience 2023; 26:106254. [PMID: 36949755 PMCID: PMC10025994 DOI: 10.1016/j.isci.2023.106254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 01/09/2022] [Accepted: 02/16/2023] [Indexed: 02/24/2023] Open
Abstract
Chemoresistance and plasticity of tumor-initiating stem-like cells (TICs) promote tumor recurrence and metastasis. The gut-originating endotoxin-TLR4-NANOG oncogenic axis is responsible for the genesis of TICs. This study investigated mechanisms as to how TICs arise through transcriptional, epigenetic, and post-transcriptional activation of oncogenic TLR4 pathways. Here, we expressed constitutively active TLR4 (caTLR4) in mice carrying pLAP-tTA or pAlb-tTA, under a tetracycline withdrawal-inducible system. Liver progenitor cell induction accelerated liver tumor development in caTLR4-expressing mice. Lentiviral shRNA library screening identified histone H3K4 methylase SETD7 as central to activation of TLR4. SETD7 combined with hypoxia induced TLR4 through HIF2 and NOTCH. LIN28 post-transcriptionally stabilized TLR4 mRNA via de-repression of let-7 microRNA. These results supported a LIN28-TLR4 pathway for the development of HCCs in a hypoxic microenvironment. These findings not only advance our understanding of molecular mechanisms responsible for TIC generation in HCC, but also represent new therapeutic targets for the treatment of HCC.
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Affiliation(s)
- Juan Carlos Hernandez
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
- MS Biotechnology Program, California State University Channel Islands, Camarillo, CA 93012, USA
| | - Chia-Lin Chen
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
- Department of Life Sciences & Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 110, Taiwan
| | - Tatsuya Machida
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Dinesh Babu Uthaya Kumar
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Stanley M. Tahara
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Jared Montana
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Linda Sher
- Department of Surgery, University of Southern California, Los Angeles, CA 90033, USA
| | | | - Jae U. Jung
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Hidekazu Tsukamoto
- Department of Pathology, University of Southern California, Los Angeles, CA 90033, USA
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA
- Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Keigo Machida
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA
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Govaere O, Anstee QM. Non-Alcoholic Fatty Liver Disease and Steatohepatitis. ENCYCLOPEDIA OF CELL BIOLOGY 2023:610-621. [DOI: 10.1016/b978-0-12-821618-7.00265-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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13
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Machida K. HCV and tumor-initiating stem-like cells. Front Physiol 2022; 13:903302. [PMID: 36187761 PMCID: PMC9520593 DOI: 10.3389/fphys.2022.903302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.
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Zhang L, Qi Q, Li Q, Ren S, Liu S, Mao B, Li X, Wu Y, Yang L, Liu L, Li Y, Duan S, Zhang L. Ultrasomics prediction for cytokeratin 19 expression in hepatocellular carcinoma: A multicenter study. Front Oncol 2022; 12:994456. [PMID: 36119507 PMCID: PMC9478580 DOI: 10.3389/fonc.2022.994456] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 08/10/2022] [Indexed: 11/16/2022] Open
Abstract
Objective The purpose of this study was to investigate the preoperative prediction of Cytokeratin (CK) 19 expression in patients with hepatocellular carcinoma (HCC) by machine learning-based ultrasomics. Methods We retrospectively analyzed 214 patients with pathologically confirmed HCC who received CK19 immunohistochemical staining. Through random stratified sampling (ratio, 8:2), patients from institutions I and II were divided into training dataset (n = 143) and test dataset (n = 36), and patients from institution III served as external validation dataset (n = 35). All gray-scale ultrasound images were preprocessed, and then the regions of interest were then manually segmented by two sonographers. A total of 1409 ultrasomics features were extracted from the original and derived images. Next, the intraclass correlation coefficient, variance threshold, mutual information, and embedded method were applied to feature dimension reduction. Finally, the clinical model, ultrasonics model, and combined model were constructed by eXtreme Gradient Boosting algorithm. Model performance was assessed by area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy. Results A total of 12 ultrasomics signatures were used to construct the ultrasomics models. In addition, 21 clinical features were used to construct the clinical model, including gender, age, Child-Pugh classification, hepatitis B surface antigen/hepatitis C virus antibody (positive/negative), cirrhosis (yes/no), splenomegaly (yes/no), tumor location, tumor maximum diameter, tumor number, alpha-fetoprotein, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, glutamyl-transpeptidase, albumin, total bilirubin, conjugated bilirubin, creatinine, prothrombin time, fibrinogen, and international normalized ratio. The AUC of the ultrasomics model was 0.789 (0.621 – 0.907) and 0.787 (0.616 – 0.907) in the test and validation datasets, respectively. However, the performance of the combined model covering clinical features and ultrasomics signatures improved significantly. Additionally, the AUC (95% CI), sensitivity, specificity, and accuracy were 0.867 (0.712 – 0.957), 0.750, 0.875, 0.861, and 0.862 (0.703 – 0.955), 0.833, 0.862, and 0.857 in the test dataset and external validation dataset, respectively. Conclusion Ultrasomics signatures could be used to predict the expression of CK19 in HCC patients. The combination of clinical features and ultrasomics signatures showed excellent effects, which significantly improved prediction accuracy and robustness.
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Affiliation(s)
- Linlin Zhang
- Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Qinghua Qi
- Department of Ultrasound, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qian Li
- Department of Ultrasound, Henan Provincial Cancer Hospital, Zhengzhou, China
| | - Shanshan Ren
- Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Shunhua Liu
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Bing Mao
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Xin Li
- Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Yuejin Wu
- Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Lanling Yang
- Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Luwen Liu
- Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Yaqiong Li
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Shaobo Duan
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
- Department of Health Management, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- *Correspondence: Lianzhong Zhang, ; Shaobo Duan,
| | - Lianzhong Zhang
- Department of Ultrasound, Henan University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Engineering Technology Research Center of Ultrasonic Molecular Imaging and Nanotechnology, Henan Provincial People's Hospital, Zhengzhou, China
- *Correspondence: Lianzhong Zhang, ; Shaobo Duan,
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Liu Y, Chen C, Wang X, Sun Y, Zhang J, Chen J, Shi Y. An Epigenetic Role of Mitochondria in Cancer. Cells 2022; 11:cells11162518. [PMID: 36010594 PMCID: PMC9406960 DOI: 10.3390/cells11162518] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/03/2022] [Accepted: 08/09/2022] [Indexed: 12/14/2022] Open
Abstract
Mitochondria are not only the main energy supplier but are also the cell metabolic center regulating multiple key metaborates that play pivotal roles in epigenetics regulation. These metabolites include acetyl-CoA, α-ketoglutarate (α-KG), S-adenosyl methionine (SAM), NAD+, and O-linked beta-N-acetylglucosamine (O-GlcNAc), which are the main substrates for DNA methylation and histone post-translation modifications, essential for gene transcriptional regulation and cell fate determination. Tumorigenesis is attributed to many factors, including gene mutations and tumor microenvironment. Mitochondria and epigenetics play essential roles in tumor initiation, evolution, metastasis, and recurrence. Targeting mitochondrial metabolism and epigenetics are promising therapeutic strategies for tumor treatment. In this review, we summarize the roles of mitochondria in key metabolites required for epigenetics modification and in cell fate regulation and discuss the current strategy in cancer therapies via targeting epigenetic modifiers and related enzymes in metabolic regulation. This review is an important contribution to the understanding of the current metabolic-epigenetic-tumorigenesis concept.
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Affiliation(s)
- Yu’e Liu
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
| | - Chao Chen
- Department of Neurosurgery, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China
| | - Xinye Wang
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
| | - Yihong Sun
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
| | - Jin Zhang
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Juxiang Chen
- Department of Neurosurgery, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China
- Correspondence: (J.C.); (Y.S.)
| | - Yufeng Shi
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
- Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai 200092, China
- Correspondence: (J.C.); (Y.S.)
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Zhou L, Yu KH, Wong TL, Zhang Z, Chan CH, Loong JH, Che N, Yu HJ, Tan KV, Tong M, Ngan ES, Ho JW, Ma S. Lineage tracing and single-cell analysis reveal proliferative Prom1+ tumour-propagating cells and their dynamic cellular transition during liver cancer progression. Gut 2022; 71:1656-1668. [PMID: 34588223 DOI: 10.1136/gutjnl-2021-324321] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 09/19/2021] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) has high intratumoral heterogeneity, which contributes to therapeutic resistance and tumour recurrence. We previously identified Prominin-1 (PROM1)/CD133 as an important liver cancer stem cell (CSC) marker in human HCC. The aim of this study was to investigate the heterogeneity and properties of Prom1+ cells in HCC in intact mouse models. DESIGN We established two mouse models representing chronic fibrotic HCC and rapid steatosis-related HCC. We performed lineage tracing post-HCC induction using Prom1C-L/+; Rosa26tdTomato/+ mice, and targeted depletion using Prom1C-L/+; Rosa26DTA/+ mice. Single-cell RNA sequencing (scRNA-seq) was carried out to analyse the transcriptomic profile of traced Prom1+ cells. RESULTS Prom1 in HCC tumours marks proliferative tumour-propagating cells with CSC-like properties. Lineage tracing demonstrated that these cells display clonal expansion in situ in primary tumours. Labelled Prom1+ cells exhibit increasing tumourigenicity in 3D culture and allotransplantation, as well as potential to form cancers of differential lineages on transplantation. Depletion of Prom1+ cells impedes tumour growth and reduces malignant cancer hallmarks in both HCC models. scRNA-seq analysis highlighted the heterogeneity of Prom1+ HCC cells, which follow a trajectory to the dedifferentiated status with high proliferation and stem cells traits. Conserved gene signature of Prom1 linage predicts poor prognosis in human HCC. The activated oxidant detoxification underlies the protective mechanism of dedifferentiated transition and lineage propagation. CONCLUSION Our study combines in vivo lineage tracing and scRNA-seq to reveal the heterogeneity and dynamics of Prom1+ HCC cells, providing insights into the mechanistic role of malignant CSC-like cells in HCC progression.
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Affiliation(s)
- Lei Zhou
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.,Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Ken Ho Yu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.,Laboratory of Data Discovery for Health Limited (D24H), Hong Kong Science Park, Hong Kong SAR, China
| | - Tin Lok Wong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China
| | - Zhao Zhang
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Chun Ho Chan
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Jane Hc Loong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Noelia Che
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Hua Jian Yu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Kel Vin Tan
- Department of Diagnostic Radiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Man Tong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.,Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China
| | - Elly S Ngan
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Joshua Wk Ho
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China .,Laboratory of Data Discovery for Health Limited (D24H), Hong Kong Science Park, Hong Kong SAR, China
| | - Stephanie Ma
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China .,Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China
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17
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Xie ZQ, Li HX, Hou XJ, Huang MY, Zhu ZM, Wei LX, Tang CX. Capsaicin suppresses hepatocarcinogenesis by inhibiting the stemness of hepatic progenitor cells via SIRT1/SOX2 signaling pathway. Cancer Med 2022; 11:4283-4296. [PMID: 35674129 DOI: 10.1002/cam4.4777] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND & AIMS Capsaicin, a functional component of chili pepper, possesses anti-inflammatory, analgesic, and anti-cancer properties. This study aimed to determine the property of capsaicin against hepatocarcinogenesis in vivo and investigate the role of the SIRT1/SOX2 pathway in the mode of action of capsaicin in hepatic progenitor cells (HPCs), which is related to hepatocarcinogenesis. MATERIALS & METHODS We prepared a diethylnitrosamine-induced liver cancer model in rats to examine hepatocarcinogenesis, and delivered liposomal capsaicin through the subcutaneous transposition of the spleen to the liver. Liver sections from rats and hepatocarcinoma patients were stained for the markers of HPCs or SIRT1/SOX2 signaling. SIRT1/SOX2 signalling expression was measured using immunoprecipitation and western blot. RESULTS We found that capsaicin significantly inhibited hepatocarcinogenesis. Notably, capsaicin inhibited HPCs activation in vivo but did not induce apoptosis in the normal hepatic progenitor cell line in rats in vitro. This suggests that capsaicin suppresses hepatocarcinogenesis by inhibiting the stemness of HPCs. Moreover, capsaicin can induce this inhibition by reducing the stability of SOX2. SIRT1 is overexpressed in liver cancer and acts as a tumor promoter via SOX2 deacetylation. Using immunoprecipitation, we identified direct binding between SIRT1 and SOX2. The capsaicin treatment resulted in SIRT1 downregulation which reduced deacetylation, and increased nuclear export as well as subsequent ubiquitous degradation of SOX2. CONCLUSIONS Altogether, we report that capsaicin suppresses hepatocarcinogenesis by inhibiting the stemness of HPCs via SIRT1/SOX2 signaling. It may serve as a promising therapeutic candidate for liver cancer.
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Affiliation(s)
- Zhi-Qin Xie
- Department of Hepatobiliary and Pancreatic Surgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou City, Hunan Province, China
| | - Hong-Xia Li
- Department of Pathology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou City, Hunan Province, China
| | - Xiao-Juan Hou
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai City, China
| | - Mei-Yuan Huang
- Department of Pathology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou City, Hunan Province, China
| | - Ze-Min Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou City, Hunan Province, China
| | - Li-Xin Wei
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai City, China
| | - Cai-Xi Tang
- Department of Hepatobiliary and Pancreatic Surgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou City, Hunan Province, China
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18
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Machida K, Tahara SM. Immunotherapy and Microbiota for Targeting of Liver Tumor-Initiating Stem-like Cells. Cancers (Basel) 2022; 14:2381. [PMID: 35625986 PMCID: PMC9139909 DOI: 10.3390/cancers14102381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/04/2022] [Accepted: 05/06/2022] [Indexed: 02/08/2023] Open
Abstract
Cancer contains tumor-initiating stem-like cells (TICs) that are resistant to therapies. Hepatocellular carcinoma (HCC) incidence has increased twice over the past few decades, while the incidence of other cancer types has trended downward globally. Therefore, an understanding of HCC development and therapy resistance mechanisms is needed for this incurable malignancy. This review article describes links between immunotherapies and microbiota in tumor-initiating stem-like cells (TICs), which have stem cell characteristics with self-renewal ability and express pluripotency transcription factors such as NANOG, SOX2, and OCT4. This review discusses (1) how immunotherapies fail and (2) how gut dysbiosis inhibits immunotherapy efficacy. Gut dysbiosis promotes resistance to immunotherapies by breaking gut immune tolerance and activating suppressor immune cells. Unfortunately, this leads to incurable recurrence/metastasis development. Personalized medicine approaches targeting these mechanisms of TIC/metastasis-initiating cells are emerging targets for HCC immunotherapy and microbiota modulation therapy.
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Affiliation(s)
- Keigo Machida
- Southern California Research Center for ALPD and Cirrhosis, Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, 2011 Zonal Ave., 503C-HMR, Los Angeles, CA 90033, USA;
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19
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Shigematsu Y, Amori G, Kanda H, Takahashi Y, Takazawa Y, Takeuchi K, Inamura K. Decreased ARG1 expression as an adverse prognostic phenotype in non-alcoholic non-virus-related hepatocellular carcinoma. Virchows Arch 2022; 481:253-263. [PMID: 35459975 DOI: 10.1007/s00428-022-03318-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 02/21/2022] [Accepted: 03/26/2022] [Indexed: 11/29/2022]
Abstract
The incidence of non-alcoholic non-virus-related hepatocellular carcinoma (NANV-HCC) is increasing along with the growing prevalence of metabolic disorders. In this subset, few useful biomarkers are available to narrow down the high-risk group for recurrence. This study aimed to evaluate the prognostic impact of decreased ARG1 (arginase-1), which is pathologically known as a marker reflecting hepatocyte differentiation, in NANV-HCC. Besides, its relationship with biliary/progenitor cell markers, whose expressions are associated with poor prognosis, was also assessed. To reveal the clinicopathological association of decreased ARG1 expression in NANV-HCC, we investigated 99 patients who underwent curative-intent hepatectomy for NANV-HCC. Tissue microarrays were employed for immunohistochemical analysis. A total of 21 NANV-HCC cases (21%; 21/99) showed decreased ARG1 expression. Decreased ARG1 expression was an independent prognostic factor for both poor DFS (hazard ratio 2.17; 95% confidence interval 1.15-4.09; p = 0.02) and OS (hazard ratio 4.09; 95% confidence interval 1.71-9.80; p = 0.002). In addition, decreased ARG1 expression was significantly associated with expressions of biliary/progenitor cell markers, CK19 and CD56 (p < 0.01). As cytologic features of tumor cells, decreased ARG1 expression was significantly associated with lipid-less cytologic morphology (p = 0.045). These findings indicate that decreased ARG1 expression is a predictive phenotype of postoperative recurrence with poor prognosis in patients with NANV-HCC. Decreased ARG1 expression may be a precursor or overlapping feature with biliary/progenitor cell marker expressions in NANV-HCC.
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Affiliation(s)
- Yasuyuki Shigematsu
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan.,Division of Pathology, Cancer Institute, JFCR, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan
| | - Gulanbar Amori
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan.,Division of Pathology, Cancer Institute, JFCR, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan
| | - Hiroaki Kanda
- Department of Pathology, Saitama Cancer Center, 780 Omuro Kitaadachi-gun, Ina-machi, Saitama, 362-0806, Japan
| | - Yu Takahashi
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, JFCR, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan
| | - Yutaka Takazawa
- Department of Pathology, Toranomon Hospital, 2-2-2 Toranomon, Minato, Tokyo, 105-8470, Japan
| | - Kengo Takeuchi
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan.,Division of Pathology, Cancer Institute, JFCR, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan.,Pathology Project for Molecular Targets, Cancer Institute, JFCR, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan
| | - Kentaro Inamura
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan. .,Division of Pathology, Cancer Institute, JFCR, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan.
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20
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Holczbauer Á, Wangensteen KJ, Shin S. Cellular origins of regenerating liver and hepatocellular carcinoma. JHEP Rep 2022; 4:100416. [PMID: 35243280 PMCID: PMC8873941 DOI: 10.1016/j.jhepr.2021.100416] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 11/30/2021] [Accepted: 12/02/2021] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant primary cancer arising from the liver and is one of the major causes of cancer-related mortality worldwide. The cellular origin of HCC has been a topic of great interest due to conflicting findings regarding whether it originates in hepatocytes, biliary cells, or facultative stem cells. These cell types all undergo changes during liver injury, and there is controversy about their contribution to regenerative responses in the liver. Most HCCs emerge in the setting of chronic liver injury from viral hepatitis, fatty liver disease, alcohol, and environmental exposures. The injuries are marked by liver parenchymal changes such as hepatocyte regenerative nodules, biliary duct cellular changes, expansion of myofibroblasts that cause fibrosis and cirrhosis, and inflammatory cell infiltration, all of which may contribute to carcinogenesis. Addressing the cellular origin of HCC is the key to identifying the earliest events that trigger it. Herein, we review data on the cells of origin in regenerating liver and HCC and the implications of these findings for prevention and treatment. We also review the origins of childhood liver cancer and other rare cancers of the liver.
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21
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Brown ZJ, Hewitt DB, Pawlik TM. Biomarkers of intrahepatic cholangiocarcinoma: diagnosis and response to therapy. FRONT BIOSCI-LANDMRK 2022; 27:85. [PMID: 35345317 DOI: 10.31083/j.fbl2703085] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/31/2022] [Accepted: 02/10/2022] [Indexed: 01/03/2025]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer behind hepatocellular carcinoma (HCC) and carries a dismal prognosis. Improved genetic analysis has paved the way for a better understanding of the distinct somatic genomic landscapes of ICC. The use of next generation sequencing has paved the way for more personalized medicine through identifying unique mutations which may prove to be therapeutic targets. The ability to identify biomarkers specific to ICC will assist in establishing a diagnosis, monitoring response to therapy, as well as assist in identifying novel therapies and personalized medicine. Herein, we discuss potential biomarkers for ICC and how these markers can assist in diagnosis, monitor response to therapy, and potentially identify novel interventions for the treatment of ICC.
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Affiliation(s)
- Zachary J Brown
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - D Brock Hewitt
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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22
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Sahu R, Sharma P, Kumar A. An Insight into Cholangiocarcinoma and Recent Advances in its Treatment. J Gastrointest Cancer 2022; 54:213-226. [PMID: 35023010 DOI: 10.1007/s12029-021-00728-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/04/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is a malignant disease of the epithelial cells of the intrahepatic and extrahepatic bile ducts. This review focuses on various aspects of cholangiocarcinoma such as its associated causes, treatment criteria, and more. METHODS Although it remains a rare malignancy and is the second most common primary malignancy of the liver, the incidence is increasing, especially the incidence of intrahepatic CCA. Several studies suggested that surgery is not only solution; recently, reported targeted drugs may have the potential to become an alternative option. RESULTS This review provides an overview of the current scenario of targeted therapies for CCA, which were tabulated with their current status and it also included its associated causes and its treatment criteria. CONCLUSION Because of its rarity and complexity, surgery remains the preferred treatment in resectable patients. Howerver, the studies suggested that the recently reported drugs may have the potential to be an alternative option for the treatment of CCA and related complications. In addition, this review will certainly benefit the community and researcher for further investigation.
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Affiliation(s)
- Rakesh Sahu
- Department of Pharmacy, School of Medical & Allied Sciences, Galgotias University, Greater Noida, 201310, Uttar Pradesh, India
- Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
| | - Praveen Sharma
- Department of Pharmacy, School of Medical & Allied Sciences, Galgotias University, Greater Noida, 201310, Uttar Pradesh, India
| | - Ajay Kumar
- Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute), Knowledge Park-II, 201306, Greater Noida, India
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23
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Extracellular vesicles from human hepatic progenitor cells accelerate deep frostbite wound healing by promoting fibroblasts proliferation and inhibiting apoptosis. J Tissue Viability 2021; 31:286-293. [PMID: 34906420 DOI: 10.1016/j.jtv.2021.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/15/2021] [Accepted: 10/19/2021] [Indexed: 11/24/2022]
Abstract
Frostbites are cold tissue damages frequently observed at high altitudes and under extremely cold conditions. Though their incidence rate is low, the resulting impact in affected patients can be very serious, often leading to amputations. Clinical management and the prediction of outcome can be of utmost importance to frostbite patients. A possible use of stem cell-derived extracellular vesicles (EVs) has been suggested for cutaneous wound healing and we, therefore, tested their use for the treatment of deep frostbite wound. To this end, the impacts of hHPC-derived EVs were evaluated in an in vivo animal model comprising of Kunming female mice as well as studied in vitro for the mechanism. We first characterized the EVs and these hHPC-derived EVs, when applied to treat frostbite wounds, accelerated wound healing in the in vivo animal model, as assessed by wound closure, re-epithelization thickness, collagen density and the expression of Collagen I and α-SMA. The proliferation and migration of human skin fibroblasts was also found to be increased by EVs in the in vitro experiments. The H2O2-induced apoptosis cell model, established to simulate the post-frostbite injury, was inhibited by EVs, with concomitant increase in the expression of Bcl-2 and decreased expression of Bax, further confirming the findings. Our novel results indicate that the application of EVs might be a promising strategy for deep frostbite wound healing.
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24
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Nahm JH, Park YN. [Up-to-date Knowledge on the Pathological Diagnosis of Hepatocellular Carcinoma]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2021; 78:268-283. [PMID: 34824185 DOI: 10.4166/kjg.2021.140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 11/09/2022]
Abstract
Hepatocellular carcinoma (HCC) has heterogeneous molecular and pathological features and biological behavior. Large-scale genetic studies of HCC were accumulated, and a pathological-molecular classification of HCC was proposed. Approximately 35% of HCCs can be classified into distinct histopathological subtypes according to their molecular characteristics. Among recently identified subtypes, macrotrabecular massive HCC, neutrophil-rich HCC, vessels encapsulating tumor clusters HCC, and progenitor phenotype HCC (HCC with CK19 expression) are associated with a poor prognosis, whereas the lymphocyte-rich HCC subtype is related to a better prognosis. This review provides up-to-date knowledge on the pathological diagnosis of HCC according to the updated World Health Organization Classification of Digestive System Tumors 5th ed.
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Affiliation(s)
- Ji Hae Nahm
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Young Nyun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.,Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
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25
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Zhuo J, Lu D, Lin Z, Yang X, Yang M, Wang J, Tao Y, Wen X, Li H, Lian Z, Cen B, Dong S, Wei X, Xie H, Zheng S, Shen Y, Xu X. The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib. Cell Death Dis 2021; 12:1084. [PMID: 34785656 PMCID: PMC8595883 DOI: 10.1038/s41419-021-04320-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 10/11/2021] [Accepted: 10/13/2021] [Indexed: 02/07/2023]
Abstract
Cytokeratin 19-positive (CK19+) hepatocellular carcinoma (HCC) is an aggressive subtype characterized by early recurrence and chemotherapy tolerance. However, there is no specific therapeutic option for CK19+ HCC. The correlation between tumor recurrence and expression status of CK19 were studied in 206 patients undergoing liver transplantation for HCC. CK19-/+ HCC cells were isolated to screen effective antitumor drugs. The therapeutic effects of regorafenib were evaluated in patient-derived xenograft (PDX) models from 10 HCC patients. The mechanism of regorafenib on CK19+ HCC was investigated. CK19 positiveness indicated aggressiveness of tumor and higher recurrence risk of HCC after liver transplantation. The isolated CK19+ HCC cells had more aggressive behaviors than CK19- cells. Regorafenib preferentially increased the growth inhibition and apoptosis of CK19+ cells in vitro, whereas sorafenib, apatinib, and 5-fluorouracil did not. In PDX models from CK19-/+ HCC patients, the tumor control rate of regorafenib achieved 80% for CK19+ HCCs, whereas 0% for CK19- HCCs. RNA-sequencing revealed that CK19+ cells had elevated expression of mitochondrial ribosomal proteins, which are essential for mitochondrial function. Further experiments confirmed that regorafenib attenuated the mitochondrial respiratory capacity in CK19+ cells. However, the mitochondrial respiration in CK19- cells were faint and hardly repressed by regorafenib. The mitochondrial respiration was regulated by the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which was inhibited by regorafenib in CK19+ cells. Hence, CK19 could be a potential marker of the therapeutic benefit of regorafenib, which facilitates the individualized therapy for HCC. STAT3/mitochondria axis determines the distinct response of CK19+ cells to regorafenib treatment.
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Affiliation(s)
- Jianyong Zhuo
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, China
| | - Di Lu
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zuyuan Lin
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyu Yang
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Modan Yang
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianguo Wang
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yaoye Tao
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xue Wen
- Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Huihui Li
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengxing Lian
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Beini Cen
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Siyi Dong
- National Center for Healthcare Quality Management in Liver Transplant, Hangzhou, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haiyang Xie
- Institute of Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
| | - Shusen Zheng
- Institute of Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, China
- National Center for Healthcare Quality Management in Liver Transplant, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, China
| | - Youqing Shen
- Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Center for Integrated Oncology and Precision Medicine, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Institute of Organ Transplantation, Zhejiang University School of Medicine, Hangzhou, China.
- National Center for Healthcare Quality Management in Liver Transplant, Hangzhou, China.
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26
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Does Neutrophil to Lymphocyte Ratio Have a Role in Identifying Cytokeratin 19-Expressing Hepatocellular Carcinoma? J Pers Med 2021; 11:jpm11111078. [PMID: 34834430 PMCID: PMC8621990 DOI: 10.3390/jpm11111078] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Cytokeratin 19-positive (CK19(+)) hepatocellular carcinomas (HCC) are generally associated with poor prognosis after hepatectomy. It is typically detected from postoperative immunochemistry. We have analyzed several clinically available biomarkers, in particular, neutrophil to lymphocyte ratio (NLR) and aim to develop a panel of biomarkers in identifying CK19 expression in (HCC) preoperatively. METHODS We retrospectively reviewed 36 HCC patients who underwent liver resections during January 2017 to March 2018 in Chang Gung Memorial Hospital. Patients were grouped based on the status of CK19 expression and their baseline characteristics, perioperative and oncologic outcomes were compared. Novel biomarkers including NLR, alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and uric acid were analyzed and correlated with CK19 expression. RESULTS NLR is highly associated with CK19 expression. NLR alone gave an AUROC of 0.728 (p-value = 0.043), higher than AFP, CEA or tumor size alone. NLR when combined with AFP, CEA and uric acid, gave an AUROC as high as 0.933 (p-value = 0.004). CONCLUSION The current study demonstrated the predictive capability of NLR in combination with AFP, CEA and uric acid for CK19 expression in HCC patients preoperatively. Further prospective, large-scale studies are warranted to validate our findings.
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Intrahepatic Cholangiocarcinoma: A Summative Review of Biomarkers and Targeted Therapies. Cancers (Basel) 2021; 13:cancers13205169. [PMID: 34680318 PMCID: PMC8533913 DOI: 10.3390/cancers13205169] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/08/2021] [Accepted: 10/14/2021] [Indexed: 01/07/2023] Open
Abstract
Simple Summary Intrahepatic cholangiocarcinoma is the second most common primary liver malignancy. Among patients with operable disease, surgical resection is the cornerstone of therapy. Among the majority of patients who present with advanced disease treatment, systemic or targeted therapy is indicated. Recent advancements have provided more novel therapeutic approaches to a subset of patients with intrahepatic cholangiocarcinoma. Abstract Although rare, intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy and the incidence of ICC has increased 14% per year in recent decades. Treatment of ICC remains difficult as most people present with advanced disease not amenable to curative-intent surgical resection. Even among patients with operable disease, margin-negative surgical resection can be difficult to achieve and the incidence of recurrence remains high. As such, there has been considerable interest in systemic chemotherapy and targeted therapy for ICC. Over the last decade, the understanding of the molecular and genetic foundations of ICC has reshaped treatment approaches and strategies. Next-generation sequencing has revealed that most ICC tumors have at least one targetable mutation. These advancements have led to multiple clinical trials to examine the safety and efficacy of novel therapeutics that target tumor-specific molecular and genetic aberrations. While these advancements have demonstrated survival benefit in early phase clinical trials, continued investigation in randomized larger-scale trials is needed to further define the potential clinical impact of such therapy.
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Rompianesi G, Di Martino M, Gordon-Weeks A, Montalti R, Troisi R. Liquid biopsy in cholangiocarcinoma: Current status and future perspectives. World J Gastrointest Oncol 2021; 13:332-350. [PMID: 34040697 PMCID: PMC8131901 DOI: 10.4251/wjgo.v13.i5.332] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/02/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCA) are a heterogeneous group of tumors in terms of aetiology, natural history, morphological subtypes, molecular alterations and management, but all sharing complex diagnosis, management, and poor prognosis. Several mutated genes and epigenetic changes have been detected in CCA, with the potential to identify diagnostic and prognostic biomarkers and therapeutic targets. Accessing tumoral components and genetic material is therefore crucial for the diagnosis, management and selection of targeted therapies; but sampling tumor tissue, when possible, is often risky and difficult to be repeated at different time points. Liquid biopsy (LB) represents a way to overcome these issues and comprises a diverse group of methodologies centering around detection of tumor biomarkers from fluid samples. Compared to the traditional tissue sampling methods LB is less invasive and can be serially repeated, allowing a real-time monitoring of the tumor genetic profile or the response to therapy. In this review, we analysis the current evidence on the possible roles of LB (circulating DNA, circulating RNA, exosomes, cytokines) in the diagnosis and management of patients affected by CCA.
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Affiliation(s)
- Gianluca Rompianesi
- Hepato-Bilio-Pancreatic, Minimally Invasive and Robotic Surgery Unit, Department of Clinical Medicine and Surgery, Federico II University Hospital, Napoli 80131, Italy
| | - Marcello Di Martino
- Hepato-Bilio-Pancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital Universitario La Princesa, Madrid 28006, Spain
| | - Alex Gordon-Weeks
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Roberto Montalti
- Hepato-Bilio-Pancreatic, Minimally Invasive and Robotic Surgery Unit, Department of Clinical Medicine and Surgery, Federico II University Hospital, Napoli 80131, Italy
| | - Roberto Troisi
- Hepato-Bilio-Pancreatic, Minimally Invasive and Robotic Surgery Unit, Department of Clinical Medicine and Surgery, Federico II University Hospital, Napoli 80131, Italy
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Chen SZ, Ling Y, Yu LX, Song YT, Chen XF, Cao QQ, Yu H, Chen C, Tang JJ, Fan ZC, Miao YS, Dong YP, Tao JY, Monga SPS, Wen W, Wang HY. 4-phenylbutyric acid promotes hepatocellular carcinoma via initiating cancer stem cells through activation of PPAR-α. Clin Transl Med 2021; 11:e379. [PMID: 33931972 PMCID: PMC8087947 DOI: 10.1002/ctm2.379] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 03/16/2021] [Accepted: 03/18/2021] [Indexed: 12/12/2022] Open
Abstract
Background and aims 4‐phenylbutyric acid (4‐PBA) is a low molecular weight fatty acid that is used in clinical practice to treat inherited urea cycle disorders. In previous reports, it acted as a chemical chaperone inhibiting endoplasmic reticulum (ER) stress and unfolded protein response signaling. A few studies have suggested its function against hepatic fibrosis in mice models. However, its role in hepatocarcinogenesis remained unknown. Methods 4‐PBA was administered alone or in combination with diethylnitrosamine to investigate its long‐term effect on liver tumorigenesis. The role of 4‐PBA in oncogene‐induced hepatocellular carcinoma (HCC) mice model using sleeping beauty system co‐expressed with hMet and β‐catenin point mutation (S45Y) was also observed. RNA‐seq and PCR array were used to screen the pathways and genes involved. In vitro and in vivo studies were conducted to explore the effect of 4‐PBA on liver and validate the underlying mechanism. Results 4‐PBA alone didn't cause liver tumor in long term. However, it promoted liver tumorigenesis in HCC mice models via initiation of liver cancer stem cells (LCSCs) through Wnt5b‐Fzd5 mediating β‐catenin signaling. Peroxisome proliferator‐activated receptors (PPAR)‐α induced by 4‐PBA was responsible for the activation of β‐catenin signaling. Thus, intervention of PPAR‐α reversed 4‐PBA‐induced initiation of LCSCs and HCC development in vivo. Further study revealed that 4‐PBA could not only upregulate the expression of PPAR‐α transcriptionally but also enhance its stabilization via protecting it from proteolysis. Moreover, high PPAR‐α expression predicted poor prognosis in HCC patients. Conclusions 4‐PBA could upregulate PPAR‐α to initiate LCSCs by activating β‐catenin signaling pathway, promoting HCC at early stage. Therefore, more discretion should be taken to monitor the potential tumor‐promoting effect of 4‐PBA under HCC‐inducing environment.
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Affiliation(s)
- Shu-Zhen Chen
- National Center for Liver Cancer, Second Military Medical University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yan Ling
- National Center for Liver Cancer, Second Military Medical University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Le-Xing Yu
- National Center for Liver Cancer, Second Military Medical University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yu-Ting Song
- National Center for Liver Cancer, Second Military Medical University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Model Animal Research Center, Nanjing University, Nanjing, Jiangsu Province, China
| | - Xiao-Fei Chen
- School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Qi-Qi Cao
- National Center for Liver Cancer, Second Military Medical University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Han Yu
- National Center for Liver Cancer, Second Military Medical University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Can Chen
- National Center for Liver Cancer, Second Military Medical University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Fujian Medical University, Fuzhou, Fujian Province, China
| | - Jiao-Jiao Tang
- National Center for Liver Cancer, Second Military Medical University, Shanghai, China.,Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui Province, China
| | - Zhe-Cai Fan
- National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Yu-Shan Miao
- National Center for Liver Cancer, Second Military Medical University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Ya-Ping Dong
- National Center for Liver Cancer, Second Military Medical University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Fujian Medical University, Fuzhou, Fujian Province, China
| | - Jun-Yan Tao
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Satdarshan P S Monga
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.,Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Wen Wen
- National Center for Liver Cancer, Second Military Medical University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Hong-Yang Wang
- National Center for Liver Cancer, Second Military Medical University, Shanghai, China.,International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Model Animal Research Center, Nanjing University, Nanjing, Jiangsu Province, China.,State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.,Fujian Medical University, Fuzhou, Fujian Province, China.,Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui Province, China
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Rhee H, Kim H, Park YN. Clinico-Radio-Pathological and Molecular Features of Hepatocellular Carcinomas with Keratin 19 Expression. Liver Cancer 2020; 9:663-681. [PMID: 33442539 PMCID: PMC7768132 DOI: 10.1159/000510522] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/28/2020] [Indexed: 02/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous neoplasm, both from the molecular and histomorphological aspects. One example of heterogeneity is the expression of keratin 19 (K19) in a subset (4-28%) of HCCs. The presence of K19 expression in HCCs has important clinical implications, as K19-positive HCCs have been associated with aggressive tumor biology and poor prognosis. Histomorphologically, K19-positive HCCs demonstrate a more infiltrative appearance, poor histological differentiation, more frequent vascular invasion, and more intratumoral fibrous stroma than K19-negative conventional HCCs. From the molecular aspect, K19-positive HCCs have been matched with various gene signatures that have been associated with stemness and poor prognosis, including the G1-3 groups, S2 class, cluster A, proliferation signature, and vascular invasion signature. K19-positive HCCs also show upregulated signatures related to transforming growth factor-β pathway and epithelial-to-mesenchymal transition. The main regulators of K19 expression include hepatocyte growth factor-MET paracrine signaling by cancer-associated fibroblast, epidermal growth factor-epidermal growth factor receptor signaling, laminin, and DNA methylation. Clinically, higher serum alpha-fetoprotein levels, frequent association with chronic hepatitis B, more invasive growth, and lymph node metastasis have been shown to be characteristics of K19-positive HCCs. Radiologic features including atypical enhancement patterns, absence of tumor capsules, and irregular tumor margins can be a clue for K19-positive HCCs. From a therapeutic standpoint, K19-positive HCCs have been associated with poor outcomes after curative resection or liver transplantation, and resistance to systemic chemotherapy and locoregional treatment, including transarterial chemoembolization and radiofrequency ablation. In this review, we summarize the currently available knowledge on the clinico-radio-pathological and molecular features of K19-expressing HCCs, including a detailed discussion on the regulation mechanism of these tumors.
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Affiliation(s)
- Hyungjin Rhee
- Department of Radiology, Research Institute of Radiological Science, Center for Clinical Imaging Data Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Haeryoung Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Young Nyun Park
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea,*Young Nyun Park, Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-gu, Seoul 03722 (Republic of Korea),
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Urban SK, Sänger H, Krawczyk M, Julich-Haertel H, Willms A, Ligocka J, Azkargorta M, Mocan T, Kahlert C, Kruk B, Jankowski K, Patkowski W, Krawczyk M, Zieniewicz K, Hołówko W, Krupa Ł, Rzucidło M, Gutkowski K, Wystrychowski W, Król R, Raszeja-Wyszomirska J, Słomka A, Schwab R, Wöhler A, Gonzalez-Carmona MA, Gehlert S, Sparchez Z, Banales JM, Strassburg CP, Lammert F, Milkiewicz P, Kornek M. Synergistic effects of extracellular vesicle phenotyping and AFP in hepatobiliary cancer differentiation. Liver Int 2020; 40:3103-3116. [PMID: 32614460 DOI: 10.1111/liv.14585] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 06/12/2020] [Accepted: 06/24/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Biliary cancer, comprising cholangio- and gallbladder carcinomas, is associated with high mortality due to asymptomatic disease onset and resulting late diagnosis. Currently, no robust diagnostic biomarker is clinically available. Therefore, we explored the feasibility of extracellular vesicles (EVs) as a liquid biopsy tool for biliary cancer screening and hepatobiliary cancer differentiation. METHODS Serum EVs of biliary cancer, hepatocellular carcinoma, colorectal cancer and non-small cell lung cancer patients, as well as from healthy individuals, were isolated by sequential two-step centrifugation and presence of indicated EVs was evaluated by fluorescence activated cell sorting (FACS) analysis. RESULTS Two directly tumour-related antigen combinations (AnnV+ CD44v6+ and AnnV+ CD44v6+ CD133+ ) and two combinations related to progenitor cells from the tumour microenvironment (AnnV+ CD133+ gp38+ and AnnV+ EpCAM+ CD133+ gp38+ ) were associated with good diagnostic performances that could potentially be used for clinical assessment of biliary cancer and differentiation from other cancer entities. With 91% sensitivity and 69% specificity AnnV+ CD44v6+ EVs showed the most promising results for differentiating biliary cancers from HCC. Moreover using a combined approach of EV levels of the four populations with serum AFP values, we obtained a perfect separation of biliary cancer and HCC with sensitivity, specificity, positive and negative predictive value all reaching 100% respectively. CONCLUSIONS EV phenotyping, especially if combined with serum AFP, represents a minimally invasive, accurate liquid biopsy tool that could improve cancer screening and differential diagnosis of hepatobiliary malignancies.
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Affiliation(s)
- Sabine K Urban
- Department of Internal Medicine I, University Medical Center Bonn, Bonn, Germany
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Hanna Sänger
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
- Institute of Experimental Immunology, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
- Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Henrike Julich-Haertel
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Arnulf Willms
- Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital, Koblenz, Germany
| | - Joanna Ligocka
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Mikel Azkargorta
- Proteomics Platform, Bizkaia Science and Technology Park, Derio, Spain
| | - Tudor Mocan
- Octavian Fodor Institute for Gastroenterology and Hepatology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Christoph Kahlert
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany
| | - Beata Kruk
- Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof Jankowski
- Department of Internal Medicine and Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Waldemar Patkowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Marek Krawczyk
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof Zieniewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Wacław Hołówko
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Łukasz Krupa
- Department of Gastroenterology and Hepatology with Internal Disease Unit, Specialist District Hospital in Rzeszow, Rzeszow, Poland
| | - Mateusz Rzucidło
- Department of Gastroenterology and Hepatology with Internal Disease Unit, Specialist District Hospital in Rzeszow, Rzeszow, Poland
| | - Krzysztof Gutkowski
- Department of Gastroenterology and Hepatology with Internal Disease Unit, Specialist District Hospital in Rzeszow, Rzeszow, Poland
| | - Wojciech Wystrychowski
- Department of General, Vascular and Transplant Surgery, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Robert Król
- Department of General, Vascular and Transplant Surgery, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Joanna Raszeja-Wyszomirska
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Artur Słomka
- Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Poland
| | - Robert Schwab
- Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital, Koblenz, Germany
| | - Aliona Wöhler
- Department of General, Visceral and Thoracic Surgery, German Armed Forces Central Hospital, Koblenz, Germany
| | | | - Sebastian Gehlert
- Department for Biosciences of Sports, Institute of Sports Science, University of Hildesheim, Hildesheim, Germany
| | - Zeno Sparchez
- Octavian Fodor Institute for Gastroenterology and Hepatology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | | | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
- Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
| | - Miroslaw Kornek
- Department of Internal Medicine I, University Medical Center Bonn, Bonn, Germany
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
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Svobodová J, Procházková J, Kabátková M, Krkoška M, Šmerdová L, Líbalová H, Topinka J, Kléma J, Kozubík A, Machala M, Vondráček J. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Disrupts Control of Cell Proliferation and Apoptosis in a Human Model of Adult Liver Progenitors. Toxicol Sci 2020; 172:368-384. [PMID: 31536130 DOI: 10.1093/toxsci/kfz202] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The aryl hydrocarbon receptor (AhR) activation has been shown to alter proliferation, apoptosis, or differentiation of adult rat liver progenitors. Here, we investigated the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated AhR activation on a human model of bipotent liver progenitors, undifferentiated HepaRG cells. We used both intact undifferentiated HepaRG cells, and the cells with silenced Hippo pathway effectors, yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which play key role(s) in tissue-specific progenitor cell self-renewal and expansion, such as in liver, cardiac, or respiratory progenitors. TCDD induced cell proliferation in confluent undifferentiated HepaRG cells; however, following YAP, and, in particular, double YAP/TAZ knockdown, TCDD promoted induction of apoptosis. These results suggested that, unlike in mature hepatocytes, or hepatocyte-like cells, activation of the AhR may sensitize undifferentiated HepaRG cells to apoptotic stimuli. Induction of apoptosis in cells with silenced YAP/TAZ was associated with upregulation of death ligand TRAIL, and seemed to involve both extrinsic and mitochondrial apoptosis pathways. Global gene expression analysis further suggested that TCDD significantly altered expression of constituents and/or transcriptional targets of signaling pathways participating in control of expansion or differentiation of liver progenitors, including EGFR, Wnt/β-catenin, or tumor growth factor-β signaling pathways. TCDD significantly upregulated cytosolic proapoptotic protein BMF (Bcl-2 modifying factor) in HepaRG cells, which could be linked with an enhanced sensitivity of TCDD-treated cells to apoptosis. Our results suggest that, in addition to promotion of cell proliferation and alteration of signaling pathways controlling expansion of human adult liver progenitors, AhR ligands may also sensitize human liver progenitor cells to apoptosis.
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Affiliation(s)
- Jana Svobodová
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno 61265, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno 61137, Czech Republic
| | - Jiřina Procházková
- Department of Chemistry and Toxicology, Veterinary Research Institute, Brno 62100, Czech Republic
| | - Markéta Kabátková
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno 61265, Czech Republic
| | - Martin Krkoška
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno 61265, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno 61137, Czech Republic
| | - Lenka Šmerdová
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno 61265, Czech Republic
| | - Helena Líbalová
- Department of Genetic Ecotoxicology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
| | - Jan Topinka
- Department of Genetic Ecotoxicology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
| | - Jiří Kléma
- Department of Computer Science, Czech Technical University, Prague 12135, Czech Republic
| | - Alois Kozubík
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno 61265, Czech Republic
| | - Miroslav Machala
- Department of Chemistry and Toxicology, Veterinary Research Institute, Brno 62100, Czech Republic
| | - Jan Vondráček
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno 61265, Czech Republic
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Ammendola M, Currò G, Memeo R, Curto LS, Luposella M, Zuccalà V, Pessaux P, Navarra G, Gadaleta CD, Ranieri G. Targeting Stem Cells with Hyperthermia: Translational Relevance in Cancer Patients. Oncology 2020; 98:755-762. [PMID: 32784294 DOI: 10.1159/000509039] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 05/27/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Tumor recurrences or metastases remain a major hurdle in improving overall cancer survival. In anticancer therapy, some patients inevitably develop chemo-/radiotherapy resistance at some point. Cancer stem cells are the driving force of tumorigenesis, recurrences, and metastases, contributing also to the failure of some cancer treatments. SUMMARY Emergent evidence suggests that stem cell diseases are at the base of human cancers, and tumor progression and chemo-/radiotherapy resistance may be dependent on just a small subpopulation of cancer stem cells. Hyperthermia can be a strong cancer treatment, especially when combined with radio- or chemotherapy. It is a relatively safe therapy, may kill or weaken tumor cells, and significantly increases the effectiveness of other treatments. However, these mechanisms remain largely unknown. A literature search was performed using PubMed including cited English publications. The search was last conducted in December 2019. Search phrases included "stem cells," "hyperthermia," "cancer," and "therapy." Abstracts, letters, editorials, and expert opinions were not considered for the drafting of the study. Key Message: Our goal was to focus on and to summarize different biological features of cancer stem cells and new therapeutic approaches using hyperthermia and its potential translation to human clinical trials.
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Affiliation(s)
- Michele Ammendola
- Science of Health Department, Digestive Surgery Unit, University "Magna Graecia" Medical School, Catanzaro, Italy,
| | - Giuseppe Currò
- Science of Health Department, Digestive Surgery Unit, University "Magna Graecia" Medical School, Catanzaro, Italy
- Department of Human Pathology of Adult and Evolutive Age, Surgical Oncology Division, University Hospital of Messina, Messina, Italy
| | - Riccardo Memeo
- Hepato-Biliary and Pancreatic Surgical Unit, "F. Miulli" Hospital, Bari, Italy
| | - Lucia Stella Curto
- Science of Health Department, Digestive Surgery Unit, University "Magna Graecia" Medical School, Catanzaro, Italy
| | - Maria Luposella
- Cardiovascular Disease Unit, "San Giovanni di Dio" Hospital, Crotone, Italy
| | - Valeria Zuccalà
- Science of Health Department, Digestive Surgery Unit, University "Magna Graecia" Medical School, Catanzaro, Italy
| | - Patrick Pessaux
- Hepato-Biliary and Pancreatic Surgical Unit, General, Digestive and Endocrine Surgery, IRCAD, IHU Mix-Surg, Institute for Minimally Invasive Image-Guided Surgery, University of Strasbourg, Strasbourg, France
| | - Giuseppe Navarra
- Department of Human Pathology of Adult and Evolutive Age, Surgical Oncology Division, University Hospital of Messina, Messina, Italy
| | - Cosmo Damiano Gadaleta
- Diagnostic and Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Girolamo Ranieri
- Diagnostic and Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
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Zhuo JY, Lu D, Tan WY, Zheng SS, Shen YQ, Xu X. CK19-positive Hepatocellular Carcinoma is a Characteristic Subtype. J Cancer 2020; 11:5069-5077. [PMID: 32742454 PMCID: PMC7378918 DOI: 10.7150/jca.44697] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 06/13/2020] [Indexed: 12/12/2022] Open
Abstract
The heterogeneity of hepatocellular carcinoma (HCC) commonly leads to therapeutic failure of HCC. Cytokeratin 19 (CK19) is well acknowledged as a biliary/progenitor cell marker and a marker of tumor stem cell. CK19-positive HCCs demonstrate aggressive behaviors and poor outcomes which including worse overall survival and early tumor recurrence after hepatectomy and liver transplantation. CK19-positive HCCs are resistant to chemotherapies as well as local treatment. This subset of HCC is thought to derive from liver progenitor cells and can be induced by extracellular stimulation such as hypoxia. Besides being a stemness marker, CK19 plays an important role in promoting malignant property of HCC. The regulatory network associated with CK19 expression has been summarized that extracellular stimulations which transmit into cytoplasm through signal transduction pathways (TGF-β, MAKP/JNK and MEK-ERK1/2), further induce important nuclear transcriptional factors (SALL4, AP1, SP1) to activate CK19 promoter. Novel noncoding RNAs are also involved in the regulation of CK19 expression. TGFβR1 becomes a therapeutic target for CK19-positive HCC. In conclusion, CK19 can be a potential biomarker for predicting poor prognosis after surgical and adjuvant therapies. CK19-pisitive HCCs exhibit distinctive molecular profiling, should be diagnosed and treated as a separate subtype of HCCs.
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Affiliation(s)
- Jian-Yong Zhuo
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China.,NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, 310003, Zhejiang Province, China
| | - Di Lu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China.,NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, 310003, Zhejiang Province, China
| | - Win-Yen Tan
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China.,NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, 310003, Zhejiang Province, China
| | - Shu-Sen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China.,NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, 310003, Zhejiang Province, China.,Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, 310003, Zhejiang Province, China
| | - You-Qing Shen
- Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310003, Zhejiang Province, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang Province, China.,NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, 310003, Zhejiang Province, China
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Pastore N, Huynh T, Herz NJ, Calcagni' A, Klisch TJ, Brunetti L, Kim KH, De Giorgi M, Hurley A, Carissimo A, Mutarelli M, Aleksieva N, D'Orsi L, Lagor WR, Moore DD, Settembre C, Finegold MJ, Forbes SJ, Ballabio A. TFEB regulates murine liver cell fate during development and regeneration. Nat Commun 2020; 11:2461. [PMID: 32424153 PMCID: PMC7235048 DOI: 10.1038/s41467-020-16300-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 04/20/2020] [Indexed: 12/29/2022] Open
Abstract
It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. However, the signaling pathways implicated in the differentiation of LPCs are still incompletely understood. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is known to be involved in osteoblast and myeloid differentiation, but its role in lineage commitment in the liver has not been investigated. Here we show that during development and upon regeneration TFEB drives the differentiation status of murine LPCs into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation. Genetic interaction studies show that Sox9, a marker of precursor and biliary cells, is a direct transcriptional target of TFEB and a primary mediator of its effects on liver cell fate. In summary, our findings identify an unexplored pathway that controls liver cell lineage commitment and whose dysregulation may play a role in biliary cancer.
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Affiliation(s)
- Nunzia Pastore
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA.
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
| | - Tuong Huynh
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Niculin J Herz
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Alessia Calcagni'
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Tiemo J Klisch
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Lorenzo Brunetti
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, 77030, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Kangho Ho Kim
- Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Marco De Giorgi
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Ayrea Hurley
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Annamaria Carissimo
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, NA, 80078, Italy
| | | | - Niya Aleksieva
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Luca D'Orsi
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, NA, 80078, Italy
| | - William R Lagor
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - David D Moore
- Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Carmine Settembre
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, NA, 80078, Italy
- Department of Translational Medicine, Medical Genetics, Federico II University, Naples, 80131, Italy
| | - Milton J Finegold
- Department of Pathology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Stuart J Forbes
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Andrea Ballabio
- Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, 77030, USA.
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, NA, 80078, Italy.
- Department of Translational Medicine, Medical Genetics, Federico II University, Naples, 80131, Italy.
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Cai X, Li H, Kaplan DE. Murine hepatoblast-derived liver tumors resembling human combined hepatocellular-cholangiocarcinoma with stem cell features. Cell Biosci 2020; 10:38. [PMID: 32190288 PMCID: PMC7071781 DOI: 10.1186/s13578-020-00395-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 02/26/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Combined hepatocellular-cholangiocarcinoma (CHC) is a primary hepatic malignancy with heterogeneously combined histological features of putative hepatic progenitor cells (HPC) origin. We describe a mouse model that exhibits the heterogenous histological and phenotypic finding similar to human CHC. METHODS We injected hepatoblasts isolated from p53-/- C57BL/6 mice into syngeneic wild-type pre-conditioned C57BL/6 mice. We confirmed that p53-/- murine hepatoblasts act as tumor-initiating cells (TICs) that generate CHC both in situ and within metastases. For comparative pathological study, 8 human cases of CHC with stem cell features were recruited by immunohistochemistry and multicolor fluorescence immunostaining. RESULTS We identified corresponding areas in murine tumors matching each WHO criteria-described subtype of human CHC. In both murine and human tumors, HPC-like cells in tumor nests and associated stem cell features/traits are suggested histologically to be the progenitor origin of the cancer. CONCLUSIONS The pathological characteristics of murine tumors recapitulate human CHC with stem cell features. These data provide additional comparative pathological evidence that CHC with stem cell features originate from HPCs and validate a model to study this cancer type in vivo.
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Affiliation(s)
- Xiong Cai
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 3400 Civic Center Drive, PCAM GI 7S, Philadelphia, PA 19104-6145 USA
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave., Wuhan, 430022 China
| | - Heli Li
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - David E. Kaplan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 3400 Civic Center Drive, PCAM GI 7S, Philadelphia, PA 19104-6145 USA
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Machida K. Cell fate, metabolic reprogramming and lncRNA of tumor-initiating stem-like cells induced by alcohol. Chem Biol Interact 2020; 323:109055. [PMID: 32171851 DOI: 10.1016/j.cbi.2020.109055] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 12/13/2019] [Accepted: 03/10/2020] [Indexed: 12/15/2022]
Abstract
Alcoholism synergizes the development of the hepatocellular carcinoma (HCC) in patients infected with hepatitis B or C virus (HBV or HCV). Tumor-initiating stem-like cells (TICs) are refractory to therapy and have expression of stemness transcription factors. Leaky-gut-derived endotoxin stimulates TLR4-NANOG pathway that skews asymmetric cell division and that metabolically reprograms hepatocytes/liver progenitor cells, leading to self-renewal. TICs isolated from mouse HCC models or human HCCs are tumorigenic and have p53 degradation via phosphorylation of the protective protein NUMB and its dissociation from p53 by the oncofetal protein TBC1D15. Furthermore, dysregulation of lncRNA promotes genesis of TICs, leading to HCC development. This review describes roles of cell fate decision, metabolic reprogramming and lncRNA for TIC genesis and liver oncogenesis. This project was supported by NIH grants 1R01AA018857-01, 5R21AA025470, P50AA11999 (Animal Core, Morphology Core, and Pilot Project Program), R24AA012885 (Non-Parenchymal Liver Cell Core) and pilot project funding (5P30DK048522-13).
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Affiliation(s)
- Keigo Machida
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA; Department of Molecular Microbiology and Immunology, Los Angeles, CA, USA.
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38
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Complement C1q mediates the expansion of periportal hepatic progenitor cells in senescence-associated inflammatory liver. Proc Natl Acad Sci U S A 2020; 117:6717-6725. [PMID: 32139604 DOI: 10.1073/pnas.1918028117] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Most hepatocellular carcinomas (HCCs) develop in patients with chronic hepatitis, which creates a microenvironment for the growth of hepatic progenitor cells (HPCs) at the periportal area and subsequent development of HCCs. We investigated the signal from the inflammatory liver for this pathogenic process in the hepatic conditional β-catenin knockout mouse model. Senescent β-catenin-depleted hepatocytes in aged mice create an inflammatory microenvironment that stimulates periportal HPC expansion but arrests differentiation, which predisposes mice to the development of liver tumors. The release of complement C1q from macrophages in the inflammatory niche was identified as the unorthodox signal that activated the β-catenin pathway in periportal HPCs and was responsible for their expansion and de-differentiation. C1q inhibitors blocked the β-catenin pathway in both the expanding HPCs and the liver tumors but spared its orthodox pathway in pericentral normal hepatocytes. This mechanism has been validated in human liver specimens from patients with chronic hepatitis. Taken together, these results demonstrate that C1q- mediated activation of β-catenin pathway in periportal HPCs is a previously unrecognized mechanism for replenishing hepatocytes in the inflammatory liver and, if unchecked, for promoting hepatocarcinogenesis. C1q may become a new target for blocking carcinogenesis in patients with chronic hepatitis.
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39
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Roos E, Strijker M, Franken LC, Busch OR, van Hooft JE, Klümpen HJ, van Laarhoven HW, Wilmink JW, Verheij J, van Gulik TM, Besselink MG. Comparison of short- and long-term outcomes between anatomical subtypes of resected biliary tract cancer in a Western high-volume center. HPB (Oxford) 2020; 22:405-414. [PMID: 31494056 DOI: 10.1016/j.hpb.2019.07.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 05/25/2019] [Accepted: 07/19/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Outcomes for the four anatomical subtypes of biliary tract carcinoma (BTC) - intrahepatic, perihilar and distal cholangiocarcinoma (ICC, PHCC, DCC) and gallbladder carcinoma (GBC) - are often combined. However, large cohorts comparing short- and long-term outcomes for the anatomical subtypes of BTC are lacking. METHODS All patients who underwent resection for pathology proven ICC, PHCC, DCC or GBC (2000-2016) from a single Western high-volume center were retrospectively selected. Clinicopathological characteristics, short- and long-term outcomes were compared between the four anatomical subtypes. RESULTS Overall, 361 patients with resected BTC were included (33 ICC, 135 PHCC, 148 DCC, 45 GBC). Clavien-Dindo grade III or higher complications were 48%, 51%, 36% and 8% (p < 0.001) and 90-day mortality was 9%, 15%, 3%, 4% (p < 0.001), for ICC, PHCC, DCC, GBC. Median overall survival was 37, 42, 29 and 41 months (p = 0.722), for ICC, PHCC, DCC, GBC. Five-year survival ranged between 29% and 37%. Anatomical subtype was not an independent predictor for overall survival. CONCLUSION In this large single-center cohort of resected BTC, major morbidity and 90-day mortality varied between the four anatomical subtypes of BTC, mainly due to differences in surgical approach However, a significant difference in overall survival was not detected.
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Affiliation(s)
- Eva Roos
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands.
| | - Marin Strijker
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Lotte C Franken
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Olivier R Busch
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Jeanin E van Hooft
- Department of Gastroenterology & Hepatology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Heinz-Josef Klümpen
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Hanneke W van Laarhoven
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Johanna W Wilmink
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Joanne Verheij
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Thomas M van Gulik
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Marc G Besselink
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands.
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40
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Ko S, Russell JO, Molina LM, Monga SP. Liver Progenitors and Adult Cell Plasticity in Hepatic Injury and Repair: Knowns and Unknowns. ANNUAL REVIEW OF PATHOLOGY 2020; 15:23-50. [PMID: 31399003 PMCID: PMC7212705 DOI: 10.1146/annurev-pathmechdis-012419-032824] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The liver is a complex organ performing numerous vital physiological functions. For that reason, it possesses immense regenerative potential. The capacity for repair is largely attributable to the ability of its differentiated epithelial cells, hepatocytes and biliary epithelial cells, to proliferate after injury. However, in cases of extreme acute injury or prolonged chronic insult, the liver may fail to regenerate or do so suboptimally. This often results in life-threatening end-stage liver disease for which liver transplantation is the only effective treatment. In many forms of liver injury, bipotent liver progenitor cells are theorized to be activated as an additional tier of liver repair. However, the existence, origin, fate, activation, and contribution to regeneration of liver progenitor cells is hotly debated, especially since hepatocytes and biliary epithelial cells themselves may serve as facultative stem cells for one another during severe liver injury. Here, we discuss the evidence both supporting and refuting the existence of liver progenitor cells in a variety of experimental models. We also debate the validity of developing therapies harnessing the capabilities of these cells as potential treatments for patients with severe and chronic liver diseases.
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Affiliation(s)
- Sungjin Ko
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
| | - Jacquelyn O Russell
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
| | - Laura M Molina
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
| | - Satdarshan P Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
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41
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Wu CD, Lee JC, Wu HC, Lee CW, Lin CF, Hsu MC, Lin CT. Preclinical verification of the efficacy by targeting peptide-linked liposomal nanoparticles for hepatocellular carcinoma therapy. Nanobiomedicine (Rij) 2019; 6:1849543519880762. [PMID: 31908670 PMCID: PMC6937529 DOI: 10.1177/1849543519880762] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 09/15/2019] [Indexed: 01/07/2023] Open
Abstract
The purpose of this study was to investigate the efficacy of targeting peptides chemotherapy to overcome adverse event in the conventional chemotherapy for human hepatocellular carcinoma. Previously we reported several cancer-targeting peptides that bind specifically to cancer cells and their vascular endothelia: L-peptide (anti-cancer cell membrane), RLLDTNRPLLPY; SP-94-peptide (anti-hepatoma cell membrane), SFSHHTPILP; PC5-52-peptide (anti-tumor endothelia), SVSVGMKPSPRP; and control peptide, RLLDTNRGGGGG. In this study, these peptides were linked to liposomal iron oxide nanoparticles to localize the targeted tumor cells and endothelia, and to dextran-coated liposomal doxorubicin (L-D) to treat nonobese diabetic severe combined immunodeficient mice bearing hepatoma xenografts. Our results showed that L-peptide-linked liposomal doxorubicin could inhibit tumor growth with very mild adverse events. Use of the control peptide led to a decrease in the xenograft size but also led to marked apoptotic change in the visceral organ. In conclusion, L-peptide-linked liposomal doxorubicin, SP-94-peptide, and PC5-52-peptide can be used for the treatment of hepatoma xenografts in nonobese diabetic severe combined immunodeficient mice with minimal adverse events.
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Affiliation(s)
- Cheng-Der Wu
- Institute and Department of Pathology, National Taiwan University Hospital, Taipei, Republic of China
| | - Jen-Chieh Lee
- Institute and Department of Pathology, National Taiwan University Hospital, Taipei, Republic of China
| | - Hang-Chung Wu
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Republic of China
| | - Chung-Wei Lee
- Department of Medical Imaging and Radiology, National Taiwan University Hospital, Taipei, Republic of China
| | - Chih-Feng Lin
- Department of Otolaryngology, National Taiwan University Hospital, Taipei, Republic of China
| | - Ming-Chen Hsu
- Institute and Department of Pathology, National Taiwan University Hospital, Taipei, Republic of China
| | - Chin-Tarng Lin
- Institute and Department of Pathology, National Taiwan University Hospital, Taipei, Republic of China
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Roy S, Glaser S, Chakraborty S. Inflammation and Progression of Cholangiocarcinoma: Role of Angiogenic and Lymphangiogenic Mechanisms. Front Med (Lausanne) 2019; 6:293. [PMID: 31921870 PMCID: PMC6930194 DOI: 10.3389/fmed.2019.00293] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 11/29/2019] [Indexed: 12/13/2022] Open
Abstract
Cholangiocarcinoma (CCA), or cancer of the biliary epithelium is a relatively rare but aggressive form of biliary duct cancer which has a 5-year survival rate post metastasis of 2%. Although a number of risk factors are established for CCA growth and progression, a careful evaluation of the existing literature on CCA reveals that an inflammatory environment near the biliary tree is the most common causal link between the risk factors and the development of CCA. The fact that inflammation predisposes affected individuals to CCA is further bolstered by multiple observations where the presence and maintenance of an inflammatory microenvironment at the site of the primary tumor plays a significant role in the development and metastasis of CCA. In addition, mechanisms activating the tumor vasculature and enhancing angiogenesis and lymphangiogenesis significantly contribute to CCA aggressiveness and metastasis. This review aims to address the role of an inflammatory microenvironment-CCA crosstalk and will present the basic concepts, observations, and current perspectives from recent research studies in the field of tumor stroma of CCA.
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Affiliation(s)
- Sukanya Roy
- Department of Medical Physiology, Texas A&M Health Science Center College of Medicine, Bryan, TX, United States
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M Health Science Center College of Medicine, Bryan, TX, United States
| | - Sanjukta Chakraborty
- Department of Medical Physiology, Texas A&M Health Science Center College of Medicine, Bryan, TX, United States
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Pez F, Gifu P, Degli-Esposti D, Fares N, Lopez A, Lefrançois L, Michelet M, Rivoire M, Bancel B, Sylla BS, Herceg Z, Merle P, Caron de Fromentel C. In vitro transformation of primary human hepatocytes: Epigenetic changes and stemness properties. Exp Cell Res 2019; 384:111643. [PMID: 31557464 DOI: 10.1016/j.yexcr.2019.111643] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 09/19/2019] [Accepted: 09/21/2019] [Indexed: 02/07/2023]
Abstract
Human hepatocarcinogenesis is a complex process with many unresolved issues, including the cell of origin (differentiated and/or progenitor/stem cells) and the initial steps leading to tumor development. With the aim of providing new tools for studying hepatocellular carcinoma initiation and progression, we developed an innovative model based on primary human hepatocytes (PHHs) lentivirus-transduced with SV40LT+ST, HRASV12 with or without hTERT. The differentiation status of these transduced-PHHs was characterized by RNA sequencing (including lncRNAs), and the expression of some differentiation markers confirmed by RT-qPCR and immunofluorescence. In addition, their transformation capacity was assessed by colony formation in soft agar and tumorigenicity evaluated in immune-deficient mice. The co-expression of SV40LT+ST and HRASV12 in PHHs, in association or not with hTERT, led to the emergence of transformed clones. These clones exhibited a poorly differentiated cell phenotype with expression of stemness and mesenchymal-epithelial transition markers and gave rise to cancer stem cell subpopulations. In vivo, they resulted in poorly differentiated hepatocellular carcinomas with a reactivation of endogenous hTERT. These experiments demonstrate for the first time that non-cycling human mature hepatocytes can be permissive to in vitro transformation. This cellular tool provides the first comprehensive in vitro model for identifying genetic/epigenetic changes driving human hepatocarcinogenesis.
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Affiliation(s)
- Floriane Pez
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
| | - Patricia Gifu
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
| | - Davide Degli-Esposti
- Epigenetics Group, International Agency for Research on Cancer (IARC), Lyon, France
| | - Nadim Fares
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
| | - Anaïs Lopez
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
| | - Lydie Lefrançois
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
| | - Maud Michelet
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
| | - Michel Rivoire
- Département de Chirurgie et Institut de Chirurgie Expérimentale, Centre Léon Bérard, Lyon, France
| | - Brigitte Bancel
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France; Hospices Civils de Lyon, Service d'Anatomopathologie, Groupement Hospitalier Lyon Nord, France
| | - Bakary S Sylla
- Infections and Cancer Biology Group, International Agency for Research on Cancer (IARC), Lyon, France
| | - Zdenko Herceg
- Epigenetics Group, International Agency for Research on Cancer (IARC), Lyon, France
| | - Philippe Merle
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France; Hospices Civils de Lyon, Service d'Hépatologie et Gastroentérologie, Groupement Hospitalier Lyon Nord, France
| | - Claude Caron de Fromentel
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France.
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Czepukojc B, Abuhaliema A, Barghash A, Tierling S, Naß N, Simon Y, Körbel C, Cadenas C, van Hul N, Sachinidis A, Hengstler JG, Helms V, Laschke MW, Walter J, Haybaeck J, Leclercq I, Kiemer AK, Kessler SM. IGF2 mRNA Binding Protein 2 Transgenic Mice Are More Prone to Develop a Ductular Reaction and to Progress Toward Cirrhosis. Front Med (Lausanne) 2019; 6:179. [PMID: 31555647 PMCID: PMC6737005 DOI: 10.3389/fmed.2019.00179] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 07/23/2019] [Indexed: 12/21/2022] Open
Abstract
The insulin-like growth factor 2 (IGF2) mRNA binding proteins (IMPs/IGF2BPs) IMP1 and 3 are regarded as oncofetal proteins, whereas the hepatic IMP2 expression in adults is controversially discussed. The splice variant IMP2-2/p62 promotes steatohepatitis and hepatocellular carcinoma. Aim of this study was to clarify whether IMP2 is expressed in the adult liver and influences progression toward cirrhosis. IMP2 was expressed at higher levels in embryonic compared to adult tissues as quantified in embryonic, newborn, and adult C57BL/6J mouse livers and suggested by analysis of publicly available human data. In an IMP2-2 transgenic mouse model microarray and qPCR analyses revealed increased expression of liver progenitor cell (LPC) markers Bex1, Prom1, Spp1, and Cdh1 indicating a de-differentiated liver cell phenotype. Induction of these LPC markers was confirmed in human cirrhotic tissue datasets. The LPC marker SPP1 has been described to play a major role in fibrogenesis. Thus, DNA methylation was investigated in order to decipher the regulatory mechanism of Spp1 induction. In IMP2-2 transgenic mouse livers single CpG sites were differentially methylated, as quantified by amplicon sequencing, whereas human HCC samples of a human publicly available dataset showed promoter hypomethylation. In order to study the impact of IMP2 on fibrogenesis in the context of steatohepatitis wild-type or IMP2-2 transgenic mice were fed either a methionine-choline deficient (MCD) or a control diet for 2-12 weeks. MCD-fed IMP2-2 transgenic mice showed a higher incidence of ductular reaction (DR), accompanied by hepatic stellate cell activation, extracellular matrix (ECM) deposition, and induction of the LPC markers Spp1, Cdh1, and Afp suggesting the occurrence of de-differentiated cells in transgenic livers. In human cirrhotic samples IMP2 overexpression correlated with LPC marker and ECM component expression. Progression of liver disease was induced by combined MCD and diethylnitrosamine (DEN) treatment. Combined MCD-DEN treatment resulted in shorter survival of IMP2-2 transgenic compared to wild-type mice. Only IMP2-2 transgenic livers progressed to cirrhosis, which was accompanied by strong DR. In conclusion, IMP2 is an oncofetal protein in the liver that promotes DR characterized by de-differentiated cells toward steatohepatitis-associated cirrhosis development with poor survival.
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Affiliation(s)
- Beate Czepukojc
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany
| | - Ali Abuhaliema
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany
| | - Ahmad Barghash
- Center for Bioinformatics, Saarland University, Saarbrücken, Germany.,Department of Computer Science, German Jordanian University, Amman, Jordan
| | - Sascha Tierling
- Genetics/Epigenetics, Saarland University, Saarbrücken, Germany
| | - Norbert Naß
- Department of Pathology, Medical Faculty, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Yvette Simon
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany
| | - Christina Körbel
- Institute of Clinical-Experimental Surgery, Saarland University Hospital, Homburg, Germany
| | - Cristina Cadenas
- Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo) at the TU Dortmund, Dortmund, Germany
| | - Noemi van Hul
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.,Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - Agapios Sachinidis
- Center for Molecular Medicine Cologne (CMMC), Institute of Neurophysiology, University of Cologne, Cologne, Germany
| | - Jan G Hengstler
- Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo) at the TU Dortmund, Dortmund, Germany
| | - Volkhard Helms
- Center for Bioinformatics, Saarland University, Saarbrücken, Germany
| | - Matthias W Laschke
- Institute of Clinical-Experimental Surgery, Saarland University Hospital, Homburg, Germany
| | - Jörn Walter
- Genetics/Epigenetics, Saarland University, Saarbrücken, Germany
| | - Johannes Haybaeck
- Department of Pathology, Medical Faculty, Otto von Guericke University Magdeburg, Magdeburg, Germany.,Institute of Pathology, Medical University of Graz, Graz, Austria.,Department of Pathology, Medical University Innsbruck, Innsbruck, Austria
| | - Isabelle Leclercq
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Alexandra K Kiemer
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany
| | - Sonja M Kessler
- Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany.,Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.,Institute of Pathology, Medical University of Graz, Graz, Austria
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45
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Roos E, Soer EC, Klompmaker S, Meijer LL, Besselink MG, Giovannetti E, Heger M, Kazemier G, Klümpen HJ, Takkenberg RB, Wilmink H, Würdinger T, Dijk F, van Gulik TM, Verheij J, van de Vijver MJ. Crossing borders: A systematic review with quantitative analysis of genetic mutations of carcinomas of the biliary tract. Crit Rev Oncol Hematol 2019; 140:8-16. [PMID: 31158800 DOI: 10.1016/j.critrevonc.2019.05.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 05/21/2019] [Indexed: 12/11/2022] Open
Abstract
Biliary tract carcinoma (BTC) comprises gallbladder and intra-/extrahepatic cholangiocarcinoma (GBC, ICC, EHC), which are currently classified by anatomical origin. Better understanding of the mutational profile of BTCs might refine classification and improve treatment. We performed a systematic review of studies reporting on mutational profiling of BTC. We included articles reporting on whole-exome/whole-genome-sequencing (WES/WGS) and targeted sequencing (TS) of BTC, published between 2000-2017. Pooled mutation proportions were calculated, stratified by anatomical region and sequencing technique. A total of 25 studies with 1806 patients were included. Overall, TP53 was the most commonly mutated gene in BTC. GBC was associated with mutations in PFKFB3, PLXN2 and PGAP1. Mutations in IDH1, IDH2 and FGFR fusions almost exclusively occurred in ICC patients. Mutations in APC, GNAS and TGFBR2 occurred exclusively in EHC patients. In conclusion, subtypes of BTCs exhibit minor differences in mutational profile, which is likely influenced by the cell of origin.
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Affiliation(s)
- E Roos
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands; Laboratory of Experimental Surgery, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - E C Soer
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands.
| | - S Klompmaker
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - L L Meijer
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, the Netherlands; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, the Netherlands
| | - M G Besselink
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - E Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, the Netherlands
| | - M Heger
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands; Laboratory of Experimental Surgery, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - G Kazemier
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam, the Netherlands
| | - H J Klümpen
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - R B Takkenberg
- Department of Hepatology and Gastroenterology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - H Wilmink
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - T Würdinger
- Department of Neurosurgery, Amsterdam, Amsterdam UMC, VU University, the Netherlands; Brain Tumour Center, Cancer Center Amsterdam, Amsterdam UMC, VU University, the Netherlands
| | - F Dijk
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - T M van Gulik
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands; Laboratory of Experimental Surgery, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - J Verheij
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - M J van de Vijver
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands.
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46
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Elshaer AM, El-Kharashi OA, Hamam GG, Nabih ES, Magdy YM, Abd El Samad AA. Involvement of TLR4/ CXCL9/ PREX-2 pathway in the development of hepatocellular carcinoma (HCC) and the promising role of early administration of lactobacillus plantarum in Wistar rats. Tissue Cell 2019; 60:38-47. [PMID: 31582017 DOI: 10.1016/j.tice.2019.07.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 06/30/2019] [Accepted: 07/30/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIM Improvement of gut microbiota may help in preventing the progression of cirrhosis. We supposed that Lactobacillus Plantarum (L. Plantarum) protects the cirrhotic liver through suppression of TLR4/ CXCL9/ PREX-2. METHODOLOGY Rats were divided into two groups. Group I, lasts for six weeks and Group II lasts for 12 weeks. Each group was subdivided into: naïve, Lactobacillus Plantarum (L. Plantarum), thioacetamide (TAA) and TAA + L. Plantarum. Liver function tests, α fetoprotein (AFP) levels, CXCL9, PREX-2 and TLR4 expression were assessed. Histological studies were performed. RESULTS TAA induced significant deterioration in liver functions and increased AFP. There was periportal cirrhosis, vacuolated hepatocytes, decrease hepatocyte parrafin-1 (hep par-1) expression, increase proliferating cell nuclear antigen (PCNA) positive nuclei and cytokeratin AE1/AE3. The PCR results showed significant increase in TLR4, CXCL9 and PREX-2 expression. Early administration of L. Plantarum significantly decreased the expression of TLR4, CXCL9 and PREX-2 together with improvement in liver function and prevented the pathological changes. CONCLUSIONS The cirrhotic complications induced by TAA are through activation of TLR4/ CXCL9/ PREX-2 pathway and could be prevented by the early administration of L. Plantarum.
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Affiliation(s)
- Asmaa M Elshaer
- Department of clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Omnyah A El-Kharashi
- Department of clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Ghada Galal Hamam
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Enas S Nabih
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Yosra M Magdy
- Department of clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Abeer A Abd El Samad
- Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
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47
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Kim HS, Park EJ, Lee CW. Implication of hepatocyte dedifferentiation in pathogenesis and treatment of hepatocellular carcinoma. PRECISION AND FUTURE MEDICINE 2019. [DOI: 10.23838/pfm.2018.00135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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48
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Pollicino T, Musolino C, Saitta C, Tripodi G, Lanza M, Raffa G, Tocco FCD, Raggi C, Bragazzi MC, Barbera A, Navarra G, Invernizzi P, Alvaro D, Raimondo G. Free episomal and integrated HBV DNA in HBsAg-negative patients with intrahepatic cholangiocarcinoma. Oncotarget 2019; 10:3931-3938. [PMID: 31231470 PMCID: PMC6570464 DOI: 10.18632/oncotarget.27002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 05/20/2019] [Indexed: 02/07/2023] Open
Abstract
There is evidence that chronic hepatitis B virus (HBV) infection is associated with an increased risk of intrahepatic cholangiocarcinoma (ICC) development, and it has been hypothesized an etiological role of HBV in the development of this tumor. Very little is known about occult HBV infection (OBI) in ICC. Aims of the study were to investigate the OBI prevalence and to characterize the HBV molecular status at intrahepatic level in OBI-positive cases with ICC. Frozen liver tumor specimens from 47 HBV surface-antigen-negative patients with ICC and 41 paired non-tumor liver tissues were tested for OBI by 4 different HBV-specific nested PCR. Covalently closed circular HBV DNA (HBV cccDNA) and viral integrations were investigated in OBI-positive cases. HBV DNA was detected in tumor and/or non-tumor specimens from 29/47 (61.7%) ICC patients. HBV cccDNA was found in tissues from 5/17 (34.5%) cases examined. HBV integration was detected in 4/10 (40%) tumor tissues tested and involved HBx and HBV-core gene sequences in 3 and 1 cases, respectively. Viral integration occurred: (a) 9,367 nucleotides upstream of the cat-eye-syndrome critical region protein-5-isoform coding sequence; (b) within the cystinosin isoform-1-precursor gene; (c) within the thromboxane-A-synthase-1 gene; (d) within the ATPase phospholipid transporting 9B gene. Occult HBV infection is highly prevalent in patients with ICC. Both free viral genomes and integrated HBV DNA can be present in these cases. These results suggest an involvement of HBV in the carcinogenic process leading to ICC development even in cases with occult infection.
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Affiliation(s)
- Teresa Pollicino
- Division of Clinical and Molecular Hepatology, University Hospital of Messina, Italy.,Department of Human Pathology, University of Messina, Italy
| | - Cristina Musolino
- Department of Clinical and Experimental Medicine, University of Messina, Italy
| | - Carlo Saitta
- Division of Clinical and Molecular Hepatology, University Hospital of Messina, Italy
| | - Gianluca Tripodi
- Department of Clinical and Experimental Medicine, University of Messina, Italy
| | - Marika Lanza
- Department of Clinical and Experimental Medicine, University of Messina, Italy
| | - Giuseppina Raffa
- Division of Clinical and Molecular Hepatology, University Hospital of Messina, Italy.,Department of Clinical and Experimental Medicine, University of Messina, Italy
| | | | - Chiara Raggi
- Humanitas Research and Clinical Center, Rozzano, Milan, Italy.,Present address: Department of Experimental and Clinical Medicine, University of Florence, Italy
| | | | - Adalberto Barbera
- Department of Human Pathology, University of Messina, Italy.,Division of Surgical Oncology, University Hospital of Messina, Italy
| | - Giuseppe Navarra
- Department of Human Pathology, University of Messina, Italy.,Division of Surgical Oncology, University Hospital of Messina, Italy
| | - Pietro Invernizzi
- Humanitas Research and Clinical Center, Rozzano, Milan, Italy.,Present address: Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano - Bicocca, Milan, Italy
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Giovanni Raimondo
- Division of Clinical and Molecular Hepatology, University Hospital of Messina, Italy.,Department of Clinical and Experimental Medicine, University of Messina, Italy
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49
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Machida K. NANOG-Dependent Metabolic Reprogramming and Symmetric Division in Tumor-Initiating Stem-like Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1032:105-113. [PMID: 30362094 PMCID: PMC6687510 DOI: 10.1007/978-3-319-98788-0_8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Alcohol abuse synergistically heightens the development of the third most deadliest cancer hepatocellular carcinoma (HCC) in patients infected with hepatitis C virus (HCV). Ectopically expressed TLR4 promotes liver tumorigenesis in alcohol-fed HCV Ns5a or Core transgenic mice. CD133+/CD49f + tumor-initiating stem cell-like cells (TICs) isolated from these models are tumorigenic have p53 degradation via phosphorylation of the protective protein NUMB and its dissociation from p53 by the oncoprotein TBC1D15. Nutrient deprivation reduces overexpressed TBC1D15 in TICs via autophagy-mediated degradation, suggesting a possible role of this oncoprotein in linking metabolic reprogramming and self-renewal.
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Affiliation(s)
- Keigo Machida
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA.
- Department of Molecular Microbiology and Immunology, Los Angeles, CA, USA.
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50
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Navas MC, Glaser S, Dhruv H, Celinski S, Alpini G, Meng F. Hepatitis C Virus Infection and Cholangiocarcinoma: An Insight into Epidemiologic Evidences and Hypothetical Mechanisms of Oncogenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1122-1132. [PMID: 30953604 DOI: 10.1016/j.ajpath.2019.01.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 12/14/2018] [Accepted: 01/08/2019] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection is a global public health problem because it is a main cause of liver cirrhosis and hepatocellular carcinoma. This human oncogenic virus is also associated with the development of non-Hodgkin lymphoma and cholangiocarcinoma (CCA). The association between HCV infection and CCA has been examined in a number of epidemiologic studies. However, in vivo and in vitro results demonstrating the oncogenic mechanisms of HCV in CCA development and progression are insufficient. Here, we review the epidemiologic association of HCV and CCA and recent publications of studies of HCV infection of cholangiocytes and CCA cell lines as well as studies of viral infection performed with liver samples obtained from patients. In addition, we also discuss the preliminary results of in vitro assays of HCV protein expression in CCA cell lines. Finally, we discuss the hypothetical role of HCV infection in CCA development by induction of epithelial-mesenchymal transition and up-regulation of hedgehog signaling, and consequently biliary tree inflammation and liver fibrosis. Further studies are required to demonstrate these hypotheses and therefore to elucidate the mechanisms of HCV as a risk factor for CCA.
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Affiliation(s)
- Maria-Cristina Navas
- Grupo Gastrohepatologia, School of Medicine, University of Antioquia, Medellin, Colombia; Department of Medical Physiology, Texas A&M University College of Medicine, Temple, Texas.
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Temple, Texas; Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas; Division of Research, Central Texas Veterans Health Care System, Temple, Texas
| | - Harshil Dhruv
- Translational Genomics Research Institute, Phoenix, Arizona
| | - Scott Celinski
- Department of Surgery, Baylor University Medical Center, Dallas, Texas
| | - Gianfranco Alpini
- Department of Medical Physiology, Texas A&M University College of Medicine, Temple, Texas; Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas; Division of Research, Central Texas Veterans Health Care System, Temple, Texas
| | - Fanyin Meng
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas; Division of Research, Central Texas Veterans Health Care System, Temple, Texas.
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