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Kaneko S, Asahina Y, Murakawa M, Ueyama S, Maeyashiki C, Watanabe H, Kusano-Kitazume A, Sato A, Uchidate K, Asakawa T, Watanabe S, Iizuka Y, Shibata I, Oooka S, Karakama Y, Fujii T, Watabe T, Akahoshi K, Tanabe M, Inada K, Mochida T, Watakabe K, Shimizu T, Tsuchiya J, Miyoshi M, Kitahata-Kawai F, Nitta S, Nakagawa M, Kakinuma S, Okamoto R. Prognostic significance of C-reactive protein in unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab. Hepatol Res 2024; 54:562-574. [PMID: 38133587 DOI: 10.1111/hepr.14001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/26/2023] [Accepted: 12/11/2023] [Indexed: 12/23/2023]
Abstract
AIM C-reactive protein (CRP) is both an inflammatory and prognostic marker in various cancers. This study aimed to elucidate the characteristics of CRP and the prognostic factors in patients who were administered with atezolizumab plus bevacizumab (ATZ + BEV) for unresectable hepatocellular carcinoma (HCC). METHODS A total of 213 patients who received ATZ + BEV for HCC from November 2020 to March 2023 at 15 hospitals were enrolled in this retrospective study. The prognosis was analyzed by subdividing the patients based on baseline characteristics, radiologic response, and treatment lines. Accuracy of survival prediction was assessed using CRP, alpha fetoprotein (AFP), C-reactive protein and alpha fetoprotein in immunotherapy (CRAFITY), and Glasgow Prognostic Score. RESULTS Compared with patients with baseline CRP <1 mg/dL, those with baseline CRP ≥1 mg/dL (n = 45) had a significantly higher baseline albumin-bilirubin score and AFP levels, significantly lower disease control rate (62.2%), and significantly shorter median overall survival (hazards ratios 2.292; 95% confidence interval 1.313-5.107; log-rank test, p < 0.001). Multivariate analysis identified CRP ≥1 mg/dL, AFP ≥100 ng/mL, and modified albumin-bilirubin grade as the significant prognostic factors. The baseline CRP, AFP, CRAFITY, and Glasgow Prognostic Score demonstrated higher discrimination for 1-year survival prediction after first-line ATZ + BEV administration, compared with beyond second line, with area under the receiver operating characteristic curves of 0.759, 0.761, 0.805, and 0.717, respectively. CONCLUSIONS CRP was a significant biomarker in patients treated with ATZ + BEV for HCC. Elevated CRP levels may indicate aggressive cancer progression and potential resistance to ATZ + BEV therapy.
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Affiliation(s)
- Shun Kaneko
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan
| | - Miyako Murakawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shunsuke Ueyama
- Department of Gastroenterology and Hepatology, Tsuchiura Kyodo General Hospital, Ibaraki, Japan
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hideki Watanabe
- Department of Gastroenterology and Hepatology, Yokosuka Kyosai Hospital, Kanagawa, Japan
| | - Akiko Kusano-Kitazume
- Department of Gastroenterology and Hepatology, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan
| | - Ayako Sato
- Department of Gastroenterology and Hepatology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
| | - Kozue Uchidate
- Department of Gastroenterology and Hepatology, JA Toride Medical Center, Ibaraki, Japan
| | - Takehito Asakawa
- Department of Gastroenterology and Hepatology, Yokohama City Minato Red Cross Hospital, Kanagawa, Japan
| | - Sho Watanabe
- Department of Gastroenterology and Hepatology, Soka Municipal Hospital, Saitama, Japan
| | - Yasuhiro Iizuka
- Department of Gastroenterology and Hepatology, Kashiwa Municipal Hospital, Chiba, Japan
| | - Isamu Shibata
- Department of Gastroenterology, National Hospital Organization Disaster Medical Center, Tokyo, Japan
| | - Shinya Oooka
- Department of Medical Oncology, Showa General Hospital, Tokyo, Japan
| | - Yuko Karakama
- Department of Gastroenterology and Hepatology, Tokyo Kyosai Hospital, Tokyo, Japan
| | - Takashi Fujii
- Department of Gastroenterology and Hepatology, Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan
| | - Taro Watabe
- Department of Gastroenterology and Hepatology, Ome Municipal General Hospital, Tokyo, Japan
| | - Keiichi Akahoshi
- Department of Hepatobiliary and Pancreatic Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Minoru Tanabe
- Department of Hepatobiliary and Pancreatic Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kento Inada
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomohiro Mochida
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Keiya Watakabe
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Taro Shimizu
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Jun Tsuchiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masato Miyoshi
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Fukiko Kitahata-Kawai
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sayuri Nitta
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mina Nakagawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Institute of Education, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sei Kakinuma
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
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Zhu L, Yu X, Tang X, Hu C, Wu L, Liu Y, Zhou Q. Evolving landscape of treatments targeting the microenvironment of liver metastases in non-small cell lung cancer. Chin Med J (Engl) 2024; 137:1019-1032. [PMID: 38251678 PMCID: PMC11062672 DOI: 10.1097/cm9.0000000000002981] [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: 12/05/2023] [Indexed: 01/23/2024] Open
Abstract
ABSTRACT Liver metastases (LMs) are common in lung cancer. Despite substantial advances in diagnosis and treatment, the survival rate of patients with LM remains low as the immune-suppressive microenvironment of the liver allows tumor cells to evade the immune system. The impact of LMs on the outcomes of immune checkpoint inhibitors in patients with solid tumors has been the main focus of recent translational and clinical research. Growing evidence indicates that the hepatic microenvironment delivers paracrine and autocrine signals from non-parenchymal and parenchymal cells. Overall, these microenvironments create pre- and post-metastatic conditions for the progression of LMs. Herein, we reviewed the epidemiology, physiology, pathology and immunology, of LMs associated with non-small cell lung cancer and the role and potential targets of the liver microenvironment in LM in each phase of metastasis. Additionally, we reviewed the current treatment strategies and challenges that should be overcome in preclinical and clinical investigations. These approaches target liver elements as the basis for future clinical trials, including combinatorial interventions reported to resolve hepatic immune suppression, such as immunotherapy plus chemotherapy, immunotherapy plus radiotherapy, immunotherapy plus anti-angiogenesis therapy, and surgical resection.
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Affiliation(s)
- Lingling Zhu
- Lung Cancer Center, Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, College of Polymer Science and Engineering, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xianzhe Yu
- Department of Gastrointestinal Surgery, Chengdu Second People’s Hospital, Chengdu, Sichuan 610041, China
| | - Xiaojun Tang
- Lung Cancer Center, Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Chenggong Hu
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Lei Wu
- Core Facility of West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yanyang Liu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Qinghua Zhou
- Lung Cancer Center, Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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Xu X, Huang A, Guo DZ, Wang YP, Zhang SY, Yan JY, Wang XY, Cao Y, Fan J, Zhou J, Fu XT, Shi YH. Integration of Inflammation-Immune Factors to Build Prognostic Model Predictive of Prognosis and Minimal Residual Disease for Hepatocellular Carcinoma. Front Oncol 2022; 12:893268. [PMID: 35756674 PMCID: PMC9213691 DOI: 10.3389/fonc.2022.893268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 05/17/2022] [Indexed: 12/24/2022] Open
Abstract
Background Tumor recurrence after hepatectomy is high for hepatocellular carcinoma (HCC), and minimal residual disease (MRD) could be the underlying mechanism. A predictive model for recurrence and presence of MRD is needed. Methods Common inflammation-immune factors were reviewed and selected to construct novel models. The model consisting of preoperative aspartate aminotransferase, C-reactive protein, and lymphocyte count, named ACLR, was selected and evaluated for clinical significance. Results Among the nine novel inflammation-immune models, ACLR showed the highest accuracy for overall survival (OS) and time to recurrence (TTR). At the optimal cutoff value of 80, patients with high ACLR (> 80) had larger tumor size, higher Edmondson’s grade, more vascular invasion, advanced tumor stage, and poorer survival than those with low ACLR (≤ 80) in the training cohort (5-year OS: 43.3% vs. 80.1%, P < 0.0001; 5-year TTR: 74.9% vs. 45.3%, P < 0.0001). Multivariate Cox analysis identified ACLR as an independent risk factor for OS [hazard ratio (HR) = 2.22, P < 0.001] and TTR (HR = 2.36, P < 0.001). Such clinical significance and prognostic value were verified in validation cohort. ACLR outperformed extant models, showing the highest area under receiver operating characteristics curve for 1-, 3-, and 5-year OS (0.737, 0.719, and 0.708) and 1-, 3-, and 5-year TTR (0.696, 0.650, and 0.629). High ACLR correlated with early recurrence (P < 0.001) and extremely early recurrence (P < 0.001). In patients with high ACLR, wide resection margin might confer survival benefit by decreasing recurrence (median TTR, 25.5 vs. 11.4 months; P = 0.037). Conclusions The novel inflammation-immune model, ACLR, could effectively predict prognosis, and the presence of MRD before hepatectomy and might guide the decision on resection margin for patients with HCC.
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Affiliation(s)
- Xin Xu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ao Huang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - De-Zhen Guo
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yu-Peng Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shi-Yu Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia-Yan Yan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xin-Yu Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ya Cao
- Cancer Research Institute, Xiangya School of Medicine, Central South University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China.,State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China.,State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Xiu-Tao Fu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying-Hong Shi
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
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4
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Scheiner B, Pomej K, Kirstein MM, Hucke F, Finkelmeier F, Waidmann O, Himmelsbach V, Schulze K, von Felden J, Fründt TW, Stadler M, Heinzl H, Shmanko K, Spahn S, Radu P, Siebenhüner AR, Mertens JC, Rahbari NN, Kütting F, Waldschmidt DT, Ebert MP, Teufel A, De Dosso S, Pinato DJ, Pressiani T, Meischl T, Balcar L, Müller C, Mandorfer M, Reiberger T, Trauner M, Personeni N, Rimassa L, Bitzer M, Trojan J, Weinmann A, Wege H, Dufour JF, Peck-Radosavljevic M, Vogel A, Pinter M. Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. J Hepatol 2022; 76:353-363. [PMID: 34648895 DOI: 10.1016/j.jhep.2021.09.035] [Citation(s) in RCA: 176] [Impact Index Per Article: 58.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 09/20/2021] [Accepted: 09/26/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need. METHODS Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204). RESULTS Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response. CONCLUSIONS The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation. LAY SUMMARY The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers.
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Affiliation(s)
- Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Katharina Pomej
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Martha M Kirstein
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Department of Medicine I, University Medical Center Schleswig-Holstein, Lübeck, Germany
| | - Florian Hucke
- Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Fabian Finkelmeier
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Oliver Waidmann
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Vera Himmelsbach
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Kornelius Schulze
- 1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johann von Felden
- 1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thorben W Fründt
- 1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marc Stadler
- Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria; Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Harald Heinzl
- Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Kateryna Shmanko
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Stephan Spahn
- Department of Internal Medicine I, Eberhard-Karls University, Tuebingen, Germany
| | - Pompilia Radu
- Hepatology-Department of Biomedical Research, University of Bern, Bern, Switzerland; University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | - Alexander R Siebenhüner
- Department of Medical Oncology and Hematology, University Hospital Zurich and University Zurich, Zurich, Switzerland; Department of Medical Oncology and Hematology, Cantonal Hospital Schaffhausen, Schaffhausen, Switzerland
| | - Joachim C Mertens
- Department of Hepatology and Gastroenterology, University Hospital Zurich and University Zurich, Zurich, Switzerland
| | - Nuh N Rahbari
- Department of Surgery at University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Fabian Kütting
- Department of Gastroenterology and Hepatology, University of Cologne, Cologne, Germany
| | | | - Matthias P Ebert
- Department of Internal Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andreas Teufel
- Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Internal Medicine II, Division of Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sara De Dosso
- Department of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Lugano, Switzerland
| | - David J Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS London, UK; Department of Translational Medicine, Università degli Studi del Piemonte Orientale, Novara, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy
| | - Tobias Meischl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Christian Müller
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria; Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Nicola Personeni
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (Milan), Italy
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (Milan), Italy
| | - Michael Bitzer
- Department of Internal Medicine I, Eberhard-Karls University, Tuebingen, Germany
| | - Jörg Trojan
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Arndt Weinmann
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Henning Wege
- 1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Cancer Center Esslingen, Klinikum Esslingen, 73730 Esslingen am Neckar, Germany
| | - Jean-François Dufour
- Hepatology-Department of Biomedical Research, University of Bern, Bern, Switzerland; University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | - Markus Peck-Radosavljevic
- Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria.
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5
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Gene knockout or inhibition of macrophage migration inhibitory factor alleviates lipopolysaccharide-induced liver injury via inhibiting inflammatory response. Hepatobiliary Pancreat Dis Int 2021; 20:469-477. [PMID: 34348873 DOI: 10.1016/j.hbpd.2021.07.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 07/13/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Liver injury is one of the most common complications during sepsis. Macrophage migration inhibitory factor (MIF) is an important proinflammatory cytokine. This study explored the role of MIF in the lipopolysaccharide (LPS)-induced liver injury through genetically manipulated mouse strains. METHODS The model of LPS-induced liver injury was established in wild-type and Mif-knockout C57/BL6 mice. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil) were detected, and the expressions of MIF, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured. Liver histopathology was conducted to assess liver injury. Moreover, the inhibitions of MIF with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and 4-iodo-6-phenylpyrimidine (4-IPP) were used to evaluate their therapeutic potential of liver injury. RESULTS Compared with wild-type mice, the liver function indices and inflammation factors presented no significant difference in the Mif-/- mice. After 72 h of the LPS-induced liver injury, serum levels of ALT, AST, and TBil as well as TNF-α and IL-1β were significantly increased, but the knockout of Mif attenuated liver injury and inflammatory response. In liver tissue, mRNA levels of TNF-α, IL-1β and NF-κB p65 were remarkably elevated in LPS-induced liver injury, while the knockout of Mif reduced these levels. Moreover, in LPS-induced liver injury, the inhibitions of MIF with ISO-1 and 4-IPP alleviated liver injury and slightly attenuated inflammatory response. Importantly, compared to mice with LPS-induced liver injury, Mif knockout or MIF inhibitions significantly prolonged the survival of the mice. CONCLUSIONS In LPS-induced liver injury, the knockout of Mif or MIF inhibitions alleviated liver injury and slightly attenuated inflammatory response, thereby prolonged the survival of the mice. Targeting MIF may be an important strategy to protect the liver from injury during sepsis.
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Jiao L, Eickhoff R, Egners A, Jumpertz S, Roth J, Erdem M, Kroh A, Duimel H, López-Iglesias C, Caro P, Heij LR, Schmeding M, Meierhofer D, Neumann UP, Cramer T. Deletion of mTOR in liver epithelial cells enhances hepatic metastasis of colon cancer. J Pathol 2021; 255:270-284. [PMID: 34309874 DOI: 10.1002/path.5768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 07/02/2021] [Accepted: 07/21/2021] [Indexed: 12/21/2022]
Abstract
Activation of the mechanistic target of rapamycin (mTOR) pathway is frequently found in cancer, but mTOR inhibitors have thus far failed to demonstrate significant antiproliferative efficacy in the majority of cancer types. Besides cancer cell-intrinsic resistance mechanisms, it is conceivable that mTOR inhibitors impact on non-malignant host cells in a manner that ultimately supports resistance of cancer cells. Against this background, we sought to analyze the functional consequences of mTOR inhibition in hepatocytes for the growth of metastatic colon cancer. To this end, we established liver epithelial cell (LEC)-specific knockout (KO) of mTOR (mTORLEC ) mice. We used these mice to characterize the growth of colorectal liver metastases with or without partial hepatectomy to model different clinical settings. Although the LEC-specific loss of mTOR remained without effect on metastasis growth in intact liver, partial liver resection resulted in the formation of larger metastases in mTORLEC mice compared with wildtype controls. This was accompanied by significantly enhanced inflammatory activity in LEC-specific mTOR KO livers after partial liver resection. Analysis of NF-ĸB target gene expression and immunohistochemistry of p65 displayed a significant activation of NF-ĸB in mTORLEC mice, suggesting a functional importance of this pathway for the observed inflammatory phenotype. Taken together, we show an unexpected acceleration of liver metastases upon deletion of mTOR in LECs. Our results support the notion that non-malignant host cells can contribute to resistance against mTOR inhibitors and encourage testing whether anti-inflammatory drugs are able to improve the efficacy of mTOR inhibitors for cancer therapy. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Long Jiao
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Roman Eickhoff
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Antje Egners
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Sandra Jumpertz
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Johanna Roth
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Merve Erdem
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Andreas Kroh
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Hans Duimel
- Microscopy Core Lab, FHML and M4I Maastricht Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, The Netherlands
| | - Carmen López-Iglesias
- Microscopy Core Lab, FHML and M4I Maastricht Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, The Netherlands
| | - Pilar Caro
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | - Lara R Heij
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany.,Pathology, RWTH University Hospital, Aachen, Germany
| | - Maximilian Schmeding
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
| | | | - Ulf P Neumann
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany.,ESCAM - European Surgery Center Aachen Maastricht, Aachen, Germany.,ESCAM - European Surgery Center Aachen Maastricht, Maastricht, The Netherlands.,Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Thorsten Cramer
- Department of General, Visceral- and Transplantation Surgery, RWTH University Hospital, Aachen, Germany.,ESCAM - European Surgery Center Aachen Maastricht, Aachen, Germany.,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
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7
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Chauhan A, Islam AU, Prakash H, Singh S. Phytochemicals targeting NF-κB signaling: Potential anti-cancer interventions. J Pharm Anal 2021; 12:394-405. [PMID: 35811622 PMCID: PMC9257438 DOI: 10.1016/j.jpha.2021.07.002] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 07/03/2021] [Accepted: 07/04/2021] [Indexed: 12/12/2022] Open
Abstract
Nuclear factor κB (NF-κB) is a ubiquitous regulator of the signalome and is indispensable for various biological cell functions. NF-κB consists of five transcription factors that execute both cytoplasmic and nuclear signaling processes in cells. NF-κB is the only signaling molecule that governs both pro- and anti-apoptotic, and pro- and anti-inflammatory responses. This is due to the canonical and non-canonical components of the NF-κB signaling pathway. Together, these pathways orchestrate cancer-related inflammation, hyperplasia, neoplasia, and metastasis. Non-canonical NF-κB pathways are particularly involved in the chemoresistance of cancer cells. In view of its pivotal role in cancer progression, NF-κB represents a potentially significant therapeutic target for modifying tumor cell behavior. Several phytochemicals are known to modulate NF-κB pathways through the stabilization of its inhibitor, IκB, by inhibiting phosphorylation and ubiquitination thereof. Several natural pharmacophores are known to inhibit the nuclear translocation of NF-κB and associated pro-inflammatory responses and cell survival pathways. In view of this and the high degree of specificity exhibited by various phytochemicals for the NF-κB component, we herein present an in-depth overview of these phytochemicals and discuss their mode of interaction with the NF-κB signaling pathways for controlling the fate of tumor cells for cancer-directed interventions.
NF-κB plays a pivotal role in the maintenance of homeostasis and various inflammation-mediated pathologies. NF-κB is involved in cancer development and progression by modulating growth signaling and apoptosis pathways. Phytochemicals modulating NF-κB activity should be exploited to design anticancer drugs with minimal side effects. Use of these phytochemicals in adjunctive chemotherapy may enhance the chemosensitivity of existing chemotherapeutic drugs.
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Affiliation(s)
- Akansha Chauhan
- Amity Institute of Physiology & Allied Sciences, Amity University, Noida, Uttar Pradesh, India
| | - Asim Ul Islam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Hridayesh Prakash
- Amity Institute of Virology & Immunology, Amity University, Noida, Uttar Pradesh, India
| | - Sandhya Singh
- Amity Institute of Physiology & Allied Sciences, Amity University, Noida, Uttar Pradesh, India
- Corresponding author.
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8
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Shen Y, Wang H, Li W, Chen J. Prognostic significance of the CRP/Alb and neutrophil to lymphocyte ratios in hepatocellular carcinoma patients undergoing TACE and RFA. J Clin Lab Anal 2019; 33:e22999. [PMID: 31418936 PMCID: PMC6868405 DOI: 10.1002/jcla.22999] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 07/11/2019] [Accepted: 07/22/2019] [Indexed: 12/18/2022] Open
Abstract
Background The C‐reactive protein (CRP)/albumin (Alb) ratio (CAR) is a basic inflammatory factor that has been related to poor survival of patients with various tumors. Our research retrospectively examined the relationship between the CAR and the prognosis of hepatocellular carcinoma (HCC). Methods This study included 172 patients with HCC who were treated with transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA). Results The CAR was weakly related to the neutrophil/lymphocyte ratio (NLR, r = .159, P = .037) and the lymphocyte/monocyte ratio (LMR, r = −.263, P = .001). The Glasgow Prognostic Score (GPS) (0/1‐2) was related to liver cirrhosis (P = .003), tumor number (P = .02), Child‐Pugh grade (P = .001), the platelet/lymphocyte ratio (PLR, P = .006), and the LMR (P = .021). Correlation analysis demonstrated that an elevated CAR was markedly correlated with the tumor size (P = .019), alpha‐fetoprotein (AFP) level (P = .033), thrombosis of the portal vein (P = .004), the NLR (P = .036), and the LMR (P = .001). Multivariate analysis indicated that the prognosis of the CAR‐High and NLR‐High cohort (mOS = 7 months) was significantly worse than those of the CAR‐High or NLR‐High cohort (mOS = 15 months) and the CAR‐Low and NLR‐Low cohort (mOS = 26.5 months). Conclusions Combination of the NLR and the CAR represents a convenient, quick, and noninvasive biological marker that could improve prognostic prediction in patients with HCC.
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Affiliation(s)
- Yanjun Shen
- Department of Oncology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Huige Wang
- Department of Gynecology, Wangjing Hospital of Chinese Academy of Chinese Medical, Beijing, China
| | - Wendong Li
- Department of Oncology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Jinglong Chen
- Department of Oncology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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9
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Khordadmehr M, Jigari-Asl F, Ezzati H, Shahbazi R, Sadreddini S, Safaei S, Baradaran B. A comprehensive review on miR-451: A promising cancer biomarker with therapeutic potential. J Cell Physiol 2019; 234:21716-21731. [PMID: 31140618 DOI: 10.1002/jcp.28888] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 05/07/2019] [Accepted: 05/09/2019] [Indexed: 12/16/2022]
Abstract
MicroRNAs (miRNAs) are proposed as a family of short noncoding molecules able to manage and control the expression of the gene targets at the posttranscriptional level. They contribute in several fundamental physiological mechanisms as well as a verity of human and animal diseases such as cancer progression. Among these tiny RNAs, miR-451 placed on chromosome 17 at 17q11.2 presents an essential role in many biological processes in health condition and also in pathogenesis of different diseases. Besides, it has been recently considered as a valuable biomarker for cancer detection, prognosis and treatment. Therefore, this review will provide the critical functions of miR-451 on biological mechanisms including cell cycle and proliferation, cell survival and apoptosis, differentiation and development as well as disease initiation and progression such as tumor formation, migration, invasion, and metastasis.
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Affiliation(s)
- Monireh Khordadmehr
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Farinaz Jigari-Asl
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Hamed Ezzati
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Roya Shahbazi
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Sanam Sadreddini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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10
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Matsui S, Zhou L, Nakayama Y, Mezawa M, Kato A, Suzuki N, Tanabe N, Nakayama T, Suzuki Y, Kamio N, Takai H, Ogata Y. MiR-200b attenuates IL-6 production through IKKβ and ZEB1 in human gingival fibroblasts. Inflamm Res 2018; 67:965-973. [PMID: 30306207 PMCID: PMC6223877 DOI: 10.1007/s00011-018-1192-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 09/28/2018] [Accepted: 10/03/2018] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE MicroRNAs (miRNAs) play important roles in biological processes such as cell differentiation, development, infection, immune response, inflammation and tumorigenesis. We previously reported that the expression of miR-200b was significantly increased in inflamed gingiva compared with non-inflamed gingiva. To elucidate the roles of miR-200b in the inflamed gingiva, we have analyzed the effects of miR-200b on the expression of IL-6 in human gingival fibroblasts (HGF). MATERIALS AND METHODS Total RNA and protein were extracted from HGF after stimulation by interleukin-1β (IL-1β; 1 ng/ml) or tumor necrosis factor-α (TNF-α; 10 ng/ml) and transfected with miR-200b expression plasmid or miR-200b inhibitor. IL-6, IL-1β, inhibitor of nuclear factor kappa-B kinaseβ (IKKβ), Zinc-finger E-box-binding homeobox 1 (ZEB1) and E-cadherin mRNA and protein levels were analyzed by real-time PCR and Western blot. RESULTS IL-1β and TNF-α increased IL-6 mRNA and protein levels, and they were significantly suppressed by miR-200b overexpression, whereas they were further increased by miR-200b inhibitor in HGF. IKKβ and ZEB1 which are target genes of miR-200b negatively regulate E-cadherin. MiR-200b suppressed the expression of IKKβ and ZEB1 and increased E-cadherin mRNA and protein levels in HGF. CONCLUSIONS These results suggest that miR-200b attenuates inflammatory response via IKKβ and ZEB1 in periodontal tissue.
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Affiliation(s)
- Sari Matsui
- Department of Periodontology, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba, 271-8587, Japan
| | - Liming Zhou
- Department of Periodontology, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba, 271-8587, Japan
- Stomatological Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yohei Nakayama
- Department of Periodontology, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba, 271-8587, Japan
- Research Institute of Oral Science, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba, 271-8587, Japan
| | - Masaru Mezawa
- Department of Periodontology, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba, 271-8587, Japan
- Research Institute of Oral Science, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba, 271-8587, Japan
| | - Ayako Kato
- Department of Periodontology, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba, 271-8587, Japan
- Research Institute of Oral Science, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba, 271-8587, Japan
| | - Naoto Suzuki
- Department of Biochemistry, Nihon University School of Dentistry, Chiyoda-ku, Tokyo, 101-8310, Japan
| | - Natsuko Tanabe
- Department of Biochemistry, Nihon University School of Dentistry, Chiyoda-ku, Tokyo, 101-8310, Japan
| | - Tomohiro Nakayama
- Laboratory of Veterinary Radiology, Nihon University College of Bioresource Sciences, Fujisawa, Kanagawa, 252-0880, Japan
| | - Yuki Suzuki
- Department of Preventive Veterinary Medicine and Animal Health, Nihon University College of Bioresource Sciences, Fujisawa, Kanagawa, 252-0880, Japan
| | - Noriaki Kamio
- Department of Microbiology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo, 101-8310, Japan
| | - Hideki Takai
- Department of Periodontology, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba, 271-8587, Japan
- Research Institute of Oral Science, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba, 271-8587, Japan
| | - Yorimasa Ogata
- Department of Periodontology, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba, 271-8587, Japan.
- Research Institute of Oral Science, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba, 271-8587, Japan.
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11
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O’Rourke JM, Sagar VM, Shah T, Shetty S. Carcinogenesis on the background of liver fibrosis: Implications for the management of hepatocellular cancer. World J Gastroenterol 2018; 24:4436-4447. [PMID: 30357021 PMCID: PMC6196335 DOI: 10.3748/wjg.v24.i39.4436] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 09/03/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is now the second leading cause of cancer-related deaths globally and many patients have incurable disease. HCC predominantly occurs in the setting of liver cirrhosis and is a paradigm for inflammation-induced cancer. The causes of chronic liver disease promote the development of transformed or premalignant hepatocytes and predisposes to the development of HCC. For HCC to grow and progress it is now clear that it requires an immunosuppressive niche within the fibrogenic microenvironment of cirrhosis. The rationale for targeting this immunosuppression is supported by responses seen in recent trials with checkpoint inhibitors. With the impact of immunotherapy, HCC progression may be delayed and long term durable responses may be seen. This makes the management of the underlying liver cirrhosis in HCC even more crucial as studies demonstrate that measures of liver function are a major prognostic factor in HCC. In this review, we discuss the development of cancer in the setting of liver inflammation and fibrosis, reviewing the microenvironment that leads to this tumourigenic climate and the implications this has for patient management.
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Affiliation(s)
- Joanne Marie O’Rourke
- Centre for Liver Research, Institute of Biomedical Research, Birmingham B15 2TT, United Kingdom
- NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, United Kingdom
| | - Vandana Mridhu Sagar
- Centre for Liver Research, Institute of Biomedical Research, Birmingham B15 2TT, United Kingdom
- NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, United Kingdom
| | - Tahir Shah
- NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, United Kingdom
| | - Shishir Shetty
- Centre for Liver Research, Institute of Biomedical Research, Birmingham B15 2TT, United Kingdom
- NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, United Kingdom
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12
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Soliman B, Salem A, Ghazy M, Abu-Shahba N, El Hefnawi M. Bioinformatics functional analysis of let-7a, miR-34a, and miR-199a/b reveals novel insights into immune system pathways and cancer hallmarks for hepatocellular carcinoma. Tumour Biol 2018; 40:1010428318773675. [PMID: 29775159 DOI: 10.1177/1010428318773675] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Let-7a, miR-34a, and miR-199 a/b have gained a great attention as master regulators for cellular processes. In particular, these three micro-RNAs act as potential onco-suppressors for hepatocellular carcinoma. Bioinformatics can reveal the functionality of these micro-RNAs through target prediction and functional annotation analysis. In the current study, in silico analysis using innovative servers (miRror Suite, DAVID, miRGator V3.0, GeneTrail) has demonstrated the combinatorial and the individual target genes of these micro-RNAs and further explored their roles in hepatocellular carcinoma progression. There were 87 common target messenger RNAs (p ≤ 0.05) that were predicted to be regulated by the three micro-RNAs using miRror 2.0 target prediction tool. In addition, the functional enrichment analysis of these targets that was performed by DAVID functional annotation and REACTOME tools revealed two major immune-related pathways, eight hepatocellular carcinoma hallmarks-linked pathways, and two pathways that mediate interconnected processes between immune system and hepatocellular carcinoma hallmarks. Moreover, protein-protein interaction network for the predicted common targets was obtained by using STRING database. The individual analysis of target genes and pathways for the three micro-RNAs of interest using miRGator V3.0 and GeneTrail servers revealed some novel predicted target oncogenes such as SOX4, which we validated experimentally, in addition to some regulated pathways of immune system and hepatocarcinogenesis such as insulin signaling pathway and adipocytokine signaling pathway. In general, our results demonstrate that let-7a, miR-34a, and miR-199 a/b have novel interactions in different immune system pathways and major hepatocellular carcinoma hallmarks. Thus, our findings shed more light on the roles of these miRNAs as cancer silencers.
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Affiliation(s)
- Bangly Soliman
- 1 Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,2 Informatics and Systems Department, Biomedical Informatics and Chemo-Informatics Group, Centre of Excellence for Advanced Sciences (CEAS), Division of Engineering Research, National Research Centre, Cairo, Egypt
| | - Ahmed Salem
- 1 Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Mohamed Ghazy
- 1 Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Nourhan Abu-Shahba
- 3 Stem Cells Research Group, Medical Centre of Excellence, Medical Molecular Genetics Department, National Research Centre, Cairo, Egypt
| | - Mahmoud El Hefnawi
- 2 Informatics and Systems Department, Biomedical Informatics and Chemo-Informatics Group, Centre of Excellence for Advanced Sciences (CEAS), Division of Engineering Research, National Research Centre, Cairo, Egypt.,4 Centre for Informatics, Nile University, Sheikh Zayed City, Egypt
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13
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Activation of Signal Transduction and Activator of Transcription 3 Signaling Contributes to Helicobacter-Associated Gastric Epithelial Proliferation and Inflammation. Gastroenterol Res Pract 2018; 2018:9050715. [PMID: 29849601 PMCID: PMC5911338 DOI: 10.1155/2018/9050715] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Revised: 12/25/2017] [Accepted: 01/14/2018] [Indexed: 02/08/2023] Open
Abstract
Background/Aim Although IL-6-mediated activation of the signal transduction and activator of transcription 3 (STAT3) axis is involved in inflammation and cancer, the role of STAT3 in Helicobacter-associated gastric inflammation and carcinogenesis is unclear. This study investigated the role of STAT3 in gastric inflammation and carcinogenesis and examined the molecular mechanism of Helicobacter-induced gastric phenotypes. Methods To evaluate the contribution of STAT3 to gastric inflammation and carcinogenesis, we used wild-type (WT) and gastric epithelial conditional Stat3-knockout (Stat3Δgec) mice. Mice were infected with Helicobacter felis and euthanized at 18 months postinfection. Mouse gastric organoids were treated with recombinant IL-6 (rIL-6) or rIL-11 and a JAK inhibitor (JAKi) to assess the role of IL-6/STAT3 signaling in vitro. Results Inflammation and mucous metaplasia were more severe in WT mice than in Stat3Δgec mice. The epithelial cell proliferation rate and STAT3 activation were increased in WT mice. Application of rIL-6 and rIL-11 induced expression of intestinal metaplasia-associated genes, such as Tff2; this induction was suppressed by JAKi administration. Conclusions Loss of STAT3 signaling in the gastric mucosa leads to decreased epithelial cell proliferation, atrophy, and metaplasia in the setting of Helicobacter infection. Therefore, activation of STAT3 signaling may play a key role in Helicobacter-associated gastric carcinogenesis.
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14
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Riedlinger T, Haas J, Busch J, van de Sluis B, Kracht M, Schmitz ML. The Direct and Indirect Roles of NF-κB in Cancer: Lessons from Oncogenic Fusion Proteins and Knock-in Mice. Biomedicines 2018; 6:biomedicines6010036. [PMID: 29562713 PMCID: PMC5874693 DOI: 10.3390/biomedicines6010036] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 03/16/2018] [Accepted: 03/17/2018] [Indexed: 12/24/2022] Open
Abstract
NF-κB signaling pathways play an important role in the regulation of cellular immune and stress responses. Aberrant NF-κB activity has been implicated in almost all the steps of cancer development and many of the direct and indirect contributions of this transcription factor system for oncogenesis were revealed in the recent years. The indirect contributions affect almost all hallmarks and enabling characteristics of cancer, but NF-κB can either promote or antagonize these tumor-supportive functions, thus prohibiting global NF-κB inhibition. The direct effects are due to mutations of members of the NF-κB system itself. These mutations typically occur in upstream components that lead to the activation of NF-κB together with further oncogenesis-promoting signaling pathways. In contrast, mutations of the downstream components, such as the DNA-binding subunits, contribute to oncogenic transformation by affecting NF-κB-driven transcriptional output programs. Here, we discuss the features of recently identified oncogenic RelA fusion proteins and the characterization of pathways that are regulating the transcriptional activity of NF-κB by regulatory phosphorylations. As NF-κB’s central role in human physiology prohibits its global inhibition, these auxiliary or cell type-specific NF-κB regulating pathways are potential therapeutic targets.
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Affiliation(s)
- Tabea Riedlinger
- Institute of Biochemistry, Justus-Liebig-University, D-35392 Giessen, Germany.
| | - Jana Haas
- Institute of Biochemistry, Justus-Liebig-University, D-35392 Giessen, Germany.
| | - Julia Busch
- Institute of Biochemistry, Justus-Liebig-University, D-35392 Giessen, Germany.
| | - Bart van de Sluis
- Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
| | - Michael Kracht
- Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University, D-35392 Giessen, Germany.
| | - M Lienhard Schmitz
- Institute of Biochemistry, Justus-Liebig-University, D-35392 Giessen, Germany.
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15
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Xing W, Xiao Y, Lu X, Zhu H, He X, Huang W, Lopez ES, Wong J, Ju H, Tian L, Zhang F, Xu H, Wang SD, Li X, Karin M, Ren H. GFI1 downregulation promotes inflammation-linked metastasis of colorectal cancer. Cell Death Differ 2017; 24:929-943. [PMID: 28387757 PMCID: PMC5423119 DOI: 10.1038/cdd.2017.50] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 02/27/2017] [Accepted: 03/06/2017] [Indexed: 12/21/2022] Open
Abstract
Inflammation is frequently associated with initiation, progression, and metastasis of colorectal cancer (CRC). Here, we unveil a CRC-specific metastatic programme that is triggered via the transcriptional repressor, GFI1. Using data from a large cohort of clinical samples including inflammatory bowel disease and CRC, and a cellular model of CRC progression mediated by cross-talk between the cancer cell and the inflammatory microenvironment, we identified GFI1 as a gating regulator responsible for a constitutively activated signalling circuit that renders CRC cells competent for metastatic spread. Further analysis of mouse models with metastatic CRC and human clinical specimens reinforced the influence of GFI1 downregulation in promoting CRC metastatic spread. The novel role of GFI1 is uncovered for the first time in a human solid tumour such as CRC. Our results imply that GFI1 is a potential therapeutic target for interfering with inflammation-induced CRC progression and spread.
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Affiliation(s)
- Wenjing Xing
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Yun Xiao
- Department of Bioinformatics, College of Bioinformatics, Harbin Medical University, Harbin 150081, China
| | - Xinliang Lu
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China.,Center of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Hongyan Zhu
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Xiangchuan He
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Wei Huang
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Elsa S Lopez
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Jerry Wong
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Huanyu Ju
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Linlu Tian
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Fengmin Zhang
- Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Hongwei Xu
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China
| | - Sheng Dian Wang
- Center of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Xia Li
- Department of Bioinformatics, College of Bioinformatics, Harbin Medical University, Harbin 150081, China
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Huan Ren
- Department of Immunology, Harbin Medical University, Harbin 150081, China.,Immunity & Infection Key laboratory of Heilongjiang Province, Harbin 150081, China.,College of basic medicine, Shanghai University Of Medicine & Health Sciences, Shanghai 201318, China
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16
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Hiramoto T, Yoshihara K, Asano Y, Sudo N. Protective Role of the Hepatic Vagus Nerve against Liver Metastasis in Mice. Neuroimmunomodulation 2017; 24:341-347. [PMID: 29621768 DOI: 10.1159/000487483] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 02/07/2018] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE(S) Although accumulating evidence has shown that the autonomic nervous system is involved in liver pathology, its role in regulating cancer development remains unclear. The purpose of this study was to elucidate its detailed mechanisms. METHODS A mouse model of liver metastasis of colorectal cancer was used. To elucidate the potential mechanisms involved, we examined the effect of selective hepatic vagotomy on the survival rate and liver-to-body weight. We further evaluated the possible involvement of the hepatic sympathetic nerve fibers in this model. RESULTS The mortality rate and the liver-to-body weight ratio after cancer inoculation were significantly higher in the vagotomized mice than in the sham-operated mice. The vagotomized mice exhibited a transient decrease in hepatic norepinephrine levels following cancer inoculation. Interestingly, the vagotomy-induced exacerbation of liver metastasis was attenuated by supplementary norepinephrine or phenylephrine, a selective α1-adrenoceptor agonist, but not by clonidine, a selective α2-adrenoceptor agonist. CONCLUSION Collectively, these results suggest that the hepatic vagus nerve may play a protective role against liver metastasis. Hepatic sympathetic nerves may also be involved as a protective efferent loop, possibly acting through the α1-adrenoceptor.
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17
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Nakanishi H, Kurosaki M, Tsuchiya K, Yasui Y, Higuchi M, Yoshida T, Komiyama Y, Takaura K, Hayashi T, Kuwabara K, Nakakuki N, Takada H, Ueda M, Tamaki N, Suzuki S, Itakura J, Takahashi Y, Izumi N. Novel Pretreatment Scoring Incorporating C-reactive Protein to Predict Overall Survival in Advanced Hepatocellular Carcinoma with Sorafenib Treatment. Liver Cancer 2016; 5:257-268. [PMID: 27781198 PMCID: PMC5075810 DOI: 10.1159/000449337] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVES This study aimed to build a prediction score of prognosis for patients with advanced hepatocellular carcinoma (HCC) after sorafenib treatment. METHODS A total of 165 patients with advanced HCC who were treated with sorafenib were analyzed. Readily available baseline factors were used to establish a scoring system for the prediction of survival. RESULTS The median survival time (MST) was 14.2 months. The independent prognostic factors were C-reactive protein (CRP) <1.0 mg/dL [hazard ratio (HR) =0.51], albumin >3.5 g/dL (HR =0.55), alpha-fetoprotein <200 ng/mL (HR =0.45), and a lack of major vascular invasion (HR =0.39). Each of these factors had a score of 1, and after classifying the patients into five groups, the total scores ranged from 0 to 4. Higher scores were linked to significantly longer survival (p<0.0001). Twenty-nine patients (17.6%) with a score of 4 had a MST as long as 36.5 months, whereas MST was as short as 2.4 and 3.7 months for seven (4.2%) and 22 (13.3%) patients with scores of 0 and 1, respectively. CONCLUSIONS A novel prognostic scoring system, which includes the CRP level, has the ability to stratify the prognosis of patients with advanced stage HCC after treatment with sorafenib.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Namiki Izumi
- *Namiki Izumi, MD, PhD, Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo (Japan), Tel. +81 422 32 3111, E-Mail
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18
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Chen Y, Teng F, Wang G, Nie Z. Overexpression of CXCR7 induces angiogenic capacity of human hepatocellular carcinoma cells via the AKT signaling pathway. Oncol Rep 2016; 36:2275-81. [PMID: 27572688 DOI: 10.3892/or.2016.5045] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 08/08/2016] [Indexed: 12/22/2022] Open
Abstract
Angiogenesis is essential for tumor growth, especially in hepatocellular carcinoma (HCC). The hypervascularity is associated with poor prognosis and highly invasive HCC. The C‑X‑C chemokine receptor type 7 (CXCR7) has been implied overexpressed in many tumor types. Our study aimed to investigate the CXCR7 function in HCC. The tube formation, Transwell migration assay of human umbilical vein endothelial cells (HUVECs) and chicken chorioallantoic membrane (CAM) assay were used. We confirmed that CXCR7 induces angiogenic capacity. Moreover, overexpressing CXCR7 increased the phosphorylated (but not total) AKT expression in HCC cells. Furthermore, overexpressing CXCR7 increased the expression of tumor necrosis factor (TNF)‑α, interleukin (IL)‑6 and IL‑8 in HCC cells. Additionally, inhibition of AKT by LY294002 abrogated CXCR7‑induced angiogenic capacity in HCC cells. Our study suggested that CXCR7 plays an important pro‑angiogenic role in HCC via activation of the AKT pathway. So CXCR7 may be a potential target for anti‑angiogenic therapy in HCC.
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Affiliation(s)
- Yuhui Chen
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China
| | - Fei Teng
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China
| | - Geying Wang
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China
| | - Zhiyu Nie
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China
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19
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Lesina M, Wörmann SM, Morton J, Diakopoulos KN, Korneeva O, Wimmer M, Einwächter H, Sperveslage J, Demir IE, Kehl T, Saur D, Sipos B, Heikenwälder M, Steiner JM, Wang TC, Sansom OJ, Schmid RM, Algül H. RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis. J Clin Invest 2016; 126:2919-32. [PMID: 27454298 PMCID: PMC4966329 DOI: 10.1172/jci86477] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 05/13/2016] [Indexed: 12/12/2022] Open
Abstract
Tumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the Kras mouse model of PDAC. Inactivation of RelA accelerated pancreatic lesion formation in Kras mice by abrogating the senescence-associated secretory phenotype (SASP) gene transcription signature. Using genetic and pharmacological tools, we determined that RelA activation promotes OIS via elevation of the SASP factor CXCL1 (also known as KC), which activates CXCR2, during pancreatic carcinogenesis. In Kras mice, pancreas-specific inactivation of CXCR2 prevented OIS and was correlated with increased tumor proliferation and decreased survival. Moreover, reductions in CXCR2 levels were associated with advanced neoplastic lesions in tissue from human pancreatic specimens. Genetically disabling OIS in Kras mice caused RelA to promote tumor proliferation, suggesting a dual role for RelA signaling in pancreatic carcinogenesis. Taken together, our data suggest a pivotal role for RelA in regulating OIS in preneoplastic lesions and implicate the RelA/CXCL1/CXCR2 axis as an essential mechanism of tumor surveillance in PDAC.
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Affiliation(s)
- Marina Lesina
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Sonja Maria Wörmann
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Jennifer Morton
- Cancer Research UK Beatson Institute, Department of Pathology, Glasgow, United Kingdom
| | | | - Olga Korneeva
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Margit Wimmer
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Henrik Einwächter
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | | | - Ihsan Ekin Demir
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Timo Kehl
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dieter Saur
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Bence Sipos
- Universitätsklinikum Tübingen, Tübingen, Germany
| | - Mathias Heikenwälder
- Institute of Virology, Technische Universität München, Helmholtz Zentrum München, Munich, Germany
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jörg Manfred Steiner
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
- Department of Small Animal Clinical Sciences, Texas A&M University, College Station, Texas, USA
| | - Timothy Cragin Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University, New York, New York, USA
| | - Owen J. Sansom
- Cancer Research UK Beatson Institute, Department of Pathology, Glasgow, United Kingdom
| | - Roland Michael Schmid
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Hana Algül
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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20
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Sanchez-Lopez E, Flashner-Abramson E, Shalapour S, Zhong Z, Taniguchi K, Levitzki A, Karin M. Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling. Oncogene 2016; 35:2634-44. [PMID: 26364612 PMCID: PMC4791217 DOI: 10.1038/onc.2015.326] [Citation(s) in RCA: 128] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 06/05/2015] [Accepted: 07/29/2015] [Indexed: 12/11/2022]
Abstract
The tumor microenvironment (TME) exerts critical pro-tumorigenic effects through cytokines and growth factors that support cancer cell proliferation, survival, motility and invasion. Insulin-like growth factor-1 (IGF-1) and signal transducer and activator of transcription 3 (STAT3) stimulate colorectal cancer development and progression via cell autonomous and microenvironmental effects. Using a unique inhibitor, NT157, which targets both IGF-1 receptor (IGF-1R) and STAT3, we show that these pathways regulate many TME functions associated with sporadic colonic tumorigenesis in CPC-APC mice, in which cancer development is driven by loss of the Apc tumor suppressor gene. NT157 causes a substantial reduction in tumor burden by affecting cancer cells, cancer-associated fibroblasts (CAF) and myeloid cells. Decreased cancer cell proliferation and increased apoptosis were accompanied by inhibition of CAF activation and decreased inflammation. Furthermore, NT157 inhibited expression of pro-tumorigenic cytokines, chemokines and growth factors, including IL-6, IL-11 and IL-23 as well as CCL2, CCL5, CXCL7, CXCL5, ICAM1 and TGFβ; decreased cancer cell migratory activity and reduced their proliferation in the liver. NT157 represents a new class of anti-cancer drugs that affect both the malignant cell and its supportive microenvironment.
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Affiliation(s)
- Elsa Sanchez-Lopez
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0723, USA
| | - Efrat Flashner-Abramson
- Unit of Cellular Signaling, Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Shabnam Shalapour
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0723, USA
| | - Zhenyu Zhong
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0723, USA
| | - Koji Taniguchi
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0723, USA
- Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Alexander Levitzki
- Unit of Cellular Signaling, Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0723, USA
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21
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Marquardt JU, Andersen JB, Thorgeirsson SS. Functional and genetic deconstruction of the cellular origin in liver cancer. Nat Rev Cancer 2015; 15:653-67. [PMID: 26493646 DOI: 10.1038/nrc4017] [Citation(s) in RCA: 224] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
During the past decade, research on primary liver cancers has particularly highlighted the uncommon plasticity of differentiated parenchymal liver cells (that is, hepatocytes and cholangiocytes (also known as biliary epithelial cells)), the role of liver progenitor cells in malignant transformation, the importance of the tumour microenvironment and the molecular complexity of liver tumours. Whereas other reviews have focused on the landscape of genetic alterations that promote development and progression of primary liver cancers and the role of the tumour microenvironment, the crucial importance of the cellular origin of liver cancer has been much less explored. Therefore, in this Review, we emphasize the importance and complexity of the cellular origin in tumour initiation and progression, and attempt to integrate this aspect with recent discoveries in tumour genomics and the contribution of the disrupted hepatic microenvironment to liver carcinogenesis.
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Affiliation(s)
- Jens U Marquardt
- Department of Medicine I, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark
| | - Snorri S Thorgeirsson
- Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
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22
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Guyer RA, Macara IG. Loss of the polarity protein PAR3 activates STAT3 signaling via an atypical protein kinase C (aPKC)/NF-κB/interleukin-6 (IL-6) axis in mouse mammary cells. J Biol Chem 2015; 290:8457-68. [PMID: 25657002 DOI: 10.1074/jbc.m114.621011] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
PAR3 suppresses tumor growth and metastasis in vivo and cell invasion through matrix in vitro. We propose that PAR3 organizes and limits multiple signaling pathways and that inappropriate activation of these pathways occurs without PAR3. Silencing Pard3 in conjunction with oncogenic activation promotes invasion and metastasis via constitutive STAT3 activity in mouse models, but the mechanism for this is unknown. We now show that loss of PAR3 triggers increased production of interleukin-6, which induces STAT3 signaling in an autocrine manner. Activation of atypical protein kinase C ι/λ (aPKCι/λ) mediates this effect by stimulating NF-κB signaling and IL-6 expression. Our results suggest that PAR3 restrains aPKCι/λ activity and thus prevents aPKCι/λ from activating an oncogenic signaling network.
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Affiliation(s)
- Richard A Guyer
- From the Department of Cell and Developmental Biology and Medical-Scientist Training Program, Vanderbilt University, Nashville, Tennessee 37232
| | - Ian G Macara
- From the Department of Cell and Developmental Biology and
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23
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Fujiwara A, Higashiyama M, Kanou T, Okami J, Tokunaga T, Tomita Y, Kodama K. Granulocyte-colony stimulating factor (G-CSF) producing malignant pleural mesothelioma: Report of a case. Thorac Cancer 2015; 6:105-9. [PMID: 26273344 PMCID: PMC4448476 DOI: 10.1111/1759-7714.12140] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 05/12/2014] [Indexed: 11/26/2022] Open
Abstract
This report presents a case of malignant pleural mesothelioma (MPM) producing granulocyte colony-stimulating factor (G-CSF) that was treated by tumor resection. A 76-year-old male presented with a huge right-side chest wall tumor, along with a slight fever and chest wall pain. Laboratory findings showed an increased white blood cell count (64600 cells/μL) and C-reactive protein level (20.57 mg/dL). The patient underwent surgical removal of the tumor along with tissue from the chest wall and histopathological analysis led to a diagnosis of sarcomatous type of MPM. Immunohistochemical findings for both anti-human G-CSF and interleukin-6 monoclonal antibodies were positive. Although the general condition of the patient quickly improved after surgery, local recurrence occurred two months later and he died of respiratory failure seven months after the operation, though surgery provided symptom relief. G-CSF-producing MPMs usually show a poor prognosis, though less-invasive surgery may be considered for relief of symptoms.
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Affiliation(s)
- Ayako Fujiwara
- Department of General Thoracic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases Osaka, Japan
| | - Masahiko Higashiyama
- Department of General Thoracic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases Osaka, Japan
| | - Takashi Kanou
- Department of General Thoracic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases Osaka, Japan
| | - Jiro Okami
- Department of General Thoracic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases Osaka, Japan
| | - Toshiteru Tokunaga
- Department of General Thoracic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases Osaka, Japan
| | - Yasuhiko Tomita
- Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases Osaka, Japan
| | - Ken Kodama
- Department of General Thoracic Surgery, Yao Municipal Hospital Yao, Japan
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24
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Wan S, Zhao E, Kryczek I, Vatan L, Sadovskaya A, Ludema G, Simeone DM, Zou W, Welling TH. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 2014; 147:1393-404. [PMID: 25181692 PMCID: PMC4253315 DOI: 10.1053/j.gastro.2014.08.039] [Citation(s) in RCA: 526] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Revised: 08/20/2014] [Accepted: 08/26/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Cancer stem cells (CSCs) can contribute to hepatocellular carcinoma (HCC) progression and recurrence after therapy. The presence of tumor-associated macrophages (TAMs) in patients with HCC is associated with poor outcomes. It is not clear whether TAMs interact with CSCs during HCC development. We investigated whether TAMs affect the activities of CSCs in the microenvironment of human HCCs. METHODS HCCs were collected from 17 patients during surgical resection and single-cell suspensions were analyzed by flow cytometry. CD14(+) TAMs were isolated from the HCC cell suspensions and placed into co-culture with HepG2 or Hep3B cells, and CSC functions were measured. The interleukin 6 (IL6) receptor was blocked with a monoclonal antibody (tocilizumab), and signal transducer and activator of transcription 3 was knocked down with small hairpin RNAs in HepG2 cells. Xenograft tumors were grown in NOD-SCID/Il2Rg(null) mice from human primary HCC cells or HepG2 cells. RESULTS CD44(+) cells from human HCCs and cell lines formed more spheres in culture and more xenograft tumors in mice than CD44(-) cells, indicating that CD44(+) cells are CSCs. Incubation of the CD44(+) cells with TAMs promoted expansion of CD44(+) cells, and increased their sphere formation in culture and formation of xenograft tumors in mice. In human HCC samples, the numbers of TAMs correlated with the numbers of CD44(+) cells. Of all cytokines expressed by TAMs, IL6 was increased at the highest level in human HCC co-cultures, compared with TAMs not undergoing co-culture. IL6 was detected in the microenvironment of HCC samples and induced expansion of CD44(+) cells in culture. Levels of IL6 correlated with stages of human HCCs and detection of CSC markers. Incubation of HCC cell lines with tocilizumab or knockdown of signal transducer and activator of transcription 3 in HCC cells reduced the ability of TAMs to promote sphere formation by CD44+ cells in culture and growth of xenograft tumors in mice. CONCLUSIONS CD44(+) cells isolated from human HCC tissues and cell lines have CSC activities in vitro and form a larger number of xenograft tumors in mice than CD44(-) cells. TAMs produce IL6, which promotes expansion of these CSCs and tumorigenesis. Levels of IL6 in human HCC samples correlate with tumor stage and markers of CSCs. Blockade of IL6 signaling with tocilizumab, a drug approved by the Food and Drug Administration for treatment of rheumatoid arthritis, inhibits TAM-stimulated activity of CD44(+) cells. This drug might be used to treat patients with HCC.
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Affiliation(s)
- Shanshan Wan
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Ende Zhao
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Ilona Kryczek
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Linda Vatan
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Anna Sadovskaya
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Gregory Ludema
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Diane M Simeone
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Weiping Zou
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
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Ciombor KK, Feng Y, Benson AB, Su Y, Horton L, Short SP, Kauh JSW, Staley C, Mulcahy M, Powell M, Amiri KI, Richmond A, Berlin J. Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): a trial of the Eastern Cooperative Oncology Group. Invest New Drugs 2014; 32:1017-27. [PMID: 24890858 PMCID: PMC4171216 DOI: 10.1007/s10637-014-0111-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Accepted: 05/09/2014] [Indexed: 12/27/2022]
Abstract
PURPOSE To evaluate the efficacy and tolerability of bortezomib in combination with doxorubicin in patients with advanced hepatocellular carcinoma, and to correlate pharmacodynamic markers of proteasome inhibition with response and survival. EXPERIMENTAL DESIGN This phase II, open-label, multicenter study examined the efficacy of bortezomib (1.3 mg/m(2) IV on d1, 4, 8, 11) and doxorubicin (15 mg/m(2) IV on d1, 8) in 21-day cycles. The primary endpoint was objective response rate. RESULTS Best responses in 38 treated patients were 1 partial response (2.6 %), 10 (26.3 %) stable disease, and 17 (44.7 %) progressive disease; 10 patients were unevaluable. Median PFS was 2.2 months. Median OS was 6.1 months. The most common grade 3 to 4 toxicities were hypertension, glucose intolerance, ascites, ALT elevation, hyperglycemia and thrombosis/embolism. Worse PFS was seen in patients with elevated IL-6, IL-8, MIP-1α and EMSA for NF-κB at the start of treatment. Worse OS was seen in patients with elevated IL-8 and VEGF at the start of treatment. Patients had improved OS if a change in the natural log of serum MIP-1α/CCL3 was seen after treatment. RANTES/CCL5 levels decreased significantly with treatment. CONCLUSIONS The combination of doxorubicin and bortezomib was well-tolerated in patients with hepatocellular carcinoma, but the primary endpoint was not met. Exploratory analyses of markers of proteasome inhibition suggest a possible prognostic and predictive role and should be explored further in tumor types for which bortezomib is efficacious.
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Affiliation(s)
- Kristen K Ciombor
- Division of Medical Oncology, Department of Internal Medicine, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, A445A Starling Loving Hall, 320 West 10th Avenue, Columbus, OH, 43212, USA,
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Bishayee A. The role of inflammation and liver cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 816:401-35. [PMID: 24818732 DOI: 10.1007/978-3-0348-0837-8_16] [Citation(s) in RCA: 193] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Persistent inflammation is known to promote and exacerbate malignancy. Primary liver cancer, mostly hepatocellular carcinoma (HCC), is a clear example of inflammation-related cancer as more than 90 % of HCCs arise in the context of hepatic injury and inflammation. HCC represents the fifth most common malignancy and the third leading cause of cancer-related death worldwide with about one million new cases diagnosed every year with almost an equal number of deaths. Chronic unresolved inflammation is associated with persistent hepatic injury and concurrent regeneration, leading to sequential development of fibrosis, cirrhosis, and eventually HCC. Irrespective of the intrinsic differences among various etiological factors, a common denominator at the origin of HCC is the perpetuation of a wound-healing response activated by parenchymal cell death and the resulting inflammatory cascade. Hence, the identification of fundamental inflammatory signaling pathways causing transition from chronic liver injury to dysplasia and HCC could depict new predictive biomarkers and targets to identify and treat patients with chronic liver inflammation. This chapter critically discusses the roles of several major cytokines, chemokines, growth factors, transcription factors, and enzymes as well as a distinct network of inflammatory signaling pathways in the development and progression of HCC. It also highlights and analyzes preclinical animal studies showing innovative approaches of targeting inflammatory mediators and signaling by a variety of natural compounds and synthetic agents to achieve effective therapy as well as prevention of hepatic malignancy. Additionally, current limitations and potential challenges associated with the inhibition of inflammatory signaling as well as future directions of research to accelerate clinical development of anti-inflammatory agents to prevent and treat liver cancer are presented.
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Affiliation(s)
- Anupam Bishayee
- Department of Pharmaceutical Sciences, School of Pharmacy, American University of Health Sciences, 1600 East Hill Street, Signal Hill, CA, 90755, USA,
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27
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Wang X, Dong JH, Zhang WZ, Leng JJ, Cai SW, Chen MY, Yang X. Double stranded RNA-dependent protein kinase promotes the tumorigenic phenotype in HepG2 hepatocellular carcinoma cells by activating STAT3. Oncol Lett 2014; 8:2762-2768. [PMID: 25360179 PMCID: PMC4214393 DOI: 10.3892/ol.2014.2560] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 08/12/2014] [Indexed: 01/08/2023] Open
Abstract
Previously known as a first-response protein upon viral infection and other stress signals, double-stranded RNA-dependent protein kinase (PKR, also termed EIF2AK2) has been found to be differentially expressed in multiple types of tumor, including hepatocellular carcinoma, suggesting that PKR may be involved in tumor initiation and development. However, whether and how PKR promotes or suppresses the development of hepatocellular carcinoma remains controversial. In the present study, PKR expression was investigated using qPCR and western blot analysis, which revealed that PKR expression was upregulated in liver tumor tissues, when compared to that of adjacent normal tissues, which were obtained from four primary liver cancer patients. Furthermore, in vitro cellular assays revealed that PKR exerts a key role in maintaining the proliferation and migration of HepG2 human hepatocellular carcinoma cells. Mouse models with xenograft transplantations also confirmed a tumorigenic role of PKR in HepG2 cells. Furthermore, a transcription factor, signal transducer and activator of transcription 3 (STAT3), was revealed to mediate the tumor-promoting function of PKR in HepG2 cells, as shown by in vitro cellular proliferation and migration assays. In conclusion, the results suggested a tumorigenic role of PKR in liver cancer and a detailed mechanism involving an oncogenic transcription factor, STAT3, is described. Therefore, PKR may present a potential novel therapeutic target for the treatment of liver cancer.
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Affiliation(s)
- Xun Wang
- Department of Hepatobiliary Surgery, The General Hospital of Chinese People's Liberation Army, Beijing 100853, P.R. China
| | - Jia-Hong Dong
- Department of Hepatobiliary Surgery, The General Hospital of Chinese People's Liberation Army, Beijing 100853, P.R. China
| | - Wen-Zhi Zhang
- Department of Hepatobiliary Surgery, The General Hospital of Chinese People's Liberation Army, Beijing 100853, P.R. China
| | - Jian-Jun Leng
- Department of Hepatobiliary Surgery, The General Hospital of Chinese People's Liberation Army, Beijing 100853, P.R. China
| | - Shou-Wang Cai
- Department of Hepatobiliary Surgery, The General Hospital of Chinese People's Liberation Army, Beijing 100853, P.R. China
| | - Ming-Yi Chen
- Department of Hepatobiliary Surgery, The General Hospital of Chinese People's Liberation Army, Beijing 100853, P.R. China
| | - Xuerui Yang
- MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China
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Kinoshita A, Onoda H, Imai N, Iwaku A, Oishi M, Tanaka K, Fushiya N, Koike K, Nishino H, Matsushima M. The C-reactive protein/albumin ratio, a novel inflammation-based prognostic score, predicts outcomes in patients with hepatocellular carcinoma. Ann Surg Oncol 2014; 22:803-10. [PMID: 25190127 DOI: 10.1245/s10434-014-4048-0] [Citation(s) in RCA: 306] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND The C-reactive protein/albumin (CRP/Alb) ratio is associated with outcomes in septic patients. We investigated the prognostic value of the CRP/Alb ratio in patients with hepatocellular carcinoma (HCC). METHODS We retrospectively evaluated 186 newly diagnosed HCC patients and investigated the correlations among the pretreatment CRP/Alb ratio, clinicopathological parameters, and overall survival (OS). Multivariate analyses were performed to identify the clinicopathological parameters associated with OS. Subsequently, we evaluated the prognostic value of the CRP/Alb ratio compared with other inflammation-based prognostic scores [Glasgow Prognostic Score (GPS), modified GPS (mGPS), and neutrophil lymphocyte ratio (NLR)] using the area under the curve (AUC). RESULTS The optimal cutoff level for the CRP/Alb ratio was 0.037. An elevated CRP/Alb ratio (≥0.037) was associated with tumor progression and reduced liver functional reserve. In the multivariate analysis, the CRP/Alb ratio [hazard ratio (HR) 3.394; p < 0.0001], Cancer Liver Italian Program score (HR 2.686; 95% CI 2.122-3.401; p < 0.0001), and vascular invasion (HR 3.376; 95% CI 1.594-7.151; p = 0.001) were independently associated with OS (HR 3.394; p < 0.0001). The CRP/Alb ratio had higher AUC values at 6 months (0.844), 12 months (0.863), and 24 months (0.82) compared with the GPS, mGPS, and NLR. CONCLUSION The CRP/Alb ratio might be an independent prognostic marker in patients with HCC, and may have comparable prognostic ability to other established inflammation-based prognostic scores. The prognostic value of this novel inflammation-based prognostic score needs to be verified in patients with other types of cancer.
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Affiliation(s)
- Akiyoshi Kinoshita
- Division of Gastroenterology and Hepatology, The Jikei University Daisan Hospital, Komae-Shi, Tokyo, Japan,
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29
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Kinoshita A, Onoda H, Imai N, Iwaku A, Oishi M, Tanaka K, Fushiya N, Koike K, Nishino H, Matsushima M, Tajiri H. The addition of C-reactive protein to validated staging systems improves their prognostic ability in patients with hepatocellular carcinoma. Oncology 2014; 86:308-17. [PMID: 24924697 DOI: 10.1159/000360704] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Accepted: 02/06/2014] [Indexed: 12/31/2022]
Abstract
OBJECTIVES C-reactive protein (CRP) is a practical prognostic marker in patients with hepatocellular carcinoma (HCC). We investigated the prognostic value of adding the CRP level to other validated staging systems (Cancer Liver Italian Program, Japan Integrated Staging, Barcelona Clinic Liver Cancer classification system, Tokyo score and tumor node metastasis classification) in HCC patients. METHODS One hundred and eighty-six newly diagnosed HCC patients were retrospectively evaluated. A multivariate analysis identified the clinicopathological variables associated with overall survival; the variables identified were then added to each staging system and compared to those without the additional variable. RESULTS In multivariate analysis, an elevated serum CRP level was independently associated with a poor prognosis (hazard ratio 3.792, p < 0.0001). The addition of the CRP level to each of the established staging systems provided a higher linear χ(2) value and a lower -2 log likelihood than those without the addition of the term. Moreover, the area under the receiver-operating characteristic curve (AUC) analysis showed that the addition of CRP improved the AUC of each staging system. CONCLUSIONS This study demonstrates that an elevated serum CRP level is independently associated with a poor prognosis in HCC patients, and the addition of the CRP level to the validated staging systems could improve the prognostic ability of each staging system.
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Affiliation(s)
- Akiyoshi Kinoshita
- Division of Gastroenterology and Hepatology, Jikei University Daisan Hospital, Tokyo, Japan
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30
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Das L, Vinayak M. Long-term effect of curcumin down-regulates expression of tumor necrosis factor-α and interleukin-6 via modulation of E26 transformation-specific protein and nuclear factor-κB transcription factors in livers of lymphoma bearing mice. Leuk Lymphoma 2014; 55:2627-36. [DOI: 10.3109/10428194.2014.889824] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Laxmidhar Das
- Biochemistry and Molecular Biology Laboratory, Department of Zoology (Center for Advanced Study), Banaras Hindu University,
Varanasi, India
| | - Manjula Vinayak
- Biochemistry and Molecular Biology Laboratory, Department of Zoology (Center for Advanced Study), Banaras Hindu University,
Varanasi, India
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Abstract
Metastasis is powered by disseminated cancer cells that re-create a full-fledged tumor in unwelcoming tissues, away from the primary site. How cancer cells moving from a tumor into the circulation manage to infiltrate distant organs and initiate metastatic growth is of interest to cancer biologists and clinical oncologists alike. Recent findings have started to define the sources, phenotypic properties, hosting niches, and signaling pathways that support the survival, self-renewal, dormancy, and reactivation of cancer cells that initiate metastasis: metastatic stem cells. By dissecting the biology of this process, vulnerabilities are being exposed that could be exploited to prevent metastasis.
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Affiliation(s)
- Thordur Oskarsson
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
| | - Eduard Batlle
- Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
| | - Joan Massagué
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
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Taniguchi K, Karin M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol 2014; 26:54-74. [PMID: 24552665 DOI: 10.1016/j.smim.2014.01.001] [Citation(s) in RCA: 526] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Accepted: 01/06/2014] [Indexed: 11/17/2022]
Abstract
Inflammatory responses play pivotal roles in cancer development, including tumor initiation, promotion, progression, and metastasis. Cytokines are now recognized as important mediators linking inflammation and cancer, and are therefore potential therapeutic and preventive targets as well as prognostic factors. The interleukin (IL)-6 family of cytokines, especially IL-6 and IL-11, is highly up-regulated in many cancers and considered as one of the most important cytokine families during tumorigenesis and metastasis. This review discusses molecular mechanisms linking the IL-6 cytokine family to solid malignancies and their treatment.
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Affiliation(s)
- Koji Taniguchi
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; UC San Diego Moores Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
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The Glasgow Prognostic Score accurately predicts survival in patients with biliary tract cancer not indicated for surgical resection. Med Oncol 2013; 31:787. [PMID: 24310810 DOI: 10.1007/s12032-013-0787-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 11/24/2013] [Indexed: 12/24/2022]
Abstract
The Glasgow Prognostic Score (GPS) and neutrophil to lymphocyte ratio (NLR) are associated with the survival in patients with various types of malignancy. The aim of this study was to investigate the prognostic value of the GPS and NLR in patients with biliary tract cancer (BTC) undergoing palliative chemotherapy or best supportive care (BSC). Fifty-two patients with newly diagnosed BTC were retrospectively evaluated. We investigated the correlation between the GPS, NLR, and the overall survival rates. The area under the receiver operating characteristics curve (AUC) was calculated to compare the predictive ability of each score. Both the univariate and multivariate analyses were performed to identify clinicopathological variables associated with the overall survival. There were significant differences between the GPS groups regarding the neutrophil levels (p < 0.0001), Hb (p = 0.024), Alb (p < 0.0001) and CRP (p < 0.0001). A significant difference in the overall survival was found between the groups stratified based on the GPS, NLR (p < 0.001). The GPS had a higher AUC value (0.905) in comparison to the NLR (0.648). In the multivariate analysis, the sex (p = 0.002), CA19-9 (p < 0.0001) and the GPS (p < 0.0001) were found to be independently associated with the overall survival. Our results demonstrate that the GPS is an independent marker of the prognosis in patients with BTC undergoing palliative chemotherapy or BSC, and is superior to the NLR in terms of its prognostic ability.
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34
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Li HP, Zeng XC, Zhang B, Long JT, Zhou B, Tan GS, Zeng WX, Chen W, Yang JY. miR-451 inhibits cell proliferation in human hepatocellular carcinoma through direct suppression of IKK-β. Carcinogenesis 2013; 34:2443-2451. [PMID: 23740840 DOI: 10.1093/carcin/bgt206] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
It has been demonstrated that nuclear factor-kappa B (NF-κB), which is overactivated in hepatocellular carcinoma (HCC), plays important roles in the development of HCC. Recently, a group of dysregulated micro RNAs were reported to be involved in HCC progression. Further understanding of micro RNA-mediated regulation of NF-κB pathway may provide novel therapeutic targets for HCC. In this study, we found that miR-451 expression was markedly downregulated in HCC cells and tissues compared with immortalized normal liver epithelial cells and adjacent non- cancerous tissues, respectively. Upregulation of miR-451 inhibited, while downregulation of miR-451 promoted, the tumorigenicity of HCC cells both in vitro and in vivo. These changes in the properties of HCC cells were associated with deregulation of two well-known cellular G1/S transitional regulators, cyclin D1 and c-Myc, which are downstream targets of NF-κB pathway. Furthermore, we demonstrated that miR-451 upregulation led to downregulation of cyclin D1 and c-Myc through inhibition of NF-κB pathway initiated by direct targeting of the IKBKB 3'-untranslated region. Therefore, these results suggest that miR-451 downregulation plays an important role in promoting proliferation of HCC cells and may provide the basis for the development of novel anti-HCC therapies.
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MESH Headings
- Animals
- Apoptosis
- Blotting, Western
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Adhesion
- Cell Cycle
- Cell Movement
- Cell Proliferation
- Cyclin D1/genetics
- Cyclin D1/metabolism
- Flow Cytometry
- Fluorescent Antibody Technique
- Gene Expression Regulation, Neoplastic
- Humans
- I-kappa B Kinase/antagonists & inhibitors
- I-kappa B Kinase/genetics
- I-kappa B Kinase/metabolism
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- MicroRNAs/genetics
- NF-kappa B/genetics
- NF-kappa B/metabolism
- Proto-Oncogene Proteins c-myc/genetics
- Proto-Oncogene Proteins c-myc/metabolism
- RNA, Messenger/genetics
- RNA, Small Interfering/genetics
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Tumor Cells, Cultured
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Affiliation(s)
- He-Ping Li
- Department of Interventional Radiology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
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Sieghart W, Pinter M, Hucke F, Graziadei I, Schöniger-Hekele M, Müller C, Vogel W, Trauner M, Peck-Radosavljevic M. Single determination of C-reactive protein at the time of diagnosis predicts long-term outcome of patients with hepatocellular carcinoma. Hepatology 2013; 57:2224-34. [PMID: 22961713 DOI: 10.1002/hep.26057] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Accepted: 08/20/2012] [Indexed: 12/15/2022]
Abstract
UNLABELLED We investigated the prognostic value of C-reactive protein (CRP) in patients with hepatocellular carcinoma (HCC) not amenable to surgery. A total of 615 patients diagnosed with HCC not amenable to surgery between April 1999 and December 2009 at the Department of Gastroenterology of the Medical Universities of Vienna and Innsbruck were included. We assessed the optimal CRP cutoff by regression spline analysis and tested its impact on median overall survival (OS) by the Kaplan-Meier method, univariate analysis (log-rank test), and multivariate analysis (Cox proportional hazard regression model) in a training cohort (n = 466, Vienna) and an independent validation cohort (n = 149, Innsbruck). We found a sigmoid-shaped association of CRP and the hazard ratio of death upon regression spline analysis and defined a CRP level <1/≥1 mg/dL as optimal cutoff for further survival assessments. Elevated CRP (≥1 mg/dL) at diagnosis was associated with poor OS (CRP-elevated versus CRP-normal; 4 versus 20 months; P < 0.001) and remained a significant negative predictor for OS upon multivariate analysis (hazard ratio, 1.7; P < 0.001), which was independent of age, Child-Pugh class, tumor characteristics, and treatment allocation. Analyses with respect to Barcelona Clinic Liver Cancer (BCLC) stage and Child-Pugh class supported the relevance of CRP (BCLC-stage C and Child-Pugh A: OS for CRP-elevated versus CRP-normal, 6 versus 14; P < 0.001; BCLC-stage C and Child-Pugh B: OS for CRP-elevated versus CRP-normal, 4 versus 15 months; P < 0.001). The prognostic significance of elevated CRP was reproducible at a second CRP determination timepoint and confirmed in the independent validation cohort. CONCLUSION Elevated CRP is associated with a dismal prognosis in HCC patients and may become a useful marker for patient selection in HCC management. (HEPATOLOGY 2012).
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Affiliation(s)
- Wolfgang Sieghart
- Department of Internal Medicine III, Division of Gastroenterology/Hepatology, Medical University of Innsbruck, Vienna, Austria
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36
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Kinoshita H, Hirata Y, Nakagawa H, Sakamoto K, Hayakawa Y, Takahashi R, Nakata W, Sakitani K, Serizawa T, Hikiba Y, Akanuma M, Shibata W, Maeda S, Koike K. Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis. PLoS One 2013; 8:e60914. [PMID: 23593346 PMCID: PMC3625204 DOI: 10.1371/journal.pone.0060914] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Accepted: 03/05/2013] [Indexed: 01/29/2023] Open
Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine that affects various functions, including tumor development. Although the importance of IL-6 in gastric cancer has been documented in experimental and clinical studies, the mechanism by which IL-6 promotes gastric cancer remains unclear. In this study, we investigated the role of IL-6 in the epithelial–stromal interaction in gastric tumorigenesis. Immunohistochemical analysis of human gastritis, gastric adenoma, and gastric cancer tissues revealed that IL-6 was frequently detected in the stroma. IL-6–positive cells in the stroma showed positive staining for the fibroblast marker α-smooth muscle actin, suggesting that stromal fibroblasts produce IL-6. We compared IL-6 knockout (IL-6−/−) mice with wild-type (WT) mice in a model of gastric tumorigenesis induced by the chemical carcinogen N-methyl-N-nitrosourea. The stromal fibroblasts expressed IL-6 in tumors from WT mice. Gastric tumorigenesis was attenuated in IL-6−/− mice, compared with WT mice. Impaired tumor development in IL-6−/− mice was correlated with the decreased activation of STAT3, a factor associated with gastric cancer cell proliferation. In vitro, when gastric cancer cell line was co-cultured with primary human gastric fibroblast, STAT3–related genes including COX-2 and iNOS were induced in gastric cancer cells and this response was attenuated with neutralizing anti-IL-6 receptor antibody. IL-6 production from fibroblasts was increased when fibroblasts were cultured in the presence of gastric cancer cell–conditioned media. IL-6 production from fibroblasts was suppressed by an interleukin-1 (IL-1) receptor antagonist and siRNA inhibition of IL-1α in the fibroblasts. IL-1α mRNA and protein were increased in fibroblast lysate, suggesting that cell-associated IL-1α in fibroblasts may be involved. Our results suggest the importance of IL-6 mediated stromal-epithelial cell interaction in gastric tumorigenesis.
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Affiliation(s)
- Hiroto Kinoshita
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshihiro Hirata
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kei Sakamoto
- Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryota Takahashi
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Wachiko Nakata
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kosuke Sakitani
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takako Serizawa
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yohko Hikiba
- Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
| | - Masao Akanuma
- Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
| | - Wataru Shibata
- Department of Gastroenterology, Yokohama City University, Yokohama, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University, Yokohama, Japan
- * E-mail:
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate school of Medicine, The University of Tokyo, Tokyo, Japan
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Zheng Z, Zhou L, Gao S, Yang Z, Yao J, Zheng S. Prognostic role of C-reactive protein in hepatocellular carcinoma: a systematic review and meta-analysis. Int J Med Sci 2013; 10:653-64. [PMID: 23569429 PMCID: PMC3619114 DOI: 10.7150/ijms.6050] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Accepted: 03/17/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND C-reactive protein (CRP) which used to be a prototypical inflammatory cytokine has been identified involving in the progression of tumor-promoting inflammation. Several studies have indicated that CRP is a predictor for hepatocellular carcinoma (HCC), but the results are controversial. METHODS We conducted a systematic review of ten studies (1885 patients) to examine the association of high serum CRP expression with overall survival (OS) and recurrence-free survival (RFS) in HCC patients by meta-analysis. Moreover, the correlation between high serum CRP and tumor clinicopathological parameters was also assessed. Hazard ratio (HR) or odds ratio (OR) with its 95% confidence interval (CI) was used as the effect size estimate. RESULTS Our pooled results showed that high expression level of serum CRP (≥ 10 mg/L) was associated with poor OS (HR: 2.15, 95% CI: 1.76-2.63) and RFS (HR: 2.66, 95% CI: 1.54-4.58) in HCC. Serum CRP overexpression (≥ 10 mg/L) was also significantly associated with the presence of tumor vascular invasion (OR: 3.05, 95% CI: 1.79-5.23), multiple tumor (OR: 2.36, 95% CI: 1.36-4.10), larger tumor size (OR: 3.41, 95% CI: 1.04-11.18), and advanced TNM stage (OR: 3.23, 95% CI: 2.29-4.57). In addition, serum CRP overexpression (≥ 10 mg/L) tended to be correlated with poor differentiation (OR: 1.58, 95% CI: 0.74-3.39), though not significantly. CONCLUSION The present systematic review and meta-analysis demonstrate that high serum level of CRP (≥ 10 mg/L) denotes a poor prognosis of patients with HCC.
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Affiliation(s)
- Zhiyun Zheng
- Key Lab of Multi-organ Transplantation, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, PR China
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Wu DW, Tsai LH, Chen PM, Lee MC, Wang L, Chen CY, Cheng YW, Lee H. Loss of TIMP-3 promotes tumor invasion via elevated IL-6 production and predicts poor survival and relapse in HPV-infected non-small cell lung cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 181:1796-806. [PMID: 22982189 DOI: 10.1016/j.ajpath.2012.07.032] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Revised: 06/19/2012] [Accepted: 07/20/2012] [Indexed: 12/21/2022]
Abstract
Human papillomavirus (HPV) 16/18 E6 oncoprotein is expressed in lung tumors and is associated with p53 inactivation. The tissue inhibitor of metalloproteinase 3 (TIMP-3) is essential for limiting inflammation; therefore, we expected that TIMP-3 loss might induce chronic inflammation, thereby promoting tumor malignancy as well as poor survival and relapse in patients with HPV-infected non-small cell lung cancer. In this study, the loss of TIMP-3 by loss of heterozygosity and/or promoter hypermethylation was more frequent in HPV16/18 E6-positive tumors than in E6-negative tumors. To explore the possible underlying mechanism, E6-negative TL4 and CL1-0 cells were transfected with an E6 cDNA plasmid. A marked decrease in TIMP-3 expression was caused by promoter hypermethylation via increased DNA (cytosine-5-)-methyltransferase 1 (DNMT1) expression. Mechanistic studies indicated that TIMP-3 loss promoted interleukin-6 (IL-6) production, which led to cell invasion and anchorage-independent growth on soft agar plates. Kaplan-Meier and Cox regression models showed that patients with low-TIMP-3/high-IL-6 tumors had shorter overall survival and relapse-free survival periods when compared with patients with high-TIMP-3/low-IL-6 tumors. In summary, loss of TIMP-3 may increase IL-6 production via the tumor necrosis factor α/nuclear factor κB axis, thereby promoting tumor malignancy and subsequent relapse and poor survival in patients with HPV-infected non-small cell lung cancer.
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Affiliation(s)
- De-Wei Wu
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taiwan
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Nakagawa H, Maeda S. Inflammation- and stress-related signaling pathways in hepatocarcinogenesis. World J Gastroenterol 2012; 18:4071-81. [PMID: 22919237 PMCID: PMC3422785 DOI: 10.3748/wjg.v18.i31.4071] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Revised: 05/28/2012] [Accepted: 06/08/2012] [Indexed: 02/06/2023] Open
Abstract
It has been established that cancer can be promoted and exacerbated by inflammation. Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and its long-term prognosis remains poor. Although HCC is a complex and heterogeneous tumor with several genomic mutations, it usually develops in the context of chronic liver damage and inflammation, suggesting that understanding the mechanism(s) of inflammation-mediated hepatocarcinogenesis is essential for the treatment and prevention of HCC. Chronic liver damage induces a persistent cycle of necro-inflammation and hepatocyte regeneration, resulting in genetic mutations in hepatocytes and expansion of initiated cells, eventually leading to HCC development. Recently, several inflammation- and stress-related signaling pathways have been identified as key players in these processes, which include the nuclear factor-κB, signal transducer and activator of transcription, and stress-activated mitogen- activated protein kinase pathways. Although these pathways may suggest potential therapeutic targets, they have a wide range of functions and complex crosstalk occurs among them. This review focuses on recent advances in our understanding of the roles of these signaling pathways in hepatocarcinogenesis.
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40
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Yang J, Kantrow S, Sai J, Hawkins OE, Boothby M, Ayers GD, Young ED, Demicco EG, Lazar AJ, Lev D, Richmond A. INK4a/ARF [corrected] inactivation with activation of the NF-κB/IL-6 pathway is sufficient to drive the development and growth of angiosarcoma. Cancer Res 2012; 72:4682-95. [PMID: 22836752 DOI: 10.1158/0008-5472.can-12-0440] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Although human angiosarcoma has been associated frequently with mutational inactivation of the tumor suppressor gene Ink4a/Arf, the underlying mechanisms have not been delineated. Here we report that malignant angiosarcoma is associated with high levels of RelA/NF-κB and IL-6 in contrast to normal vessels or benign hemagiomas. Studies of Ink4a/Arf deficient mice not only recapitulate genetic traits observed in human angiosarcoma, but also unveil a possible therapeutic link comprised of the NF-kB/IL-6/Stat3 signaling axis. In Ink4a/Arf(-/-) cells, NF-κB controlled Stat3 signaling by transcriptionally controlling the expression of IL-6, gp130, and Jak2. Further, IL-6 mediated Stat3 signaling through the sIL-6R. Inhibition of Ikkβ solely in myeloid cells was insufficient to block angiosarcoma development; in contrast, systemic inhibition of Ikkβ, IL-6, or Stat3 markedly inhibited angiosarcoma growth. Our findings offer clinical implications for targeting the NF-kB/IL-6/STAT3 pathway as a rational strategy to treat angiosarcoma.
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Affiliation(s)
- Jinming Yang
- Veterans Affairs Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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41
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Sakamoto K, Hikiba Y, Nakagawa H, Hirata Y, Hayakawa Y, Kinoshita H, Nakata W, Sakitani K, Takahashi R, Akanuma M, Kamata H, Maeda S. Promotion of DNA repair by nuclear IKKβ phosphorylation of ATM in response to genotoxic stimuli. Oncogene 2012; 32:1854-62. [PMID: 22614018 DOI: 10.1038/onc.2012.192] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Ataxia-telangiectasia mutated (ATM) is one of the key molecules involved in the cellular response to DNA damage. A portion of activated ATM is exported from the nucleus into the cytoplasm, where it activates the I kappa B kinase/nuclear factor kappa B (IKK/NF-κB) signaling pathway. It has been thought that activated IKKβ, which is a critical kinase for NF-κB activation, generally resides in the cytoplasm and phosphorylates cytoplasmic downstream molecules, such as IκBα. Here, we identified a new role for IKKβ during the response to DNA damage. ATM phosphorylation in response to alkylating agents consisted of two phases: the early phase (up to 3 h) and late phase (after 6 h). A portion of the activated IKKβ generated during the DNA damage response was found to translocate into the nucleus and directly phosphorylate ATM in the late phase. Furthermore, the phosphorylation of ATM by nuclear IKKβ was suggested to promote DNA repair. In parallel, activated IKKβ induced classical NF-κB activation and was involved in anti-apoptosis. Our findings define the function of IKKβ during the response to DNA damage, which promotes cell survival and DNA repair, and maintains cellular homeostasis.
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Affiliation(s)
- K Sakamoto
- Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
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42
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Tanaka T, Nakayama H, Yoshitake Y, Irie A, Nagata M, Kawahara K, Takamune Y, Yoshida R, Nakagawa Y, Ogi H, Shinriki S, Ota K, Hiraki A, Ikebe T, Nishimura Y, Shinohara M. Selective inhibition of nuclear factor-κB by nuclear factor-κB essential modulator-binding domain peptide suppresses the metastasis of highly metastatic oral squamous cell carcinoma. Cancer Sci 2012; 103:455-63. [PMID: 22136381 DOI: 10.1111/j.1349-7006.2011.02174.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Nuclear factor-κB (NF-κB) activation contributes to the development of metastasis, thus leading to a poor prognosis in many cancers, including OSCC. However, little in vivo experimental data are available about the effects of NF-κB inhibition on OSCC metastasis. OSCC sublines were established from a GFP-expressing parental cell line, GSAS, and designated GSAS/N3 and N5 according to the in vivo passage number after cervical lymph node metastasis by a serial orthotopic transplantation model. In vitro migration and invasion were assessed in these cells, and the NF-κB activities and expression of NF-κB-regulated metastasis-related molecules were also examined. In in vivo experiments, the metastasis and survival of tumor-engrafted mice were monitored. Furthermore, the effects of a selective NF-κB inhibitor, NEMO-binding domain (NBD) peptide, on metastasis in GSAS/N5-engrafted mice were assessed, and engrafted tongue tumors were immunohistochemically examined. Highly metastatic GSAS/N3 and N5 cells showed an enhanced NF-κB activity, thus contributing to increased migration, invasion, and a poor prognosis compared with the parent cells. Furthermore, the expression levels of NF-κB-regulated metastasis-related molecules, such as fibronectin, β1 integrin, MMP-1, -2, -9, and -14, and VEGF-C, were upregulated in the highly metastatic cells. The NBD peptide suppressed metastasis and tongue tumor growth in GSAS/N5-inoculated mice, and was accompanied by the downregulation of the NF-κB-regulated metastasis-related molecules in engrafted tongue tumors. Our results suggest that the selective inhibition of NF-κB activation by NBD peptide may provide an effective approach for the treatment of highly metastatic OSCC.
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Affiliation(s)
- Takuya Tanaka
- Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
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43
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Li S, Wang N, Brodt P. Metastatic cells can escape the proapoptotic effects of TNF-α through increased autocrine IL-6/STAT3 signaling. Cancer Res 2011; 72:865-75. [PMID: 22194466 DOI: 10.1158/0008-5472.can-11-1357] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The liver is a common site for cancer metastases in which the entrance of tumor cells has been shown to trigger a rapid inflammatory response. In considering how an inflammatory response may affect metastatic colonization in this setting, we hypothesized that tumor cells may acquire resistance to the proapoptotic and tumoricidal effects of TNF-α, a cytokine that is elevated in a proinflammatory tissue microenvironment. In this study, we investigated molecular mechanisms by which such resistance may emerge using tumor cells in which the overexpression of the type I insulin-like growth factor receptor (IGF-IR) enhanced the inflammatory and metastatic capacities of poorly metastatic cells in the liver. Mechanistic investigations in vitro revealed that IGF-IR overexpression increased cell survival in the presence of high levels of TNF-α, in a manner associated with increased autocrine production of interleukin-6 (IL)-6. In turn, tumor cell-derived IL-6 induced gp130 and IL-6R-dependent activation of STAT3, leading to reduced caspase-3 activation and apoptosis. We found that IL-6 production and cell death resistance were dose dependent with increasing TNF-α levels. In addition, RNA interference-mediated knockdown of either IL-6 or gp130 that established a blockade to autocrine STAT3 induction was sufficient to abolish the prosurvival effect of TNF-α and to inhibit liver metastasis. Taken together, our findings define an IGF-IR-mediated mechanism of cancer cell survival that is critical for metastatic colonization of the liver.
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Affiliation(s)
- Shun Li
- Department of Medicine, McGill University and the McGill University Health Center-Royal Victoria Hospital, Montreal, Quebec, Canada
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44
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Zou C, Zhang H, Li Q, Xiao H, Yu L, Ke S, Zhou L, Liu W, Wang W, Huang H, Ma N, Liu Q, Wang X, Zhao W, Zhou H, Gao X. Heme oxygenase-1: a molecular brake on hepatocellular carcinoma cell migration. Carcinogenesis 2011; 32:1840-8. [PMID: 22016469 DOI: 10.1093/carcin/bgr225] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a fatal disease with great public health impact worldwide. Heme oxygenase (HO)-1 has recently been reported as an important player in tumor angiogenesis and metastasis. However, the role of HO-1 in liver cancer metastasis is unclear. In this study, we explored genetic differences and downstream signal transduction pathways of HO-1 in liver cancer cell lines. HO-1 wild-type and mutant cell lines were generated from human liver cancer cell line HepG2. The overexpression of wild-type HO-1 decreased the migration of HepG2 cells. In contrast, the overexpression of mutant HO-1G143H increased the migration of the cancer cells. Interleukin (IL)-6 is one of the major downstream molecules that mediated this process because IL-6 expression and migration are suppressed by HO-1 and increased when HO-1 is knocked down by shRNA. In addition, we demonstrated carbon monoxide (CO) and p38MAPK are the cofactors in this signal pathway. In vivo animal model demonstrated HO-1 inhibited the tumor growth. In conclusion, in vitro and in vivo data show HO-1 inhibits the human HCC cells migration and tumor growth by suppressing the expression of IL-6. The heme degradation product CO is a cofactor in this process and inhibits p38MAPK phosphorylation.
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Affiliation(s)
- C Zou
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin 150081, China
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45
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Lee J, Lim KT. Preventive effect of phytoglycoprotein (38 kDa) on expression of alpha-fetoprotein and matrix metalloproteinase-9 in diethylnitrosamine-treated ICR mice. Drug Chem Toxicol 2011; 35:277-84. [PMID: 21939363 DOI: 10.3109/01480545.2011.600762] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Metastasis is one of the major causes of cancer-associated mortality. Aberrant expression of matrix metalloproteinase-9 (MMP-9) has been implicated in the metastasis of various cancer cells. The aim of this study was to investigate the inhibitory effect of a glycoprotein (38 kDa) isolated from Styrax japonica Siebold et al Zuccarini (SJSZ) on metastasis of hepatocellular carcinoma (HCC) in diethylnitrosamine (DEN)-treated imprinting control region (ICR) mice. To study the chemopreventive effect of SJSZ glycoprotein on the metastasis of HCC, ICR mice were injected intraperitoneally with DEN (75 mg/kg) for 11 weeks. Subsequently, we evaluated nitric oxide (NO), alpha-fetoprotein (AFP), activator protein (AP)-1, cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), matrix metalloproteinase (MMP)-9, and interleukin (IL)-6 using biochemical reaction, immunoblot analysis, and reverse-transcription polymerase chain reaction. Here, the results showed that SJSZ glycoprotein (10 mg/kg body weight) reduced the production of NO in DEN (75 mg/kg)-treated ICR mice. Also, it suppressed the activity of AFP, AP-1 (c-Jun and c-Fos), COX-2, iNOS, and MMP-9. Taken together, SJSZ glycoprotein inhibits the activity of MMP-9 as a metastasis factor.
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Affiliation(s)
- Jin Lee
- Molecular Biochemistry Laboratory, Biotechnology Research Institute and Center for the Control of Animal Hazards Using Biotechnology (BK21), Chonnam National University, Gwang-ju, South Korea
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46
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The liver prometastatic reaction of cancer patients: implications for microenvironment-dependent colon cancer gene regulation. CANCER MICROENVIRONMENT 2011; 4:163-80. [PMID: 21870094 DOI: 10.1007/s12307-011-0084-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2011] [Accepted: 08/08/2011] [Indexed: 02/07/2023]
Abstract
Colon cancer frequently metastasizes to the liver but the genetic and phenotypic properties of specific cancer cells able to implant and grow in this organ have not yet been established. The contribution of the patient's genetic, physiologic and pathologic backgrounds to the incidence and development of hepatic colon cancer metastases is also presently misunderstood. At a transcriptional level, hepatic metastasis development is in part associated with marked changes in gene expression of colon cancer cells that may originate in the primary tumor. Other changes occur in the liver and are regulated by hepatic cells, which represent the new microenvironment for metastatic colon cancer cells. However, hepatic parenchymal and non-parenchymal cell functions are also affected by both tumor-derived factors and systemic host factors, which suggests that the hepatic metastasis microenvironment is a functional linkage between the hepatic pathophysiology of the colon cancer patient and the biology of its cancer cells. Therefore, together with metastasis-related gene profiles suggesting the existence of liver metastasis potential in primary tumors, new biomarkers of the prometastatic microenvironment supported by the liver reaction to colon cancer factors may be helpful for the individual assessment of hepatic metastasis risk in colon cancer patients. In addition, knowledge on hepatic metastasis gene regulation by the hepatic microenvironment may open multiple opportunities for therapeutic intervention during colon cancer metastasis at both subclinical and advanced stages.
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Kojima K, Takata A, Vadnais C, Otsuka M, Yoshikawa T, Akanuma M, Kondo Y, Kang YJ, Kishikawa T, Kato N, Xie Z, Zhang WJ, Yoshida H, Omata M, Nepveu A, Koike K. MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma. Nat Commun 2011; 2:338. [PMID: 21654638 DOI: 10.1038/ncomms1345] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2011] [Accepted: 05/11/2011] [Indexed: 12/18/2022] Open
Abstract
α-fetoprotein (AFP) is not only a widely used biomarker in hepatocellular carcinoma (HCC) surveillance, but is also clinically recognized as linked with aggressive tumour behaviour. Here we show that deregulation of microRNA122, a liver-specific microRNA, is a cause of both AFP elevation and a more biologically aggressive phenotype in HCC. We identify CUX1, a direct target of microRNA122, as a common central mediator of these two effects. Using liver tissues from transgenic mice in which microRNA122 is functionally silenced, an orthotopic xenograft tumour model, and human clinical samples, we further demonstrate that a microRNA122/CUX1/microRNA214/ZBTB20 pathway regulates AFP expression. We also show that the microRNA122/CUX1/RhoA pathway regulates the aggressive characteristics of tumours. We conclude that microRNA122 and associated signalling proteins may represent viable therapeutic targets, and that serum AFP levels in HCC patients may be a surrogate marker for deregulated intracellular microRNA122 signalling pathways in HCC tissues.
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Affiliation(s)
- Kentaro Kojima
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
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48
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Abstract
Hepatocellular carcinoma (HCC), the major form of primary liver cancer, is one of the most deadly human cancers. The pathogenesis of HCC is frequently linked with continuous hepatocyte death, inflammatory cell infiltration and compensatory liver regeneration. Understanding the molecular signaling pathways driving or mediating these processes during liver tumorigenesis is important for the identification of novel therapeutic targets for this dreadful disease. The classical IKKβ-dependent NF-κB signaling pathway has been shown to promote hepatocyte survival in both developing and adult livers. In addition, it also plays a crucial role in liver inflammatory responses by controlling the expression of an array of growth factors and cytokines. One of these cytokines is IL-6, which is best known for its role in the liver acute phase response. IL-6 exerts many of its functions via activation of STAT3, a transcription factor found to be important for HCC development. This review will focus on recent studies on the roles of NF-κB and STAT3 in liver cancer. Interactions between the two pathways and their potential as therapeutic targets will also be discussed.
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Affiliation(s)
- Guobin He
- Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive MC 0723, La Jolla, CA 92093-0723, USA
- Current address: Isis Pharmaceuticals Inc., 1896 Rutherford Road, Carlsbad, CA 92008–7326. E-mail:
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive MC 0723, La Jolla, CA 92093-0723, USA
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Perez CO, Mirabolfathinejad SG, Venado AR, Evans SE, Gagea M, Evans CM, Dickey BF, Moghaddam SJ. Interleukin 6, but not T helper 2 cytokines, promotes lung carcinogenesis. Cancer Prev Res (Phila) 2011; 4:51-64. [PMID: 21098042 PMCID: PMC3058282 DOI: 10.1158/1940-6207.capr-10-0180] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Several epidemiologic studies have found that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, have an increased risk of lung cancer compared with smokers without COPD. We have shown a causal role for COPD-like airway inflammation in lung cancer promotion in the CCSP(Cre)/LSL-K-ras(G12D) mouse model (CC-LR). In contrast, existing epidemiologic data do not suggest any definite association between allergic airway inflammation and lung cancer. To test this, CC-LR mice were sensitized to ovalbumin (OVA) and then challenged with an OVA aerosol weekly for 8 weeks. This resulted in eosinophilic lung inflammation associated with increased levels of T helper 2 cytokines and mucous metaplasia of airway epithelium, similar to what is seen in asthmatic patients. However, this type of inflammation did not result in a significant difference in lung surface tumor number (49 ± 9 in OVA vs. 52 ± 5 in control) in contrast to a 3.2-fold increase with COPD-like inflammation. Gene expression analysis of nontypeable Haemophilus influenzae (NTHi)-treated lungs showed upregulation of a different profile of inflammatory genes, including interleukin 6 (IL-6), compared with OVA-treated lungs. Therefore, to determine the causal role of cytokines that mediate COPD-like inflammation in lung carcinogenesis, we genetically ablated IL-6 in CC-LR mice. This not only inhibited intrinsic lung cancer development (1.7-fold) but also inhibited the promoting effect of extrinsic COPD-like airway inflammation (2.6-fold). We conclude that there is a clear specificity for the nature of inflammation in lung cancer promotion, and IL-6 has an essential role in lung cancer promotion.
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Affiliation(s)
- Cesar Ochoa Perez
- Departments of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
- Tecnológico de Monterrey School of Medicine, Monterrey, Nuevo León, Mexico
| | | | - Ana Ruiz Venado
- Tecnológico de Monterrey School of Medicine, Monterrey, Nuevo León, Mexico
| | - Scott E. Evans
- Departments of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
- Institute of Biosciences and Technology, Center for Inflammation and Infection, Houston, Texas, USA
| | - Mihai Gagea
- Department of Veterinary Medicine & Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
| | - Christopher M. Evans
- Departments of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
- Institute of Biosciences and Technology, Center for Inflammation and Infection, Houston, Texas, USA
| | - Burton F. Dickey
- Departments of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
- Institute of Biosciences and Technology, Center for Inflammation and Infection, Houston, Texas, USA
| | - Seyed Javad Moghaddam
- Departments of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
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50
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NF-κB, JNK, and TLR Signaling Pathways in Hepatocarcinogenesis. Gastroenterol Res Pract 2010; 2010:367694. [PMID: 21151655 PMCID: PMC2995932 DOI: 10.1155/2010/367694] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2010] [Accepted: 10/22/2010] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third largest cause of cancer deaths worldwide. The role of molecular changes in HCC have been used to identify prognostic markers and chemopreventive or therapeutic targets. It seems that toll-like receptors (TLRs) as well as the nuclear factor (NF)-κB, and JNK pathways are critical regulators for the production of the cytokines associated with tumor promotion. The cross-talk between an inflammatory cell and a neoplastic cell, which is instigated by the activation of NF-κB and JNKs, is critical for tumor organization. JNKs also regulate cell proliferation and act as oncogenes, making them the main tumor-promoting protein kinases. TLRs play roles in cytokine and hepatomitogen expression mainly in myeloid cells and may promote liver tumorigenesis. A better understanding of these signaling pathways in the liver will help us understand the mechanism of hepatocarcinogenesis and provide a new therapeutic target for HCC.
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