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Horikoshi K, Sakai N, Oshima M, Yamauchi H, Ikeda M, Hayashi K, Yanagisawa H, Yamamori F, Kajikawa S, Hayashi D, Koshino A, Sako K, Yuasa T, Tamai A, Minami T, Nakagawa S, Kitajima S, Toyama T, Hara A, Shimizu M, Oota S, Ishida Y, Wada T, Iwata Y. Autotaxin concentrations in peritoneal dialysis effluent reflect peritoneal function. Ther Apher Dial 2025; 29:276-284. [PMID: 39326924 DOI: 10.1111/1744-9987.14211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/13/2024] [Accepted: 09/06/2024] [Indexed: 09/28/2024]
Abstract
INTRODUCTION Peritoneal equilibration test (PET) has been used to monitor peritoneal function. A more convenient marker would be useful in clinical situations including home medical care. Autotaxin is known to leak into the interstitium as vascular permeability increases during the progression of tissue fibrosis. Therefore, we hypothesized that autotaxin concentrations in peritoneal dialysis (PD) effluent might reflect peritoneal function. METHODS This study enrolled 45 patients undergoing PD from 2016 to 2021. Autotaxin concentrations measured in PD effluent were evaluated for their associations with markers obtained from PET. RESULTS Mean age was 69 years, and 33 patients were men. Univariate and multivariate analyses revealed that autotaxin concentrations are associated with dialysate/plasma creatinine ratio, end/start dialysate glucose ratio, and the dip in the dialysate sodium concentration, a marker of ultrafiltration capacity, at baseline (all p < 0.05). CONCLUSIONS Autotaxin concentrations in PD effluent might be an adjunct marker that reflects peritoneal function.
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Affiliation(s)
- Keisuke Horikoshi
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Norihiko Sakai
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
- Division of Blood Purification, Kanazawa University Hospital, Kanazawa, Japan
| | - Megumi Oshima
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Hiroyuki Yamauchi
- Department of Nephrology, Seika Town National Health Insurance Hospital, Kyoto, Japan
| | - Megumi Ikeda
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Kaho Hayashi
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Hiroyoshi Yanagisawa
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Fumitaka Yamamori
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Sho Kajikawa
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Daiki Hayashi
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Akihiko Koshino
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Keisuke Sako
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Takahiro Yuasa
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Akira Tamai
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Taichiro Minami
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Shiori Nakagawa
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Shinji Kitajima
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
- Division of Blood Purification, Kanazawa University Hospital, Kanazawa, Japan
| | - Tadashi Toyama
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Akinori Hara
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Miho Shimizu
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Satoshi Oota
- Department of Internal medicine, Toyama City Hospital, Toyama, Japan
| | - Yoichi Ishida
- Department of Internal medicine, Toyama City Hospital, Toyama, Japan
| | - Takashi Wada
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Yasunori Iwata
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
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Spalding VA, Fellenstein BA, Ahodantin J, Jeyarajan AJ, Wang Y, Khan SK, Xu M, Lin W, Alatrakchi N, Su L, Chung RT, Salloum S. YAP mediates HIV-related liver fibrosis. JHEP Rep 2024; 6:101163. [PMID: 39524207 PMCID: PMC11544392 DOI: 10.1016/j.jhepr.2024.101163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 06/18/2024] [Accepted: 06/26/2024] [Indexed: 11/16/2024] Open
Abstract
Background & Aims HIV accelerates liver fibrosis attributable to multiple etiologies, including HCV, HBV, and steatotic liver disease. Evidence also suggests that HIV infection itself is associated with liver fibrogenesis. Recent studies have implicated Yes-associated protein 1 (YAP1) and the upstream lysophosphatidic acid (LPA)/PI3K/AKT pathway as critical regulators of hepatic fibrogenesis, and suggest a connection to HIV-related liver fibrosis. However, the relationship between YAP/PI3K/AKT pathway activation and HIV-related liver fibrosis remains uncertain. Methods qPCR, western blot, immunofluorescence, and ELISA (replicates n ≥3) were performed in an unbiased humanized mouse model (NRG-hu HSC mice, n = 6), the precision cut liver slice ex vivo model, and both traditional in vitro models as well as a 3D spheroid system. Results YAP target gene mRNA and protein levels (ANKRD, CTGF, CYR61) were upregulated across all models exposed to HIV. Humanized mice infected with HIV had significant increases in the percentage of YAP-positive nuclei (2.2-fold) and the percentage area of Sirius Red collagen staining (3.3-fold) compared to control mice. Serum concentrations of LPA were increased 5.8-fold in people living with HIV compared to healthy controls. Modulation of LPAR1, PI3K, and AKT by either inhibitors or small-interfering RNAs abrogated the fibrotic effects of HIV exposure and downregulated YAP target genes within cultured liver cells. Conclusions The LPAR/PI3K/AKT axis is vital for the activation of YAP and hepatic fibrogenesis due to HIV infection. This novel mechanistic insight suggests new pharmacologic targets for treatment of liver fibrosis in people living with HIV. Impact and implications There are currently no FDA-approved treatments for cirrhosis, while liver disease is the second leading cause of mortality among people living with HIV after AIDS. Increased lysophosphatidic acid concentrations and AKT activation after HIV infection found in recent work suggest that the Hippo pathway may be a key regulator of HIV-related fibrogenesis. By linking lysophosphatidic acid signaling, YAP activation, and HIV-related fibrogenesis, this mechanism presents a target for future research into therapeutic interventions for not only HIV but also other liver diseases, e.g. metabolic dysfunction- or alcohol-associated liver disease.
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Affiliation(s)
- Volney A. Spalding
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Brian A. Fellenstein
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - James Ahodantin
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Andre J. Jeyarajan
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Yongtao Wang
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Sanjoy K. Khan
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Min Xu
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Wenyu Lin
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Nadia Alatrakchi
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Lishan Su
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Raymond T. Chung
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Shadi Salloum
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
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Hiyama Y, Fujino H, Namba M, Fujii Y, Uchikawa S, Ono A, Nakahara T, Murakami E, Kawaoka T, Miki D, Tsuge M, Oka S. Value of autotaxin for hepatocellular carcinoma risk assessment in chronic hepatitis B patients treated with nucleos(t)ide analogs. Hepatol Res 2024; 54:981-992. [PMID: 38539054 DOI: 10.1111/hepr.14042] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 02/23/2024] [Accepted: 03/14/2024] [Indexed: 11/03/2024]
Abstract
AIM Autotaxin (ATX) is a newly identified liver fibrosis biomarker; however, its clinical usefulness remains unclear. Therefore, we analyzed the changes in patients with chronic hepatitis B virus infection treated with nucleos(t)ide analogs (NAs) to evaluate its usefulness. We also investigated the predictors of hepatocellular carcinoma development, including ATX, in patients with chronic hepatitis B based on their clinical characteristics. METHODS This retrospective study included 179 patients with hepatitis B virus infection treated with NAs for >2 years. First, we measured the ATX levels before and up to 10 years after initiating entecavir (therapy for 88 patients whose serial ATX levels could be measured before and during entecavir therapy. Subsequently, for 179 patients whose ATX levels could be measured at the commencement of NAs, we examined the factors involved in developing hepatocellular carcinoma, including ATX. RESULTS The ATX levels showed a gradual and significant decrease during the observation period of up to 10 years. Multivariable analysis showed that a baseline ATX/upper limits of normal ratio ≥1.214, age, and alkaline phosphatase levels were independent risk factors for hepatocellular carcinoma development. The combination of age and ATX/upper limits of normal ratio was used to stratify the high-risk groups for liver carcinogenesis. CONCLUSIONS A decrease in ATX levels up to 10 years after the commencement of therapy suggested that ATX is a helpful biomarker in evaluating fibrosis in patients undergoing long-term NA therapy. Furthermore, this study showed that combining age and the baseline ATX/upper limits of normal ratio may help identify high-risk carcinogenesis groups.
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Affiliation(s)
- Yuichi Hiyama
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Clinical Research Center in Hiroshima, Hiroshima University Hospital, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Maiko Namba
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasutoshi Fujii
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Cancer Treatment Center, Hiroshima University Hospital, Hiroshima, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shiro Oka
- Department of Gastroenterology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Li X, Koyama Y, Taura K, Nishio T, Yoh T, Nishino H, Uemoto Y, Kimura Y, Nakamura D, Nam NH, Sato M, Seo S, Iwaisako K, Hatano E. High expression of autotaxin is associated with poor recurrence-free survival in cholangiocarcinoma. Hepatol Res 2024; 54:817-826. [PMID: 38430513 DOI: 10.1111/hepr.14031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 02/08/2024] [Accepted: 02/12/2024] [Indexed: 03/04/2024]
Abstract
BACKGROUND AND AIM Autotaxin (ATX) is an extracellular lysophospholipase D that catalyzes the hydrolysis of lysophosphatidylcholine into lysophosphatidic acid (LPA). Recent accumulating evidence indicates the biological roles of ATX in malignant tumors. However, the expression and clinical implications of ATX in human cholangiocarcinoma (CCA) remain elusive. METHODS In this study, the expression of ATX in 97 human CCA tissues was evaluated by immunohistochemistry. Serum ATX levels were determined in CCA patients (n = 26) and healthy subjects (n = 8). Autotaxin expression in cell types within the tumor microenvironment was characterized by immunofluorescence staining. RESULTS High ATX expression in CCA tissue was significantly associated with a higher frequency of lymph node metastasis (p = 0.050). High ATX expression was correlated with shorter overall survival (p = 0.032) and recurrence-free survival (RFS) (p = 0.001) than low ATX expression. In multivariate Cox analysis, high ATX expression (p = 0.019) was an independent factor for shorter RFS. Compared with low ATX expression, high ATX expression was significantly associated with higher Ki-67-positive cell counts (p < 0.001). Serum ATX levels were significantly higher in male CCA patients than in healthy male subjects (p = 0.030). In the tumor microenvironment of CCA, ATX protein was predominantly expressed in tumor cells, cancer-associated fibroblasts, plasma cells, and biliary epithelial cells. CONCLUSIONS Our study highlights the clinical evidence and independent prognostic value of ATX in human CCA.
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Affiliation(s)
- Xuefeng Li
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yukinori Koyama
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Gastroenterological Surgery and Oncology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan
| | - Takahiro Nishio
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomoaki Yoh
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroto Nishino
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yusuke Uemoto
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yusuke Kimura
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Daichi Nakamura
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Nguyen Hai Nam
- Department of Liver Tumor, Cancer Center, Cho Ray Hospital, Ho Chi Minh City, Vietnam
| | - Motohiko Sato
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoru Seo
- Department of Surgery, Kochi Medical School, Kochi, Japan
| | - Keiko Iwaisako
- Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan
| | - Etsuro Hatano
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Laface C, Ricci AD, Vallarelli S, Ostuni C, Rizzo A, Ambrogio F, Centonze M, Schirizzi A, De Leonardis G, D’Alessandro R, Lotesoriere C, Giannelli G. Autotaxin-Lysophosphatidate Axis: Promoter of Cancer Development and Possible Therapeutic Implications. Int J Mol Sci 2024; 25:7737. [PMID: 39062979 PMCID: PMC11277072 DOI: 10.3390/ijms25147737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/03/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
Autotaxin (ATX) is a member of the ectonucleotide pyrophosphate/phosphodiesterase (ENPP) family; it is encoded by the ENPP2 gene. ATX is a secreted glycoprotein and catalyzes the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is responsible for the transduction of various signal pathways through the interaction with at least six G protein-coupled receptors, LPA Receptors 1 to 6 (LPAR1-6). The ATX-LPA axis is involved in various physiological and pathological processes, such as angiogenesis, embryonic development, inflammation, fibrosis, and obesity. However, significant research also reported its connection to carcinogenesis, immune escape, metastasis, tumor microenvironment, cancer stem cells, and therapeutic resistance. Moreover, several studies suggested ATX and LPA as relevant biomarkers and/or therapeutic targets. In this review of the literature, we aimed to deepen knowledge about the role of the ATX-LPA axis as a promoter of cancer development, progression and invasion, and therapeutic resistance. Finally, we explored its potential application as a prognostic/predictive biomarker and therapeutic target for tumor treatment.
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Affiliation(s)
- Carmelo Laface
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Angela Dalia Ricci
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Simona Vallarelli
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Carmela Ostuni
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Alessandro Rizzo
- Medical Oncology, IRCCS Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Francesca Ambrogio
- Section of Dermatology and Venereology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Matteo Centonze
- Personalized Medicine Laboratory, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy;
| | - Annalisa Schirizzi
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, “IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.)
| | - Giampiero De Leonardis
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, “IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.)
| | - Rosalba D’Alessandro
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, “IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.)
| | - Claudio Lotesoriere
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
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Wu K, Zhang G, Shen C, Zhu L, Yu C, Sartorius K, Ding W, Jiang Y, Lu Y. Role of T cells in liver metastasis. Cell Death Dis 2024; 15:341. [PMID: 38755133 PMCID: PMC11099083 DOI: 10.1038/s41419-024-06726-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 04/24/2024] [Accepted: 05/07/2024] [Indexed: 05/18/2024]
Abstract
The liver is a major metastatic site (organ) for gastrointestinal cancers (such as colorectal, gastric, and pancreatic cancers) as well as non-gastrointestinal cancers (such as lung, breast, and melanoma cancers). Due to the innate anatomical position of the liver, the apoptosis of T cells in the liver, the unique metabolic regulation of hepatocytes and other potential mechanisms, the liver tends to form an immunosuppressive microenvironment and subsequently form a pre-metastatic niche (PMN), which can promote metastasis and colonization by various tumor cells(TCs). As a result, the critical role of immunoresponse in liver based metastasis has become increasingly appreciated. T cells, a centrally important member of adaptive immune response, play a significant role in liver based metastases and clarifying the different roles of the various T cells subsets is important to guide future clinical treatment. In this review, we first introduce the predisposing factors and related mechanisms of liver metastasis (LM) before introducing the PMN and its transition to LM. Finally, we detail the role of different subsets of T cells in LM and advances in the management of LM in order to identify potential therapeutic targets for patients with LM.
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Affiliation(s)
- Kejia Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Guozhu Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Department of Emergency Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Changbing Shen
- Department of Hepatobiliary and Pancreatic Surgery, Taizhou Second People's Hospital Affiliated with Yangzhou University, Taizhou, China
| | - Li Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China
- Department of Emergency Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Chongyuan Yu
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Kurt Sartorius
- School of Laboratory Medicine and Molecular Sciences, University of Kwazulu-Natal, Durban, South Africa
- Africa Hepatopancreatobiliary Cancer Consortium, Mayo Clinic, Jacksonville, FL, USA
| | - Wei Ding
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China.
- Department of General Surgery, The Wujin Clinical College of Xuzhou Medical University, Changzhou, China.
- Changzhou Medical Center, Nanjing Medical University, Changzhou, China.
| | - Yong Jiang
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China.
| | - Yunjie Lu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
- Africa Hepatopancreatobiliary Cancer Consortium, Mayo Clinic, Jacksonville, FL, USA.
- Department of General Surgery, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China.
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Takemura K, Nakamae M, Okamura H, Sakatoku K, Ido K, Makuuchi Y, Kuno M, Takakuwa T, Hirose A, Nishimoto M, Nakashima Y, Koh H, Igarashi K, Kubota H, Hino M, Nakamae H. Autotaxin is a potential predictive marker for the development of veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Ann Hematol 2024; 103:1705-1715. [PMID: 38494552 DOI: 10.1007/s00277-024-05685-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 02/25/2024] [Indexed: 03/19/2024]
Abstract
Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT), and stratification of the high-risk group before transplantation is significant. Serum autotaxin (ATX) levels have been reported to increase in patients with liver fibrosis caused by metabolic inhibition from liver sinusoidal endothelial cells. Considering that the pathophysiology of VOD/SOS begins with liver sinusoidal endothelial cell injury, an increase in serum ATX levels may precede the onset of VOD/SOS. A retrospective study with 252 patients, including 12 patients with VOD/SOS, who had received allo-HCT was performed. The cumulative incidence of VOD/SOS was higher in the group with serum ATX levels before conditioning (baseline ATX) above the upper reference limit (high ATX group, p < 0.001), and 1-year cumulative incidences were 22.7% (95% confidence interval [95%CI], 3.1-42.4%) and 3.5% (95%CI, 1.1-5.8%), respectively. In the multivariate analysis, elevated baseline ATX was identified as an independent risk factor for VOD/SOS development and showed an additive effect on the predictive ability of known risk factors. Furthermore, the incidence of VOD/SOS-related mortality was greater in the high ATX group (16.7% vs. 1.3%; p = 0.005). Serum ATX is a potential predictive marker for the development of VOD/SOS.
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Affiliation(s)
- Kazuya Takemura
- Department of Central Clinical Laboratory, Osaka Metropolitan University Hospital, Osaka, Japan
| | - Mika Nakamae
- Department of Central Clinical Laboratory, Osaka Metropolitan University Hospital, Osaka, Japan.
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
- Department of Laboratory Medicine and Medical Informatics, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka, 545-8585, Japan.
| | - Hiroshi Okamura
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- Department of Laboratory Medicine and Medical Informatics, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka, 545-8585, Japan
| | - Kazuki Sakatoku
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kentaro Ido
- Department of Central Clinical Laboratory, Osaka Metropolitan University Hospital, Osaka, Japan
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- Department of Laboratory Medicine and Medical Informatics, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka, 545-8585, Japan
| | - Yosuke Makuuchi
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Masatomo Kuno
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Teruhito Takakuwa
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Asao Hirose
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Mitsutaka Nishimoto
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Yasuhiro Nakashima
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Hideo Koh
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- Department of Preventive Medicine and Environmental Health, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Koji Igarashi
- Bioscience Division, Tosoh Corporation, Kanagawa, Japan
| | - Hiroshi Kubota
- Department of Central Clinical Laboratory, Osaka Metropolitan University Hospital, Osaka, Japan
| | - Masayuki Hino
- Department of Central Clinical Laboratory, Osaka Metropolitan University Hospital, Osaka, Japan
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- Department of Laboratory Medicine and Medical Informatics, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka, 545-8585, Japan
| | - Hirohisa Nakamae
- Department of Central Clinical Laboratory, Osaka Metropolitan University Hospital, Osaka, Japan
- Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
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8
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Tobita H, Sakai H, Yamaguchi A, Notsu Y, Kataoka M, Yazaki T, Nabika T, Ishihara S, Kobayashi H. Association of lysophosphatidic acid molecules with liver fibrosis: different roles indicated. J Clin Biochem Nutr 2023; 73:255-261. [PMID: 37970549 PMCID: PMC10636581 DOI: 10.3164/jcbn.23-58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 08/08/2023] [Indexed: 11/17/2023] Open
Abstract
Lysophosphatidic acid is composed of lysophosphatidic acid (LPA) molecules with varied chemical forms. The present cross-sectional study was conducted to investigate the associations of various LPA molecules with liver fibrosis. Forty-six patients affected by various types of liver disease who underwent an ultrasound-guided liver biopsy were recruited for this study. Liver fibrosis was evaluated using histological grading, as well as shear wave velocity (Vs) and serum level of type IV collagen 7S (T4c7s). Serum levels of LPA molecules were determined using liquid-chromatography tandem mass-spectrometry (LC-MSMS). Total LPA showed a significant positive association with fibrosis severity evaluated based on histological grading, Vs, and T4c7s used as parameters, following adjustment for other confounding factors, including disease type, age, gender, body mass index, and high-sensitivity C-reactive protein. This association was replicated when 16:0-LPA was substituted for total LPA. In contrast, when 20:4-LPA was substituted for total LPA, no significant association with liver fibrosis was observed. In conclusion, the degree of association varied among the different LPA molecule chemical forms, suggesting different pathophysiological roles of individual LPA molecules, although total LPA concentration was shown to be associated with liver fibrosis.
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Affiliation(s)
- Hiroshi Tobita
- Division of Hepatology, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Department of Internal Medicine II, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Hiromichi Sakai
- Interdisciplinary Center for Science Research, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Metabolizumo Project, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Akane Yamaguchi
- Interdisciplinary Center for Science Research, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Metabolizumo Project, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Yoshitomo Notsu
- Central Clinical Laboratory, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Metabolizumo Project, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Masatoshi Kataoka
- Division of Hepatology, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Department of Internal Medicine II, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Tomotaka Yazaki
- Division of Hepatology, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Department of Internal Medicine II, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Toru Nabika
- School of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Metabolizumo Project, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Shunji Ishihara
- Department of Internal Medicine II, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Hironori Kobayashi
- Central Clinical Laboratory, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
- Metabolizumo Project, Shimane University Hospital, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
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9
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Méaux MN, Regnier M, Portefaix A, Borel O, Alioli C, Peyruchaud O, Legrand M, Bacchetta J. Circulating autotaxin levels in healthy teenagers: Data from the Vitados cohort. Front Pediatr 2023; 11:1094705. [PMID: 36861069 PMCID: PMC9969100 DOI: 10.3389/fped.2023.1094705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 01/16/2023] [Indexed: 02/17/2023] Open
Abstract
Autotaxin (ATX) is a secreted enzyme with a lysophospholipase D activity, mainly secreted by adipocytes and widely expressed. Its major function is to convert lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), an essential bioactive lipid involved in multiple cell processes. The ATX-LPA axis is increasingly studied because of its involvement in numerous pathological conditions, more specifically in inflammatory or neoplastic diseases, and in obesity. Circulating ATX levels gradually increase with the stage of some pathologies, such as liver fibrosis, thus making them a potentially interesting non-invasive marker for fibrosis estimation. Normal circulating levels of ATX have been established in healthy adults, but no data exist at the pediatric age. The aim of our study is to describe the physiological concentrations of circulating ATX levels in healthy teenagers through a secondary analysis of the VITADOS cohort. Our study included 38 teenagers of Caucasian origin (12 males, 26 females). Their median age was 13 years for males and 14 years for females, ranging from Tanner 1 to 5. BMI was at the 25th percentile for males and 54th percentile for females, and median blood pressure was normal. ATX median levels were 1,049 (450-2201) ng/ml. There was no difference in ATX levels between sexes in teenagers, which was in contrast to the male and female differences described in the adult population. ATX levels significantly decreased with age and pubertal status, reaching adult levels at the end of puberty. Our study also suggested positive correlations between ATX levels and blood pressure (BP), lipid metabolism, and bone biomarkers. However, except for LDL cholesterol, these factors were also significantly correlated with age, which might be a confounding factor. Still, a correlation between ATX and diastolic BP was described in obese adult patients. No correlation was found between ATX levels and inflammatory marker C-reactive protein (CRP), Body Mass Index (BMI), and biomarkers of phosphate/calcium metabolism. In conclusion, our study is the first to describe the decline in ATX levels with puberty and the physiological concentrations of ATX levels in healthy teenagers. It will be of utmost importance when performing clinical studies in children with chronic diseases to keep these kinetics in mind, as circulating ATX might become a non-invasive prognostic biomarker in pediatric chronic diseases.
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Affiliation(s)
- Marie-Noëlle Méaux
- INSERM, UMR 1033, Lyon, France.,Centre de Référence des Maladies Rares du Calcium et du Phosphate, filière OSCAR, Lyon, France.,Service de Néphrologie, Rhumatologie et Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Maitena Regnier
- INSERM, UMR 1033, Lyon, France.,Centre de Référence des Maladies Rares du Calcium et du Phosphate, filière OSCAR, Lyon, France.,Service de Néphrologie, Rhumatologie et Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Aurélie Portefaix
- Centre d'Investigation Clinique, CIC 1407, Hospices Civils de Lyon, Bron, France
| | | | | | | | - Mélanie Legrand
- INSERM, UMR 1033, Lyon, France.,Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France.,Service de Rhumatologie, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Justine Bacchetta
- INSERM, UMR 1033, Lyon, France.,Centre de Référence des Maladies Rares du Calcium et du Phosphate, filière OSCAR, Lyon, France.,Service de Néphrologie, Rhumatologie et Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.,Faculté de Médecine Lyon Est, Université Claude Bernard Lyon 1, Lyon, France
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10
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Pemafibrate improves liver dysfunction and non-invasive surrogates for liver fibrosis in patients with non-alcoholic fatty liver disease with hypertriglyceridemia: a multicenter study. Hepatol Int 2022; 17:606-614. [PMID: 36583842 DOI: 10.1007/s12072-022-10453-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 11/04/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND This retrospective, multicenter study evaluated the effect of pemafibrate treatment on liver function and fibrosis by liver function tests (LFTs) and various fibrotic biomarkers including FibroScan in non-alcoholic fatty liver disease (NAFLD) with hypertriglyceridemia. METHODS A total of 138 NAFLD patients treated with pemafibrate at three hospitals between September 2018 and April 2021 were included. To evaluate the effect of pemafibrate treatment, FibroScan-aspartate aminotransferase (FAST) score, a novel index of steatohepatitis that can be calculated based on the aspartate aminotransferase (AST) value, controlled attenuation parameter (CAP), and liver stiffness measurement (LSM) was used. RESULTS Serum TG levels were significantly decreased 4 weeks after pemafibrate treatment (p = 0.003). The levels of AST (p = 0.038), alanine aminotransferase (ALT) (p = 0.003), and gamma-glutamyl transferase (GGT) (p = 0.047) also significantly diminished 12 weeks after pemafibrate administration compared to before administration (p < 0.05). However, serum HDL-cholesterol (p = 0.193), LDL-cholesterol (p = 0.967), and eGFR (p = 0.909) levels were not significantly altered 12 weeks after pemafibrate administration. In addition, the fibrosis biomarkers' Type IV collagen (p = 0.753) and FIB-4 index (p = 0.333) did not significantly differ, while Autotaxin (p = 0.006) and the AST-to-platelet ratio index (APRI) (p = 0.003) significantly decreased 48 weeks after pemafibrate administration. No significant reductions in LSM (p = 0.959) and CAP (p = 0.266) were detected using FibroScan 48 weeks after pemafibrate administration. FAST score was significantly improved (p = 0.0475). CONCLUSION Pemafibrate improved LFTs, including fibrotic biomarkers and FAST score, due to the hepatic anti-inflammatory effect, suggesting that pemafibrate may prevent disease progression in NAFLD patients with hypertriglyceridemia.
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11
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Shimura T, Kurano M, Okamoto K, Jubishi D, Hashimoto H, Kano K, Igarashi K, Shimamoto S, Aoki J, Moriya K, Yatomi Y. Decrease in serum levels of autotaxin in COVID-19 patients. Ann Med 2022; 54:3189-3200. [PMID: 36369824 PMCID: PMC9665086 DOI: 10.1080/07853890.2022.2143554] [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] [Indexed: 11/15/2022] Open
Abstract
INTRODUCTION In order to identify therapeutic targets in Coronavirus disease 2019 (COVID-19), it is important to identify molecules involved in the biological responses that are modulated in COVID-19. Lysophosphatidic acids (LPAs) are involved in the pulmonary inflammation and fibrosis are one of the candidate molecules. The aim of this study was to evaluate the association between the serum levels of autotaxin (ATX), which are enzymes involved in the synthesis of lysophosphatidic acids. MATERIAL AND METHODS We enrolled 134 subjects with COVID-19 and 58 normal healthy subjects for the study. We measured serum ATX levels longitudinally in COVID-19 patients and investigated the time course and the association with severity and clinical parameters. RESULTS The serum ATX levels were reduced in all patients with COVID-19, irrespective of the disease severity, and were negatively associated with the serum CRP, D-dimer, and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody levels. DISCUSSION Considering the biological properties of LPAs in the pulmonary inflammation and fibrosis, modulation of ATX might be compensatory biological responses to suppress immunological overreaction especially in the lung, which is an important underlying mechanism for the mortality of the disease. CONCLUSIONS COVID-19 patients showed a decrease in the serum levels of ATX, irrespective of the disease severity. Key MessagesAutotaxin (ATX) is an enzyme involved in the synthesis of lysophosphatidic acid (LPA), which has been reported to be involved in pulmonary inflammation and fibrosis. Patients with COVID-19 show decrease in the serum levels of ATX. Modulation of ATX might be compensatory biological responses to suppress immunological overreaction.
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Affiliation(s)
- Takuya Shimura
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
| | - Makoto Kurano
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan.,Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Koh Okamoto
- Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan
| | - Daisuke Jubishi
- Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan
| | - Hideki Hashimoto
- Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan
| | - Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Koji Igarashi
- Bioscience Division, TOSOH Corporation, Kanagawa, Japan
| | | | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Kyoji Moriya
- Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan.,Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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12
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Drosouni A, Panagopoulou M, Aidinis V, Chatzaki E. Autotaxin in Breast Cancer: Role, Epigenetic Regulation and Clinical Implications. Cancers (Basel) 2022; 14:5437. [PMID: 36358855 PMCID: PMC9658281 DOI: 10.3390/cancers14215437] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/31/2022] [Accepted: 10/31/2022] [Indexed: 08/02/2023] Open
Abstract
Autotaxin (ATX), the protein product of Ectonucleotide Pyrophosphatase Phosphodiesterase 2 (ENPP2), is a secreted lysophospholipase D (lysoPLD) responsible for the extracellular production of lysophosphatidic acid (LPA). ATX-LPA pathway signaling participates in several normal biological functions, but it has also been connected to cancer progression, metastasis and inflammatory processes. Significant research has established a role in breast cancer and it has been suggested as a therapeutic target and/or a clinically relevant biomarker. Recently, ENPP2 methylation was described, revealing a potential for clinical exploitation in liquid biopsy. The current review aims to gather the latest findings about aberrant signaling through ATX-LPA in breast cancer and discusses the role of ENPP2 expression and epigenetic modification, giving insights with translational value.
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Affiliation(s)
- Andrianna Drosouni
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Maria Panagopoulou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece
- Institute of Agri-Food and Life Sciences, Hellenic Mediterranean University Research Centre, 71410 Heraklion, Greece
| | - Vassilis Aidinis
- Institute of BioInnovation, Biomedical Sciences Research Center Alexander Fleming, 16672 Athens, Greece
| | - Ekaterini Chatzaki
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece
- Institute of Agri-Food and Life Sciences, Hellenic Mediterranean University Research Centre, 71410 Heraklion, Greece
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13
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Liu C, Mohan SC, Wei J, Seki E, Liu M, Basho R, Giuliano AE, Zhao Y, Cui X. Breast cancer liver metastasis: Pathogenesis and clinical implications. Front Oncol 2022; 12:1043771. [PMID: 36387238 PMCID: PMC9641291 DOI: 10.3389/fonc.2022.1043771] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 10/04/2022] [Indexed: 09/30/2023] Open
Abstract
Breast cancer is the most common malignant disease in female patients worldwide and can spread to almost every place in the human body, most frequently metastasizing to lymph nodes, bones, lungs, liver and brain. The liver is a common metastatic location for solid cancers as a whole, and it is also the third most common metastatic site for breast cancer. Breast cancer liver metastasis (BCLM) is a complex process. Although the hepatic microenvironment and liver sinusoidal structure are crucial factors for the initial arrest of breast cancer and progression within the liver, the biological basis of BCLM remains to be elucidated. Importantly, further understanding of the interaction between breast cancer cells and hepatic microenvironment in the liver metastasis of breast cancer will suggest ways for the development of effective therapy and prevention strategies for BCLM. In this review, we provide an overview of the recent advances in the understanding of the molecular mechanisms of the hepatic microenvironment in BCLM formation and discuss current systemic therapies for treating patients with BCLM as well as potential therapeutic development based on the liver microenvironment-associated signaling proteins governing BCLM.
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Affiliation(s)
- Cuiwei Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Srivarshini C. Mohan
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Jielin Wei
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ekihiro Seki
- Department of Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Manran Liu
- Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Reva Basho
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- The Lawrence J. Ellison Institute for Transformative Medicine, Los Angeles, CA, United States
| | - Armando E. Giuliano
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Yanxia Zhao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaojiang Cui
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
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14
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Ueno T, Takase K, Toyama C, Deguchi K, Masahata K, Nomura M, Watanabe M, Kamiyama M, Tazuke Y, Bessho K, Okuyama H. Clinical implications of serum autotoxin in regular follow up after pediatric living donor liver transplantation for biliary atresia. J Pediatr Surg 2022; 57:1215-1220. [PMID: 35396089 DOI: 10.1016/j.jpedsurg.2022.02.041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 02/23/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Pediatric patients sometimes develop graft fibrosis after living donor liver transplant (LDLT). Autotaxin is a recently developed serum marker for hepatic fibrosis. We studied the relationship between serum autotaxin levels and histological findings in patients after LDLT for biliary atresia (BA). METHODS Information on patients aged <19 years who received LDLT for BA and were followed for at least 1 year after LDLT was gathered. Autotaxin levels were compared with pathological fibrosis scores. RESULTS The study included 52 patients, of whom 4 patients had no fibrosis (F0), 36 patients had F1 fibrosis, and 12 patients had F2. The median serum autotaxin level was 0.89 mg/L. In patients with portal vein (PV) complications such as stenosis or thrombosis (n = 7), the mean autotoxin level was 1.25 mg/L compared with 0.95 mg/L in patients without PV complications (p = 0.004). Among patients without PV complications, the mean autotaxin level was 0.90, 0.88, and 1.18 mg/L in F0, F1, and F2 fibrosis, respectively. The mean autotaxin was higher in F2 fibrosis than in F0 or F1 fibrosis (p<0.05). Autotoxin had a high area under the curve (0.86) with the cut-off level of 0.897 mg/L. CONCLUSION Serum autotaxin is a novel marker for liver fibrosis in patients after pediatric LDLT for BA. TYPE OF STUDY Study of Diagnostic Test. LEVEL OF EVIDENCE Level II.
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Affiliation(s)
- Takehisa Ueno
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Koki Takase
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Chiyoshi Toyama
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Koichi Deguchi
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Kazunori Masahata
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Motonari Nomura
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Miho Watanabe
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Masafumi Kamiyama
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Yuko Tazuke
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Kazuhiko Bessho
- Department of Pediatrics, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Hiroomi Okuyama
- Department of Pediatric Surgery, Osaka University of Graduation School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
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15
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Ando W, Kaneko F, Shimamoto S, Igarashi K, Otori K, Yokomori H. Long-term prediction of hepatocellular carcinoma using serum autotaxin levels after antiviral therapy for hepatitis C. Ann Hepatol 2022; 27:100660. [PMID: 35007770 DOI: 10.1016/j.aohep.2022.100660] [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: 11/22/2021] [Accepted: 12/31/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Continuous monitoring for hepatocellular carcinoma is necessary following treatment with direct-acting antivirals in patients with hepatitis C virus infection. We investigated whether the long-term follow-up of serum autotaxin levels could predict the development of hepatocellular carcinoma. PATIENTS AND METHODS This prospective observational study enrolled adult patients with chronic hepatitis C virus infection who presented to the study center from January 2016 to March 2021. Among the patients who achieved a sustained viral response, the relationship between the development of hepatocellular carcinoma and serum autotaxin levels was assessed before treatment with direct-acting antivirals; at the end of therapy; at 12 and 24 weeks; and at 12, 24, 36, and 48 months after treatment. RESULTS Data were analyzed for 139 patients. Thirteen patients developed hepatocellular carcinoma 48 months after treatment. The cut-off serum autotaxin values that predicted hepatocellular carcinoma after 24 weeks were 1.22 (men) and 1.92 (women) mg/L. The area under the curve for serum autotaxin was 0.83 (95% confidence interval [CI]:0.71-0.95) in men and 0.90 (95% CI: 0.82-0.99) in women. The positive predictive value of serum autotaxin was 0.208 (95% CI: 0.139-0.248), and the negative predictive value was 0.971 (95% CI: 0.939-0.990). The cumulative incidence of hepatocellular carcinoma was significantly higher when serum autotaxin levels were above the cut-off value after 24 weeks (p < 0.0001). CONCLUSIONS Serum autotaxin is a candidate biomarker for predicting hepatocellular carcinoma during the long-term follow-up of patients with a sustained viral response following treatment with direct-acting antivirals.
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Affiliation(s)
- Wataru Ando
- Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
| | - Fumihiko Kaneko
- Department of Gastroenterology and Hepatology, Saitama City Hospital, 2460 Mimuro, Midori-ku, Saitama 336-8522, Japan
| | - Satoshi Shimamoto
- Bioscience Division, Tosoh Corporation, 2743-1 Hayakawa, Ayase-shi, Kanagawa 252-1123, Japan
| | - Koji Igarashi
- Bioscience Division, Tosoh Corporation, 2743-1 Hayakawa, Ayase-shi, Kanagawa 252-1123, Japan
| | - Katsuya Otori
- Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
| | - Hiroaki Yokomori
- Department of Internal Medicine, Kitasato University Medical Center, 6-100 Arai, Kitamoto-shi, Saitama 364-8641, Japan
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16
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Lua I, Balog S, Yanagi A, Tateno C, Asahina K. Loss of lysophosphatidic acid receptor 1 in hepatocytes reduces steatosis via down-regulation of CD36. Prostaglandins Other Lipid Mediat 2021; 156:106577. [PMID: 34147666 PMCID: PMC8490298 DOI: 10.1016/j.prostaglandins.2021.106577] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 05/19/2021] [Accepted: 06/15/2021] [Indexed: 12/13/2022]
Abstract
Nonalcoholic steatohepatitis is a major public health concern and is characterized by the accumulation of triglyceride in hepatocytes and inflammation in the liver. Steatosis is caused by dysregulation of the influx and efflux of lipids, lipogenesis, and mitochondrial β-oxidation. Extracellular lysophosphatidic acid (LPA) regulates a broad range of cellular processes in development, tissue injury, and cancer. In the present study, we examined the roles of LPA in steatohepatitis induced by a methionine-choline-deficient (MCD) diet in mice. Hepatocytes express LPA receptor (Lpar) 1-3 mRNAs. Steatosis developed in mice fed the MCD diet was reduced by treatment with inhibitors for pan-LPAR or LPAR1. Hepatocyte-specific deletion of the Lpar1 gene also reduced the steatosis in the MCD model. Deletion of the Lpar1 gene in hepatocytes reduced expression of Cd36, a gene encoding a fatty acid transporter. Although LPA/LPAR1 signaling induces expression of Srebp1 mRNA in hepatocytes, LPA does not fully induce expression of SREBP1-target genes involved in lipogenesis. Human hepatocytes repopulated in chimeric mice are known to develop steatosis and treatment with an LPAR1 inhibitor reduces expression of CD36 mRNA and steatosis. Our data indicate that antagonism of LPAR1 reduces steatosis in mouse and human hepatocytes by down-regulation of Cd36.
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Affiliation(s)
- Ingrid Lua
- The Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine, University of Southern California, CA, 90033, United States
| | - Steven Balog
- The Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine, University of Southern California, CA, 90033, United States
| | - Ami Yanagi
- Department of Research and Development, PhoenixBio Co., Ltd., Higashi-Hiroshima, Hiroshima, 739-0046, Japan
| | - Chise Tateno
- Department of Research and Development, PhoenixBio Co., Ltd., Higashi-Hiroshima, Hiroshima, 739-0046, Japan
| | - Kinji Asahina
- The Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine, University of Southern California, CA, 90033, United States.
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17
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Litchfield M, Wuest M, Glubrecht D, Briard E, Auberson YP, McMullen TPW, Brindley DN, Wuest F. Positron Emission Tomography Imaging of Autotaxin in Thyroid and Breast Cancer Models Using [ 18F]PRIMATX. Mol Pharm 2021; 18:3352-3364. [PMID: 34319110 DOI: 10.1021/acs.molpharmaceut.1c00265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Autotaxin (ATX) is a secreted enzyme responsible for producing lysophosphatidic acid (LPA). The ATX/LPA signaling axis is typically activated in wound healing and tissue repair processes. The ATX/LPA axis is highjacked and upregulated in the progression and persistence of several chronic inflammatory diseases, including cancer. As ATX inhibitors are now progressing to clinical testing, innovative diagnostic tools such as positron emission tomography (PET) are needed to measure ATX expression in vivo accurately. The radiotracer, [18F]PRIMATX, was recently developed and tested for PET imaging of ATX in vivo in a murine melanoma model. The goal of the present work was to further validate [18F]PRIMATX as a PET imaging agent by analyzing its in vivo metabolic stability and suitability for PET imaging of ATX in models of human 8305C thyroid tumor and murine 4T1 breast cancer. [18F]PRIMATX displayed favorable metabolic stability in vivo (65% of intact radiotracer after 60 min p.i.) and provided sufficient tumor uptake profiles in both tumor models. Radiotracer uptake could be blocked by 8-12% in 8305C thyroid tumors in the presence of ATX inhibitor AE-32-NZ70 as determined by PET and ex vivo biodistribution analyses. [18F]PRIMATX also showed high brain uptake, which was reduced by 50% through the administration of ATX inhibitor AE-32-NZ70. [18F]PRIMATX is a suitable radiotracer for PET imaging of ATX in the brain and peripheral tumor tissues.
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Affiliation(s)
- Marcus Litchfield
- Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton T6G 1Z2, Alberta, Canada.,Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Alberta, Canada
| | - Melinda Wuest
- Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton T6G 1Z2, Alberta, Canada
| | - Daryl Glubrecht
- Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton T6G 1Z2, Alberta, Canada
| | - Emmanuelle Briard
- Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Fabristrasse 2, Novartis Campus, Basel CH-4056, Switzerland
| | - Yves P Auberson
- Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Fabristrasse 2, Novartis Campus, Basel CH-4056, Switzerland
| | - Todd P W McMullen
- Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton T6G 1Z2, Alberta, Canada.,Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Alberta, Canada
| | - David N Brindley
- Department of Biochemistry, University of Alberta, Edmonton T6G 1Z2, Alberta, Canada.,Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Alberta, Canada
| | - Frank Wuest
- Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton T6G 1Z2, Alberta, Canada.,Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Alberta, Canada
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18
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Fujita K, Masaki T. Serum Biomarkers of Liver Fibrosis Staging in the Era of the Concept "Compensated Advanced Chronic Liver Disease". J Clin Med 2021; 10:3340. [PMID: 34362121 PMCID: PMC8347037 DOI: 10.3390/jcm10153340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/12/2021] [Accepted: 07/25/2021] [Indexed: 12/12/2022] Open
Abstract
Non-invasive indexes of liver fibrosis based on blood examinations have been developed for decades, partially replacing liver biopsy examinations. Recently, the concept of liver cirrhosis was revised and converted to "compensated advanced chronic liver diseases" since the Baveno VI consensus statement in 2015. The term "compensated advanced chronic liver diseases" was established based on the premise that serum biomarkers were not able to differentiate cirrhosis from severe fibrosis. The difficulty to histologically distinguish cirrhosis from severe fibrosis had been pointed out in 1977, when the definition and nomenclatures of cirrhosis had been determined by the World Health Organization. That was decades before serum biomarkers available at present were investigated. Though we are accustomed to differentiating the fibrosis stage as stage 1, 2, 3 (severe fibrosis), and 4 (cirrhosis), differentiation of cirrhosis from severe fibrosis is difficult even by histopathological examination. The current review will provide readers a framework to revise how to apply serum biomarkers on liver fibrosis staging in an era of the concept of "compensated advanced chronic liver disease".
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Affiliation(s)
- Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita District, Kagawa 761-0793, Japan;
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19
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Ueno T, Toyama C, Yoneyama T, Deguchi K, Nomura M, Saka R, Watanabe M, Tazuke Y, Bessho K, Okuyama H. Impact of serum autotaxin level correlating with histological findings in biliary atresia. J Pediatr Surg 2021; 56:1174-1178. [PMID: 33965235 DOI: 10.1016/j.jpedsurg.2021.03.034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 03/12/2021] [Indexed: 11/19/2022]
Abstract
PURPOSE Portoenterostomy is the standard treatment for biliary atresia (BA) that reduces jaundice in two thirds of cases. However, progressive liver fibrosis is common, leading to cirrhosis in most patients. Autotaxin is a new marker for the progression of hepatic fibrosis. We examined the relationship between serum autotaxin levels and liver histological findings in patients with BA. METHODS BA patients with native livers were identified in our hospital. Patients underwent protocol liver biopsies every 1 to 5 years, and liver fibrosis was evaluated based on the METAVIR score. Serum autotaxin levels were compared with the last available pathological findings. RESULTS Thirty-five patients were included and the median age was 10.6 years. Serum autotaxin levels was median 1.6 mg/L. The mean autotaxin level was 1.08 mg/L in F0, 1.07 mg/L in F1, 0.95 mg/L in F2, 2.17 mg/L in F3, and 2.50 mg/L in F4; it was significantly higher in F4 than in F0-F2 (P<0.0024). For predicting cirrhosis (F4) and advanced liver fibrosis (≥F3), autotaxin had the almost same areas under the curve (AUCs 0.78 and 0.90, respectively) as well as M2BPGi. CONCLUSION Autotaxin levels could be used to evaluate the status of native liver fibrosis.
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Affiliation(s)
- Takehisa Ueno
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Chiyoshi Toyama
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Tomohisa Yoneyama
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Koichi Deguchi
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Motonari Nomura
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Ryuta Saka
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Miho Watanabe
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Yuko Tazuke
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Kazuhiko Bessho
- Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Hiroomi Okuyama
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
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20
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Takemura K, Takizawa E, Tamori A, Nakamae M, Kubota H, Uchida-Kobayashi S, Enomoto M, Kawada N, Hino M. Association of serum autotaxin levels with liver fibrosis in patients pretreatment and posttreatment with chronic hepatitis C. J Gastroenterol Hepatol 2021; 36:217-224. [PMID: 32453907 DOI: 10.1111/jgh.15114] [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: 02/15/2020] [Revised: 04/25/2020] [Accepted: 05/16/2020] [Indexed: 01/13/2023]
Abstract
BACKGROUND AND AIM The evaluation of liver fibrosis in patients with chronic hepatitis C virus (HCV) infection is important as it is a risk factor for hepatocellular carcinoma. In the recent years, autotaxin (ATX) has been established as a new noninvasive biomarker to predict liver fibrosis. However, antiviral treatment has been reported to decrease serum ATX, but it is unclear whether posttreatment ATX levels reflect liver fibrosis. In the present study, the correlation between ATX and liver fibrosis in pretreatment and posttreatment patients with HCV infection was analyzed. METHODS A total of 199 samples from 136 patients with HCV infection who had undergone hepatic biopsy before and/or after antiviral treatment at Osaka City University Hospital were used. Posttreatment patients included 38 interferon-treated patients and 80 interferon-free direct-acting antiviral-treated patients; all patients achieved a sustained virological response (SVR). Serum ATX levels were determined by enzyme immunoassay with an AIA-2000 analyzer. RESULTS Serum ATX levels were largely correlated with liver fibrosis stage in patients with HCV infection before and after antiviral treatment. The measured values decreased even in similar liver fibrosis stages after treatment. The area under the receiver operating characteristic curve for the ability of ATX to diagnose above F2 stage before treatment was 0.81 (both male and female) and that after achieving SVR, it was 0.71 (male) and 0.72 (female). CONCLUSIONS Serum ATX levels were correlated with histological liver fibrosis stage after achieving SVR. However, separate cutoff values before and after antiviral therapy should be established.
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Affiliation(s)
- Kazuya Takemura
- Department of Central Clinical Laboratory, Osaka City University Hospital, Osaka, Japan
| | - Etsuko Takizawa
- Department of Central Clinical Laboratory, Osaka City University Hospital, Osaka, Japan
| | - Akihiro Tamori
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Mika Nakamae
- Department of Central Clinical Laboratory, Osaka City University Hospital, Osaka, Japan.,Department of Hematology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Hiroshi Kubota
- Department of Central Clinical Laboratory, Osaka City University Hospital, Osaka, Japan
| | | | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Masayuki Hino
- Department of Central Clinical Laboratory, Osaka City University Hospital, Osaka, Japan.,Department of Hematology, Graduate School of Medicine, Osaka City University, Osaka, Japan
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21
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Saleh SAB, Abdelwahab KM, Mady AM, Mohamed GA. The impact of achieving a sustained virological response with direct-acting antivirals on serum autotaxin levels in chronic hepatitis C patients. EGYPTIAN LIVER JOURNAL 2020. [DOI: 10.1186/s43066-020-00060-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Abstract
Background
Autotaxin (ATX) is an emerging biomarker for liver fibrosis. Achievement of sustained virological response (SVR) by direct-acting antivirals (DAAs) results in hepatic fibrosis regression in chronic hepatitis C (CHC) patients. In this context, the clinical implications of ATX have not yet been well-defined. In this study, we aimed to assess the impact of achieving SVR with DAA therapy on serum ATX levels and whether these levels can reflect the regression of hepatic fibrosis in CHC patients. We evaluated serum ATX levels at baseline and 12 weeks post-DAA therapy in 48 CHC patients. We compared ATX with FIB4 score and AST-to-Platelet Ratio Index (APRI) as regards the detection of grade F3–4 fibrosis.
Results
Serum ATX levels were significantly declined in 47 patients after the achievement of SVR12 (p < 0.001). The diagnostic ability of ATX for the detection of grade F3–4 fibrosis was inferior to FIB4 and APRI scores at baseline and SVR12.
Conclusion
Achievement of SVR with DAA therapy causes a significant decline in serum autotaxin concentrations, suggesting early regression of hepatic fibrosis in CHC patients. However, its diagnostic capability for routine patient monitoring and follow-up is still under debate.
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22
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Nie C, Zhang L, Chen X, Li Y, Ha F, Liu H, Han T. Autotaxin: An Early Warning Biomarker for Acute-on-chronic Liver Failure. J Clin Transl Hepatol 2020; 8:240-245. [PMID: 33083245 PMCID: PMC7562802 DOI: 10.14218/jcth.2020.00045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/09/2020] [Accepted: 06/30/2020] [Indexed: 02/06/2023] Open
Abstract
Background and Aims: Recent accumulating evidence indicates the biological actions of autotaxin (ATX) in liver disease. However, the relationship between ATX and liver failure has not been reported. The present study aimed to examine alterations of serum ATX in acute-on-chronic liver failure (ACLF) and evaluate whether serum ATX could be useful as an early warning biomarker of ACLF. Methods: Serum ATX was measured in 50 patients with hepatitis B-related ACLF, 14 patients with alcohol-related ACLF, 11 patients with hepatitis B-related pre-ACLF, 11 patients with alcohol-related Child-Pugh A cirrhosis, 39 patients with hepatitis B-related Child-Pugh A cirrhosis, 26 patients with chronic hepatitis B, and 38 healthy volunteers by enzyme-linked immunosorbent assay. Results: Serum ATX level was significantly higher in the pre-ACLF group than in the Child-Pugh A cirrhosis and chronic hepatitis B groups but lower than in the ACLF group; furthermore, patients with pre-ACLF deteriorated to ACLF had significantly higher serum ATX levels than pre-ACLF patients that did not progress to ACLF. Serum ATX levels were significantly higher among male ACLF patients with preclinical infection, spontaneous bacterial peritonitis or pneumonia, as compared to patients with ACLF but no spontaneous bacterial peritonitis or pneumonia. Serum ATX levels were well correlated with serum biochemical parameters of liver function and model for end-stage liver disease score. Serum ATX ≥ 584.1 ng/mL was a poor prognostic factor for ACLF (hazard ratio of 4.750, 95% confidence interval of 1.106-20.392, p=0.036). Conclusions: Serum ATX level may be a useful early warning biomarker for ACLF.
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Affiliation(s)
- Caiyun Nie
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Lei Zhang
- Department of Clinical Laboratory, Tianjin Third Central Hospital, Tianjin, China
| | - Xiaobing Chen
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Ying Li
- The Third Central Clinical College of Tianjin Medical University, Tianjin, China
- The Affiliated Hospital of Nankai University, Tianjin, China
- Department of Hepatology and Gastroenterology, Tianjin Third Central Hospital, Tianjin, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
- Artificial Cell Engineering Technology Research Center, Tianjin, China
- Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Fushuang Ha
- The Affiliated Hospital of Nankai University, Tianjin, China
- Department of Hepatology and Gastroenterology, Tianjin Third Central Hospital, Tianjin, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
- Artificial Cell Engineering Technology Research Center, Tianjin, China
- Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Hua Liu
- The Third Central Clinical College of Tianjin Medical University, Tianjin, China
- The Affiliated Hospital of Nankai University, Tianjin, China
- Department of Hepatology and Gastroenterology, Tianjin Third Central Hospital, Tianjin, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
- Artificial Cell Engineering Technology Research Center, Tianjin, China
- Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Tao Han
- The Third Central Clinical College of Tianjin Medical University, Tianjin, China
- The Affiliated Hospital of Nankai University, Tianjin, China
- Department of Hepatology and Gastroenterology, Tianjin Third Central Hospital, Tianjin, China
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China
- Artificial Cell Engineering Technology Research Center, Tianjin, China
- Tianjin Institute of Hepatobiliary Disease, Tianjin, China
- Correspondence to: Tao Han, Department of Hepatology and Gastroenterology, Tianjin Institute of Hepatobiliary Disease, Tianjin Key Laboratory of Artificial Cells, Tianjin Third Central Hospital, 83 Jintang Road, Tianjin 300170, China. Tel: +86-22-84112298, Fax: +86-22-84112208, E-mail:
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23
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Role of Adipose Tissue-Derived Autotaxin, Lysophosphatidate Signaling, and Inflammation in the Progression and Treatment of Breast Cancer. Int J Mol Sci 2020; 21:ijms21165938. [PMID: 32824846 PMCID: PMC7460696 DOI: 10.3390/ijms21165938] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/07/2020] [Accepted: 08/14/2020] [Indexed: 12/15/2022] Open
Abstract
Autotaxin (ATX) is a secreted enzyme that produces lysophosphatidate (LPA), which signals through six G-protein coupled receptors, promoting tumor growth, metastasis, and survival from chemotherapy and radiotherapy. Many cancer cells produce ATX, but breast cancer cells express little ATX. In breast tumors, ATX is produced by tumor-associated stroma. Breast tumors are also surrounded by adipose tissue, which is a major bodily source of ATX. In mice, a high-fat diet increases adipocyte ATX production. ATX production in obesity is also increased because of low-level inflammation in the expanded adipose tissue. This increased ATX secretion and consequent LPA signaling is associated with decreased adiponectin production, which results in adverse metabolic profiles and glucose homeostasis. Increased ATX production by inflamed adipose tissue may explain the obesity-breast cancer association. Breast tumors produce inflammatory mediators that stimulate ATX transcription in tumor-adjacent adipose tissue. This drives a feedforward inflammatory cycle since increased LPA signaling increases production of more inflammatory mediators and cyclooxygenase-2. Inhibiting ATX activity, which has implications in breast cancer adjuvant treatments, attenuates this cycle. Targeting ATX activity and LPA signaling may potentially increase chemotherapy and radiotherapy efficacy, and decrease radiation-induced fibrosis morbidity independently of breast cancer type because most ATX is not derived from breast cancer cells.
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24
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Takemura K, Takizawa E, Tamori A, Nakamae M, Kubota H, Uchida-Kobayashi S, Enomoto M, Kawada N, Hino M. Post-Treatment M2BPGi Level and the Rate of Autotaxin Reduction are Predictive of Hepatocellular Carcinoma Development after Antiviral Therapy in Patients with Chronic Hepatitis C. Int J Mol Sci 2020; 21:E4517. [PMID: 32630450 PMCID: PMC7350226 DOI: 10.3390/ijms21124517] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 06/22/2020] [Accepted: 06/23/2020] [Indexed: 01/10/2023] Open
Abstract
Patients with chronic hepatitis C virus (HCV) develop hepatocellular carcinoma (HCC) regardless of achieving a sustained viral response (SVR). Because advanced liver fibrosis is a powerful risk factor for HCC, we analyzed the association between autotaxin (ATX), a liver fibrosis marker, and post-SVR HCC development within 3 years after antiviral treatment. We included 670 patients with HCV who received direct-acting antivirals, achieved SVR and were followed up for at least 6 months (270 of them were followed up for 3 years or more). We measured serum ATX levels before treatment and 12/24 weeks after treatment. The diagnosis of HCC was based on imaging modalities, such as dynamic computed tomography and dynamic magnetic resonance imaging and/or liver biopsy. The present study revealed that high levels of serum ATX predicted post-SVR HCC development (area under the receiver operating characteristic: 0.70-0.76). However, Wisteria floribunda agglutinin positive Mac-2 binding protein (M2BPGi), another liver fibrosis marker, was a more useful predictive marker especially post-treatment according to a multivariate analysis. Patients with a high rate of ATX reduction before and after antiviral treatment did not develop HCC regardless of high pretreatment ATX levels. In conclusion, post-treatment M2BPGi level and the combination of pretreatment ATX levels and rate of ATX reduction were useful predictive markers for post-SVR HCC development in patients with chronic HCV infection.
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MESH Headings
- Aged
- Antigens, Neoplasm/blood
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/metabolism
- Antiviral Agents/therapeutic use
- Biomarkers/blood
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Female
- Hepacivirus/pathogenicity
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/metabolism
- Humans
- Liver Cirrhosis/complications
- Liver Neoplasms/etiology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Male
- Membrane Glycoproteins/blood
- Middle Aged
- Phosphoric Diester Hydrolases/blood
- Phosphoric Diester Hydrolases/metabolism
- Phosphoric Diester Hydrolases/physiology
- Risk Factors
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Affiliation(s)
- Kazuya Takemura
- Department of Central Clinical Laboratory, Osaka City University Hospital, 1-5-7, Asahi-machi, Abeno-ku, Osaka-shi, Osaka 545-8586, Japan; (K.T.); (E.T.); (M.N.); (H.K.); (M.H.)
| | - Etsuko Takizawa
- Department of Central Clinical Laboratory, Osaka City University Hospital, 1-5-7, Asahi-machi, Abeno-ku, Osaka-shi, Osaka 545-8586, Japan; (K.T.); (E.T.); (M.N.); (H.K.); (M.H.)
| | - Akihiro Tamori
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka 545-8585, Japan; (S.U.-K.); (M.E.); (N.K.)
| | - Mika Nakamae
- Department of Central Clinical Laboratory, Osaka City University Hospital, 1-5-7, Asahi-machi, Abeno-ku, Osaka-shi, Osaka 545-8586, Japan; (K.T.); (E.T.); (M.N.); (H.K.); (M.H.)
- Department of Hematology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka 545-8585, Japan
| | - Hiroshi Kubota
- Department of Central Clinical Laboratory, Osaka City University Hospital, 1-5-7, Asahi-machi, Abeno-ku, Osaka-shi, Osaka 545-8586, Japan; (K.T.); (E.T.); (M.N.); (H.K.); (M.H.)
| | - Sawako Uchida-Kobayashi
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka 545-8585, Japan; (S.U.-K.); (M.E.); (N.K.)
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka 545-8585, Japan; (S.U.-K.); (M.E.); (N.K.)
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka 545-8585, Japan; (S.U.-K.); (M.E.); (N.K.)
| | - Masayuki Hino
- Department of Central Clinical Laboratory, Osaka City University Hospital, 1-5-7, Asahi-machi, Abeno-ku, Osaka-shi, Osaka 545-8586, Japan; (K.T.); (E.T.); (M.N.); (H.K.); (M.H.)
- Department of Hematology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka-shi, Osaka 545-8585, Japan
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25
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Shimizu Y, Fukasawa K, Yamamoto S, Shibaike Y, Tsukahara R, Ishikawa M, Iwasa K, Yoshikawa K, Gotoh M, Murakami-Murofushi K. Evaluation of the pharmacokinetics of 2-carba-cyclic phosphatidic acid by liquid chromatography-triple quadrupole mass spectrometry. Prostaglandins Other Lipid Mediat 2020; 150:106450. [PMID: 32298781 DOI: 10.1016/j.prostaglandins.2020.106450] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 03/04/2020] [Accepted: 03/31/2020] [Indexed: 01/24/2023]
Abstract
Cyclic phosphatidic acid (cPA) is a lysophospholipid mediator that suppresses cancer metastasis and osteoarthritis. It also has neuroprotective roles in diseases such as multiple sclerosis and delayed neuronal death following transient ischemia. In order to take advantage of the properties of cPA for the development of new therapeutic strategies, we have synthesized several cPA derivatives and discovered 2-carba-cPA (2ccPA) as a promising candidate. To develop 2ccPA as a therapeutic agent, we investigated the pharmacokinetic profile of 2ccPA by liquid chromatography-triple quadrupole mass spectrometry in this study. When 2ccPA was administered intraperitoneally to mice at a dose of 1.6 mg/kg, the half-life of 2ccPA in plasma was 16 min. The 2ccPA, dosed intraperitoneally to mice at 16 mg/kg, distributed to each organ including brain at 20 min after dosing. It was found that 2ccPA was stable in neutral or alkaline conditions (e.g., intestine) but unstable in acidic conditions (e.g., stomach). When 2ccPA was orally administrated to rats as a gastro-resistant form using an enterosoluble capsule, plasma 2ccPA levels peaked at 2 h, slowly declined thereafter and persistently detected even at 10 h after administration. Here, we present the findings on the effect of the continuous release of 2ccPA from the capsule to reduce the lysophospholipase D activity and also decrease plasma levels of lysophosphatidic acid in rat. These findings will be useful in further studies for evaluating the application of 2ccPA in several disorders.
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Affiliation(s)
| | - Keiko Fukasawa
- Ochadai Academic Production, Ochanomizu University, Tokyo, Japan
| | - Shinji Yamamoto
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Yuki Shibaike
- Institute for Human Life Innovation, Ochanomizu University, Tokyo, Japan; Research Organization for the Promotion of Global Women's Leadership, Ochanomizu University, Tokyo, Japan
| | - Ryoko Tsukahara
- Ochadai Academic Production, Ochanomizu University, Tokyo, Japan
| | - Masaki Ishikawa
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Kensuke Iwasa
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Keisuke Yoshikawa
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Mari Gotoh
- Ochadai Academic Production, Ochanomizu University, Tokyo, Japan; Institute for Human Life Innovation, Ochanomizu University, Tokyo, Japan.
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26
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Tang X, Benesch MGK, Brindley DN. Role of the autotaxin-lysophosphatidate axis in the development of resistance to cancer therapy. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158716. [PMID: 32305571 DOI: 10.1016/j.bbalip.2020.158716] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/31/2020] [Accepted: 04/09/2020] [Indexed: 12/17/2022]
Abstract
Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidate (LPA), which signals through six G-protein coupled receptors (GPCRs). Signaling through LPA is terminated by its degradation by a family of three lipid phosphate phosphatases (LPPs). LPP1 also attenuates signaling downstream of the activation of LPA receptors and some other GPCRs. The ATX-LPA axis mediates a plethora of activities such as cell proliferation, survival, migration, angiogenesis and inflammation, which perform an important role in facilitating wound healing. This wound healing response is hijacked by cancers where there is decreased expression of LPP1 and LPP3 and increased expression of ATX. This maladaptive regulation of LPA signaling also causes chronic inflammation, which has been recognized as one of the hallmarks in cancer. The increased LPA signaling promotes cell survival and migration and attenuates apoptosis, which stimulates tumor growth and metastasis. The wound healing functions of increased LPA signaling also protect cancer cells from effects of chemotherapy and radiotherapy. In this review, we will summarize knowledge of the ATX-LPA axis and its role in the development of resistance to chemotherapy and radiotherapy. We will also offer insights for developing strategies of targeting ATX-LPA axis as a novel part of cancer treatment. This article is part of a Special Issue entitled Lysophospholipids and their receptors: New data and new insights into their function edited by Susan Smyth, Viswanathan Natarajan and Colleen McMullen.
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Affiliation(s)
- Xiaoyun Tang
- Department of Biochemistry, University of Alberta, Edmonton T6G 2S2, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Canada
| | - Matthew G K Benesch
- Department of Biochemistry, University of Alberta, Edmonton T6G 2S2, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Canada; Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador A1B 3V6, Canada
| | - David N Brindley
- Department of Biochemistry, University of Alberta, Edmonton T6G 2S2, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Canada.
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27
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Shao X, Uojima H, Setsu T, Okubo T, Atsukawa M, Furuichi Y, Arase Y, Hidaka H, Tanaka Y, Nakazawa T, Kako M, Kagawa T, Iwakiri K, Terai S, Koizumi W. Usefulness of autotaxin for the complications of liver cirrhosis. World J Gastroenterol 2020; 26:97-108. [PMID: 31933517 PMCID: PMC6952300 DOI: 10.3748/wjg.v26.i1.97] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 12/04/2019] [Accepted: 12/14/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Autotaxin (ATX) has been reported as a direct biomarker for estimating the evaluation of liver fibrosis. But available data on ATX as a useful biomarker for the complications of liver cirrhosis (LC) are scant.
AIM To assess the clinical usefulness of ATX for assessing the complications of LC.
METHODS This multicenter, retrospective study was conducted at six locations in Japan. We include patients with LC, n = 400. The ATX level was evaluated separately in men and women because of its high level in female patients. To assess the clinical usefulness of ATX for the complications of LC, the area under the curve (AUC) of ATX assessing for the severe complications was analyzed in comparison with the model for end-stage liver disease score, albumin-bilirubin (ALBI) score, fibrosis-4 index, and aspartate aminotransferase-to-platelet ratio index.
RESULTS The mean age was 68.4 ± 11.4 years, 240 patients (60.0%) were male. A total of 213 (53.3%) and 187 (46.8%) patients were compensated and decompensated, respectively. The numbers of patients with varix rupture, hepatic ascites, and hepatic encephalopathy were 35 (8.8%), 131 (32.8%), and 103 (25.8%), respectively. The AUCs of ATX in men for hepatic encephalopathy, hepatic ascites, and varix ruptures were 0.853, 0.816, and 0.706, respectively. The AUCs of ATX in women for hepatic encephalopathy, hepatic ascites, and varix rupture were 0.759, 0.717, and 0.697, respectively. The AUCs of ATX in men were higher than those in women, as were all the other biomarkers used to detect encephalopathy and varix ruptures. However, for detecting ascites, the AUC of ALBI in men was more effective than using ATX.
CONCLUSION ATX in men was more effective than any other biomarkers for detecting hepatic encephalopathy and varix ruptures.
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Affiliation(s)
- Xue Shao
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0375, Japan
- Department of Hepatopancreatobiliary Medicine, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Haruki Uojima
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0375, Japan
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa 247-8533, Japan
| | - Toru Setsu
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Tomomi Okubo
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Chiba 270-1694, Japan
| | - Masanori Atsukawa
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Yoshihiro Furuichi
- Department of Gastroenterology and Hepatology, Tokyo Medical University Hospital, Shinjuku, Tokyo 113-8510, Japan
| | - Yoshitaka Arase
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa 259-1193, Japan
| | - Hisashi Hidaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0375, Japan
| | - Yoshiaki Tanaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0375, Japan
| | - Takahide Nakazawa
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0375, Japan
| | - Makoto Kako
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kamakura, Kanagawa 247-8533, Japan
| | - Tatehiro Kagawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa 259-1193, Japan
| | - Katsuhiko Iwakiri
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Wasaburo Koizumi
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0375, Japan
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28
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Peyruchaud O, Saier L, Leblanc R. Autotaxin Implication in Cancer Metastasis and Autoimunne Disorders: Functional Implication of Binding Autotaxin to the Cell Surface. Cancers (Basel) 2019; 12:cancers12010105. [PMID: 31906151 PMCID: PMC7016970 DOI: 10.3390/cancers12010105] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 12/19/2019] [Accepted: 12/29/2019] [Indexed: 12/18/2022] Open
Abstract
Autotaxin (ATX) is an exoenzyme which, due to its unique lysophospholipase D activity, is responsible for the synthesis of lysophosphatidic acid (LPA). ATX activity is responsible for the concentration of LPA in the blood. ATX expression is increased in various types of cancers, including breast cancer, where it promotes metastasis. The expression of ATX is also remarkably increased under inflammatory conditions, particularly in the osteoarticular compartment, where it controls bone erosion. Biological actions of ATX are mediated by LPA. However, the phosphate head group of LPA is highly sensitive to degradation by the action of lipid phosphate phosphatases, resulting in LPA inactivation. This suggests that for efficient action, LPA requires protection, which is potentially achieved through docking to a carrier protein. Interestingly, recent reports suggest that ATX might act as a docking molecule for LPA and also support the concept that binding of ATX to the cell surface through its interaction with adhesive molecules (integrins, heparan sulfate proteoglycans) could facilitate a rapid route of delivering active LPA to its cell surface receptors. This new mechanism offers a new vision of how ATX/LPA works in cancer metastasis and inflammatory bone diseases, paving the way for new therapeutic developments.
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Affiliation(s)
- Olivier Peyruchaud
- INSERM, Unit 1033, Université Claude Bernard Lyon 1, 69372 Lyon, France;
- Correspondence: ; Tel.: +3-34-78-77-86-72
| | - Lou Saier
- INSERM, Unit 1033, Université Claude Bernard Lyon 1, 69372 Lyon, France;
| | - Raphaël Leblanc
- Centre de Recherche en Cancérologie de Marseille, Institut Poli-Calmettes, INSERM, Unit 1068, University Aix/Marseille, 13009 Marseille, France;
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29
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Elevated Autotaxin and LPA Levels During Chronic Viral Hepatitis and Hepatocellular Carcinoma Associate with Systemic Immune Activation. Cancers (Basel) 2019; 11:cancers11121867. [PMID: 31769428 PMCID: PMC6966516 DOI: 10.3390/cancers11121867] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 11/20/2019] [Accepted: 11/21/2019] [Indexed: 12/16/2022] Open
Abstract
Circulating autotaxin (ATX) is elevated in persons with liver disease, particularly in the setting of chronic hepatitis C virus (HCV) and HCV/HIV infection. It is thought that plasma ATX levels are, in part, attributable to impaired liver clearance that is secondary to fibrotic liver disease. In a discovery data set, we identified plasma ATX to be associated with parameters of systemic immune activation during chronic HCV and HCV/HIV infection. We and others have observed a partial normalization of ATX levels within months of starting interferon-free direct-acting antiviral (DAA) HCV therapy, consistent with a non-fibrotic liver disease contribution to elevated ATX levels, or HCV-mediated hepatocyte activation. Relationships between ATX, lysophosphatidic acid (LPA) and parameters of systemic immune activation will be discussed in the context of HCV infection, age, immune health, liver health, and hepatocellular carcinoma (HCC).
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30
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Magkrioti C, Galaris A, Kanellopoulou P, Stylianaki EA, Kaffe E, Aidinis V. Autotaxin and chronic inflammatory diseases. J Autoimmun 2019; 104:102327. [PMID: 31471142 DOI: 10.1016/j.jaut.2019.102327] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Accepted: 08/17/2019] [Indexed: 12/18/2022]
Abstract
Autotaxin (ATX) is a secreted glycoprotein, widely present in biological fluids including blood. ATX catalyzes the hydrolysis of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a growth factor-like, signaling phospholipid. LPA exerts pleiotropic effects mediated by its G-protein-coupled receptors that are widely expressed and exhibit overlapping specificities. Although ATX also possesses matricellular properties, the majority of ATX reported functions in adulthood are thought to be mediated through the extracellular production of LPA. ATX-mediated LPA synthesis is likely localized at the cell surface through the possible interaction of ATX with integrins or other molecules, while LPA levels are further controlled by a group of membrane-associated lipid-phosphate phosphatases. ATX expression was shown to be necessary for embryonic development, and ATX deficient embryos exhibit defective vascular homeostasis and aberrant neuronal system development. In adult life, ATX is highly expressed in the adipose tissue and has been implicated in diet-induced obesity and glucose homeostasis with multiple implications in metabolic disorders. Additionally, LPA has been shown to affect multiple cell types, including stromal and immune cells in various ways. Therefore, LPA participates in many processes that are intricately involved in the pathogenesis of different chronic inflammatory diseases such as vascular homeostasis, skeletal and stromal remodeling, lymphocyte trafficking and immune regulation. Accordingly, increased ATX and LPA levels have been detected, locally and/or systemically, in patients with chronic inflammatory diseases, most notably idiopathic pulmonary fibrosis (IPF), chronic liver diseases, and rheumatoid arthritis. Genetic and pharmacological studies in mice have confirmed a pathogenetic role for ATX expression and LPA signaling in chronic inflammatory diseases, and provided the proof of principle for therapeutic interventions, as exemplified by the ongoing clinical trials for IPF.
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Affiliation(s)
| | - Apostolos Galaris
- Biomedical Sciences Research Center Alexander Fleming, 16672, Athens, Greece
| | | | | | - Eleanna Kaffe
- Biomedical Sciences Research Center Alexander Fleming, 16672, Athens, Greece
| | - Vassilis Aidinis
- Biomedical Sciences Research Center Alexander Fleming, 16672, Athens, Greece.
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31
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The involvement of autotaxin in renal interstitial fibrosis through regulation of fibroblast functions and induction of vascular leakage. Sci Rep 2019; 9:7414. [PMID: 31092842 PMCID: PMC6520387 DOI: 10.1038/s41598-019-43576-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 04/24/2019] [Indexed: 12/25/2022] Open
Abstract
The accumulation of fibroblasts is a critical step in the development of fibrosis, and lysophosphatidic acid (LPA) promotes fibrosis by regulating multiple fibroblast functions. Autotaxin (ATX) is a key LPA-producing enzyme, and we hypothesized that ATX contributes to the development of renal interstitial fibrosis through LPA-mediated effects on fibroblast functions. In a mouse model of renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO), the levels of renal ATX protein and activity increased with the progression of fibrosis in ligated kidneys, despite concurrent reductions in renal ATX mRNA. UUO enhanced vascular permeability in the renal interstitium, and ATX protein localized to areas of vascular leak, suggesting that vascular leak allowed ATX to enter the renal interstitium. In vitro studies showed that ATX induces the migration and proliferation of renal fibroblasts and enhances the vascular permeability of endothelial monolayers. Finally, pharmacological inhibition of ATX partially attenuated renal interstitial fibrosis. These results suggest that during the development of renal fibrosis, ATX accumulates in the renal interstitium and drives fibroblast accumulation and promotes renal interstitial vascular leak, thereby partially contributing to the pathogenesis of renal interstitial fibrosis. Taken together, ATX inhibition may have the potential to be a novel therapeutic strategy to combat renal interstitial fibrosis.
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32
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Yokomori H, Ando W, Kaneko F, Suzuki H, Igarashi K, Oda M. Autotaxin and vascular endothelial growth factor receptor-2 and -3 are related to vascular development during the progression of chronic viral hepatitis C. APMIS 2018; 126:913-921. [PMID: 30456868 DOI: 10.1111/apm.12904] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 10/15/2018] [Indexed: 11/28/2022]
Abstract
Vascular endothelial growth factor (VEGF) and autotaxin (ATX) play important roles in embryonic vasculogenesis and cancer progression. This study examines whether these two angiogenic factors cooperate in the mechanism that regulates vascular development during the progression of chronic viral hepatitis C (CVH-C) (Inuyama classification, F1-F4). First, surgical wedge biopsy specimens and needle biopsy specimens were obtained. Immunohistochemical staining for ATX and vascular endothelial growth factor receptor was assessed in serial sections. Immunoelectron microscopy was conducted with a perfusion-fixation method. In normal control liver tissue specimens, ATX was expressed at low levels within the branches of the hepatic artery and hepatic sinusoids. In F1 CVH-C liver tissue specimens, ATX was expressed within the branches of the hepatic artery. Additionally, VEGFR-2 was expressed within the branches of the hepatic artery and capillaries. In F3-F4 CVH-C liver tissue specimens, positive staining for ATX and VEGFR-2 or VEGFR-3 was detected in the branches of the hepatic artery or microlymphatic vessels. ATX-1 reaction products were specifically expressed on the plasma membrane of some microvascular endothelial cells (ECs) in the proliferative capillary artery. VEGFR-2 was expressed on caveolae in ECs and vascular smooth muscle cells. VEGFR-3 immunogold particles were also observed in lymphatic ECs. These results suggest functional interactions among ATX, VEGFR-2, and VEGFR-3 in the modulation of hemovascular and lymphovascular cell activation during vascular development.
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Affiliation(s)
- Hiroaki Yokomori
- Department of Internal Medicine, Kitasato University Medical Center, Saitama, Japan
| | - Wataru Ando
- Department of Clinical Pharmacy, School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Fumihiko Kaneko
- Department of Internal Medicine, Saitama Medical Center, Saitama, Japan
| | - Hidekazu Suzuki
- Medical Education Center, School of Medicine, Keio University, Tokyo, Japan
| | - Koji Igarashi
- Bioscience Division, Reagent Development Department, AIA Research Group Tosoh Corp., Kanagawa, Japan
| | - Masaya Oda
- Organized Center of Clinical Medicine, International University of Health and Welfare, Tokyo, Japan
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33
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Tintut Y, Hsu JJ, Demer LL. Lipoproteins in Cardiovascular Calcification: Potential Targets and Challenges. Front Cardiovasc Med 2018; 5:172. [PMID: 30533416 PMCID: PMC6265366 DOI: 10.3389/fcvm.2018.00172] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 11/08/2018] [Indexed: 12/16/2022] Open
Abstract
Previously considered a degenerative process, cardiovascular calcification is now established as an active process that is regulated in several ways by lipids, phospholipids, and lipoproteins. These compounds serve many of the same functions in vascular and valvular calcification as they do in skeletal bone calcification. Hyperlipidemia leads to accumulation of lipoproteins in the subendothelial space of cardiovascular tissues, which leads to formation of mildly oxidized phospholipids, which are known bioactive factors in vascular cell calcification. One lipoprotein of particular interest is Lp(a), which showed genome-wide significance for the presence of aortic valve calcification and stenosis. It carries an important enzyme, autotaxin, which produces lysophosphatidic acid (LPA), and thus has a key role in inflammation among other functions. Matrix vesicles, extruded from the plasma membrane of cells, are the sites of initiation of mineral formation. Phosphatidylserine, a phospholipid in the membranes of matrix vesicles, is believed to complex with calcium and phosphate ions, creating a nidus for hydroxyapatite crystal formation in cardiovascular as well as in skeletal bone mineralization. This review focuses on the contributions of lipids, phospholipids, lipoproteins, and autotaxin in cardiovascular calcification, and discusses possible therapeutic targets.
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Affiliation(s)
- Yin Tintut
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Physiology, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, CA, United States
| | - Jeffrey J Hsu
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Linda L Demer
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Physiology, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, United States
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34
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Ovadia C, Lövgren-Sandblom A, Edwards LA, Langedijk J, Geenes V, Chambers J, Cheng F, Clarke L, Begum S, Noori M, Pusey C, Padmagirison R, Agarwal S, Peerless J, Cheesman K, Heneghan M, Oude Elferink R, Patel VC, Marschall HU, Williamson C. Therapeutic plasma exchange as a novel treatment for severe intrahepatic cholestasis of pregnancy: Case series and mechanism of action. J Clin Apher 2018; 33:638-644. [PMID: 30321466 DOI: 10.1002/jca.21654] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 07/19/2018] [Accepted: 07/30/2018] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Intrahepatic cholestasis of pregnancy is characterised by pruritus and elevated serum bile acids. The pruritus can be severe, and pharmacological options achieve inconsistent symptomatic improvement. Raised bile acids are linearly associated with adverse fetal outcomes, with existing management of limited benefit. We hypothesised that therapeutic plasma exchange removes pruritogens and lowers total bile acid concentrations, and improves symptoms and biochemical abnormalities in severe cases that have not responded to other treatments. METHODS Four women with severe pruritus and hypercholanemia were managed with therapeutic plasma exchange. Serial blood biochemistry and visual analogue scores of itch severity were obtained. Blood and waste plasma samples were collected before and after exchange; individual bile acids and sulfated progesterone metabolites were measured with HPLC-MS, autotaxin activity and cytokine profiles with enzymatic methods. Results were analysed using segmental linear regression to describe longitudinal trends, and ratio t tests. RESULTS Total bile acids and visual analogue itch scores demonstrated trends to transiently improve following plasma exchange, with temporary symptomatic benefit reported. Individual bile acids (excluding the drug ursodeoxycholic acid), and the sulfated metabolites of progesterone reduced following exchange (P = .03 and P = .04, respectively), whilst analysis of waste plasma demonstrated removal of autotaxin and cytokines. CONCLUSIONS Therapeutic plasma exchange can lower potentially harmful bile acids and improve itch, likely secondary to the demonstrated removal of pruritogens. However, the limited current experience and potential complications, along with minimal sustained symptomatic benefit, restrict its current use to women with the most severe disease for whom other treatment options have been exhausted.
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Affiliation(s)
- Caroline Ovadia
- Department of Women and Children's Health, King's College London, London, United Kingdom
| | - Anita Lövgren-Sandblom
- Department of Clinical Chemistry, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Lindsey A Edwards
- Division of Transplantation, Immunology and Mucosal Biology, King's College London, London, United Kingdom
| | - Jacqueline Langedijk
- Academic Medical Center, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
| | - Victoria Geenes
- Department of Women and Children's Health, King's College London, London, United Kingdom
| | - Jenny Chambers
- Department of Women and Children's Health, King's College London, London, United Kingdom.,Women's Health Research Centre, Imperial College London, London, United Kingdom
| | - Floria Cheng
- Women's Health Research Centre, Imperial College London, London, United Kingdom
| | - Louise Clarke
- Department of Women and Children's Health, King's College London, London, United Kingdom
| | - Shahina Begum
- Department of Women and Children's Health, King's College London, London, United Kingdom
| | - Muna Noori
- Department of Obstetrics and Gynaecology, Imperial College Hospitals, London, United Kingdom
| | - Charles Pusey
- Department of Medicine, Imperial College London, London, United Kingdom
| | - Radhika Padmagirison
- Department of Obstetrics and Gynaecology, Lister Hospital, Stevenage, Hertfordshire, United Kingdom
| | - Sangita Agarwal
- Department of Rheumatology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - James Peerless
- Department of Anaesthetics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Kate Cheesman
- Department of Anaesthetics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Michael Heneghan
- Division of Transplantation, Immunology and Mucosal Biology, King's College London, London, United Kingdom
| | - Ronald Oude Elferink
- Academic Medical Center, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
| | - Vishal C Patel
- Division of Transplantation, Immunology and Mucosal Biology, King's College London, London, United Kingdom
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Catherine Williamson
- Department of Women and Children's Health, King's College London, London, United Kingdom
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35
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Yang F, Chen GX. Production of extracellular lysophosphatidic acid in the regulation of adipocyte functions and liver fibrosis. World J Gastroenterol 2018; 24:4132-4151. [PMID: 30271079 PMCID: PMC6158478 DOI: 10.3748/wjg.v24.i36.4132] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 04/24/2018] [Accepted: 05/05/2018] [Indexed: 02/06/2023] Open
Abstract
Lysophosphatidic acid (LPA), a glycerophospholipid, consists of a glycerol backbone connected to a phosphate head group and an acyl chain linked to sn-1 or sn-2 position. In the circulation, LPA is in sub-millimolar range and mainly derived from hydrolysis of lysophosphatidylcholine, a process mediated by lysophospholipase D activity in proteins such as autotaxin (ATX). Intracellular and extracellular LPAs act as bioactive lipid mediators with diverse functions in almost every mammalian cell type. The binding of LPA to its receptors LPA1-6 activates multiple cellular processes such as migration, proliferation and survival. The production of LPA and activation of LPA receptor signaling pathways in the events of physiology and pathophysiology have attracted the interest of researchers. Results from studies using transgenic and gene knockout animals with alterations of ATX and LPA receptors genes, have revealed the roles of LPA signaling pathways in metabolic active tissues and organs. The present review was aimed to summarize recent progresses in the studies of extracellular and intracellular LPA production pathways. This includes the functional, structural and biochemical properties of ATX and LPA receptors. The potential roles of LPA production and LPA receptor signaling pathways in obesity, insulin resistance and liver fibrosis are also discussed.
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Affiliation(s)
- Fang Yang
- School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan 430065, Hubei Province, China
| | - Guo-Xun Chen
- Department of Nutrition, University of Tennessee at Knoxville, Knoxville, TN 37996, United States
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36
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Leblanc R, Sahay D, Houssin A, Machuca-Gayet I, Peyruchaud O. Autotaxin-β interaction with the cell surface via syndecan-4 impacts on cancer cell proliferation and metastasis. Oncotarget 2018; 9:33170-33185. [PMID: 30237860 PMCID: PMC6145688 DOI: 10.18632/oncotarget.26039] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Accepted: 08/10/2018] [Indexed: 01/16/2023] Open
Abstract
Autotaxin (ATX) promotes cancer cell metastasis through the production of lysophosphatidic acid (LPA). ATX binds to αvβ3 integrins controlling metastasis of breast cancer cells. We screened a series of cancer cell lines derived from diverse human and mouse solid tumors for the capacity of binding to ATX and found only a modest correlation with their level of αvβ3 integrin expression. These results strongly suggested the existence of another cell surface ATX-interacting factor. Indeed, ATXα has been shown to bind heparan-sulfate chains because of its unique polybasic insertion sequence, although the biological significance is unknown. We demonstrated here, that among all cell surface heparan-sulfate proteoglycans, syndecan-4 (SDC4) was essential for cancer cell interaction with ATXβ but was restrained by heparan-sulfate chains. In addition, exogenous ATXβ-induced MG63 osteosarcoma cell proliferation required physical interaction of ATXβ with the cell surface via an SDC4-dependent mechanism. In a preclininal mouse model, targeting SDC4 on 4T1 mouse breast cancer cells inhibited early bone metastasis formation. Furthermore, SDC4-prometastatic activity was totally abolished in absence of ATX expression. In conclusion our results determined that ATX and SDC4 are engaged in a reciprocal collaboration for cancer cell metastasis providing the rational for the development of novel anti-metastasis therapies.
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Affiliation(s)
- Raphael Leblanc
- Centre de Recherche en Cancérologie de Marseille, Marseille, France.,Institut Poli-Calmettes, Marseille, France.,INSERM, Unit 1068, Marseille, France.,University Aix-Marseille, Marseille, France
| | - Debashish Sahay
- Department of Medicine, Colombia University Medical Center, New York City, NY, USA
| | - Audrey Houssin
- INSERM, Unit 1033, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | - Irma Machuca-Gayet
- INSERM, Unit 1033, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | - Olivier Peyruchaud
- INSERM, Unit 1033, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
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Ramesh S, Govindarajulu M, Suppiramaniam V, Moore T, Dhanasekaran M. Autotaxin⁻Lysophosphatidic Acid Signaling in Alzheimer's Disease. Int J Mol Sci 2018; 19:ijms19071827. [PMID: 29933579 PMCID: PMC6073975 DOI: 10.3390/ijms19071827] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 06/12/2018] [Accepted: 06/18/2018] [Indexed: 12/14/2022] Open
Abstract
The brain contains various forms of lipids that are important for maintaining its structural integrity and regulating various signaling cascades. Autotaxin (ATX) is an ecto-nucleotide pyrophosphatase/phosphodiesterase-2 enzyme that hydrolyzes extracellular lysophospholipids into the lipid mediator lysophosphatidic acid (LPA). LPA is a major bioactive lipid which acts through G protein-coupled receptors (GPCRs) and plays an important role in mediating cellular signaling processes. The majority of synthesized LPA is derived from membrane phospholipids through the action of the secreted enzyme ATX. Both ATX and LPA are highly expressed in the central nervous system. Dysfunctional expression and activity of ATX with associated changes in LPA signaling have recently been implicated in the pathogenesis of Alzheimer’s disease (AD). This review focuses on the current understanding of LPA signaling, with emphasis on the importance of the autotaxin–lysophosphatidic acid (ATX–LPA) pathway and its alterations in AD and a brief note on future therapeutic applications based on ATX–LPA signaling.
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Affiliation(s)
- Sindhu Ramesh
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
| | - Manoj Govindarajulu
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
| | - Vishnu Suppiramaniam
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
| | - Timothy Moore
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
| | - Muralikrishnan Dhanasekaran
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
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Lysophosphatidic acid receptor, LPA 6, regulates endothelial blood-brain barrier function: Implication for hepatic encephalopathy. Biochem Biophys Res Commun 2018; 501:1048-1054. [PMID: 29778535 DOI: 10.1016/j.bbrc.2018.05.106] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 05/15/2018] [Indexed: 11/22/2022]
Abstract
Cerebral edema is a life-threatening neurological condition characterized by brain swelling due to the accumulation of excess fluid both intracellularly and extracellularly. Fulminant hepatic failure (FHF) develops cerebral edema by disrupting blood-brain barrier (BBB). However, the mechanisms by which mediator induces brain edema in FHF remain to be elucidated. Here, we assessed a linkage between brain edema and lysophosphatidic acid (LPA) signaling by utilizing an animal model of FHF and in vitro BBB model. Azoxymethane-treated mice developed FHF and hepatic encephalopathy, associated with higher autotaxin (ATX) activities in serum than controls. Using in vitro BBB model, LPA disrupted the structural integrity of tight junction proteins including claudin-5, occludin, and ZO-1. Furthermore, LPA decreased transendothelial electrical resistances in in vitro BBB model, and induced cell contraction in brain endothelial monolayer cultures, both being inhibited by a Rho-associated protein kinase inhibitor, Y-27632. The brain capillary endothelial cells predominantly expressed LPA6 mRNA, whose knockdown blocked the LPA-induced endothelial cell contraction. Taken together, the up-regulation of serum ATX in hepatic encephalopathy may activate the LPA-LPA6-G12/13-Rho pathway in brain capillary endothelial cells, leading to enhancement of BBB permeability and brain edema.
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Yamazaki T, Joshita S, Umemura T, Usami Y, Sugiura A, Fujimori N, Kimura T, Matsumoto A, Igarashi K, Ota M, Tanaka E. Changes in serum levels of autotaxin with direct-acting antiviral therapy in patients with chronic hepatitis C. PLoS One 2018; 13:e0195632. [PMID: 29617443 PMCID: PMC5884565 DOI: 10.1371/journal.pone.0195632] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 03/25/2018] [Indexed: 12/25/2022] Open
Abstract
Sustained virological response (SVR) rates have increased remarkably since the introduction of direct-acting antiviral agents (DAAs) for chronic hepatitis C. Autotaxin (ATX) is a secreted enzyme converting lysophosphatidylcholine to lysophosphatidic acid and a newly established biomarker for liver fibrosis. Interferon-free DAA regimens for chronic hepatitis C could improve liver stiffness in SVR patients according to several non-invasive evaluation methods, but the clinical response and significance of ATX in this context have not yet been defined. We therefore investigated sequential serum ATX levels at baseline, 4 weeks after the start of treatment, and 24 weeks after treatment in 159 hepatitis C virus (HCV)-infected patients who received DAA therapy. Other non-invasive fibrosis markers (aspartate aminotransferase-to-platelet ratio and FIB-4 index) were examined as well. Baseline median ATX levels were comparable between the 144 patients who achieved a SVR and the 15 who did not (1.54 vs. 1.62 mg/L), but median ATX levels became significantly decreased during and after DAA therapy in the SVR group only (from 1.54 to 1.40 and 1.31 mg/L, respectively; P < 0.001). ATX was significantly decreased between baseline and 4 weeks of treatment in overall, male, and female SVR patients (all P < 0.001). In subjects with low necroinflammatory activity in the liver (i.e., alanine aminotransferase < 30 U/L), ATX levels were significantly reduced from baseline to 4 weeks of treatment and remained low (P < 0.001) in patients with a SVR. Thus, interferon-free DAA therapy was associated with a significant decrease in serum ATX levels in patients achieving a SVR, suggesting early regression of liver fibrosis in addition to inflammation treatment.
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Affiliation(s)
- Tomoo Yamazaki
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
- Research Center for Next Generation Medicine, Shinshu University, Matsumoto, Japan
| | - Takeji Umemura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
- Research Center for Next Generation Medicine, Shinshu University, Matsumoto, Japan
- * E-mail:
| | - Yoko Usami
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Ayumi Sugiura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Naoyuki Fujimori
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takefumi Kimura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akihiro Matsumoto
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Koji Igarashi
- Bioscience Division, TOSOH Corporation, Ayase, Japan
| | - Masao Ota
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Eiji Tanaka
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
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Fujimori N, Umemura T, Kimura T, Tanaka N, Sugiura A, Yamazaki T, Joshita S, Komatsu M, Usami Y, Sano K, Igarashi K, Matsumoto A, Tanaka E. Serum autotaxin levels are correlated with hepatic fibrosis and ballooning in patients with non-alcoholic fatty liver disease. World J Gastroenterol 2018; 24:1239-1249. [PMID: 29568204 PMCID: PMC5859226 DOI: 10.3748/wjg.v24.i11.1239] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 02/10/2018] [Accepted: 03/03/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To examine the relationship between serum autotaxin (ATX) concentrations and clinicopathological findings in non-alcoholic fatty liver disease (NAFLD) patients.
METHODS One hundred eighty-six NAFLD patients who had undergone liver biopsy between 2008 and 2017 were retrospectively enrolled. Serum samples were collected at the time of biopsy and ATX was measured by enzyme immunoassays. Sera obtained from 160 healthy, non-obese individuals were used as controls. Histological findings were graded according to an NAFLD scoring system and correlations with serum ATX were calculated by Spearman’s test. Diagnostic accuracy was evaluated using the area under the receiver operating characteristic curve (AUC). Cut-off values were identified by the Youden index, and the nearest clinically applicable value to the cutoff was considered the optimal threshold for clinical convenience.
RESULTS Serum ATX levels were significantly higher in NAFLD patients than in controls (0.86 mg/L vs 0.76 mg/L, P < 0.001) and correlated significantly with ballooning score and fibrosis stage (r = 0.36, P < 0.001 and r = 0.45, P < 0.001, respectively). Such tendencies were stronger in female patients. There were no remarkable relationships between ATX and serum alanine aminotransferase, lipid profiles, or steatosis scores. The AUC values of ATX for predicting the presence of fibrosis (≥ F1), significant fibrosis (≥ F2), severe fibrosis (≥ F3), and cirrhosis (F4), were all more than 0.70 in respective analyses.
CONCLUSION Serum ATX levels may at least partially reflect histological severity in NAFLD.
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Affiliation(s)
- Naoyuki Fujimori
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Takeji Umemura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Takefumi Kimura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan, and Research Center for Agricultural Food Industry, Shinshu University, Matsumoto, 390-8621, Japan
| | - Ayumi Sugiura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Tomoo Yamazaki
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Satoru Joshita
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Michiharu Komatsu
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Yoko Usami
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto 390-8621, Japan
| | - Kenji Sano
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto 390-8621, Japan
| | - Koji Igarashi
- Bioscience Division, TOSOH Corporation, Kanagawa 252-1123, Japan
| | - Akihiro Matsumoto
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Eiji Tanaka
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
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41
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Benesch MGK, MacIntyre ITK, McMullen TPW, Brindley DN. Coming of Age for Autotaxin and Lysophosphatidate Signaling: Clinical Applications for Preventing, Detecting and Targeting Tumor-Promoting Inflammation. Cancers (Basel) 2018; 10:cancers10030073. [PMID: 29543710 PMCID: PMC5876648 DOI: 10.3390/cancers10030073] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 03/10/2018] [Accepted: 03/12/2018] [Indexed: 12/13/2022] Open
Abstract
A quarter-century after the discovery of autotaxin in cell culture, the autotaxin-lysophosphatidate (LPA)-lipid phosphate phosphatase axis is now a promising clinical target for treating chronic inflammatory conditions, mitigating fibrosis progression, and improving the efficacy of existing cancer chemotherapies and radiotherapy. Nearly half of the literature on this axis has been published during the last five years. In cancer biology, LPA signaling is increasingly being recognized as a central mediator of the progression of chronic inflammation in the establishment of a tumor microenvironment which promotes cancer growth, immune evasion, metastasis, and treatment resistance. In this review, we will summarize recent advances made in understanding LPA signaling with respect to chronic inflammation and cancer. We will also provide perspectives on the applications of inhibitors of LPA signaling in preventing cancer initiation, as adjuncts extending the efficacy of current cancer treatments by blocking inflammation caused by either the cancer or the cancer therapy itself, and by disruption of the tumor microenvironment. Overall, LPA, a simple molecule that mediates a plethora of biological effects, can be targeted at its levels of production by autotaxin, LPA receptors or through LPA degradation by lipid phosphate phosphatases. Drugs for these applications will soon be entering clinical practice.
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Affiliation(s)
- Matthew G K Benesch
- Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL AlB 3V6, Canada.
- Signal Transduction Research Group, Cancer Research Institute of Northern Alberta, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2S2, Canada.
| | - Iain T K MacIntyre
- Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL AlB 3V6, Canada.
| | - Todd P W McMullen
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2G7, Canada.
| | - David N Brindley
- Signal Transduction Research Group, Cancer Research Institute of Northern Alberta, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2S2, Canada.
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YATOMI Y, KURANO M, IKEDA H, IGARASHI K, KANO K, AOKI J. Lysophospholipids in laboratory medicine. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2018; 94:373-389. [PMID: 30541965 PMCID: PMC6374142 DOI: 10.2183/pjab.94.025] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Lysophospholipids (LPLs), such as lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), and lysophosphatidylserine (LysoPS), are attracting attention as second-generation lipid mediators. In our laboratory, the functional roles of these lipid mediators and the mechanisms by which the levels of these mediators are regulated in vivo have been studied. Based on these studies, the clinical introduction of assays for LPLs and related proteins has been pursued and will be described in this review. Although assays of these lipids themselves are possible, autotaxin (ATX), apolipoprotein M (ApoM), and phosphatidylserine-specific phospholipase A1 (PS-PLA1) are more promising as alternate biomarkers for LPA, S1P, and LysoPS, respectively. Presently, ATX, which produces LPA through its lysophospholipase D activity, has been shown to be a useful laboratory test for the diagnosis and staging of liver fibrosis, whereas PS-PLA1 and ApoM are considered to be promising clinical markers reflecting the in vivo actions induced by LysoPS and S1P.
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Affiliation(s)
- Yutaka YATOMI
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Correspondence should be addressed: Y. Yatomi, Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan (e-mail: )
| | - Makoto KURANO
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hitoshi IKEDA
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Koji IGARASHI
- Bioscience Division, TOSOH Corporation, Kanagawa, Japan
| | - Kuniyuki KANO
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan
| | - Junken AOKI
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan
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Ikeda H, Kobayashi M, Kumada H, Enooku K, Koike K, Kurano M, Sato M, Nojiri T, Kobayashi T, Ohkawa R, Shimamoto S, Igarashi K, Aoki J, Yatomi Y. Performance of autotaxin as a serum marker for liver fibrosis. Ann Clin Biochem 2017; 55:469-477. [PMID: 29065699 DOI: 10.1177/0004563217741509] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Background Because autotaxin reportedly has a better performance than hyaluronic acid as a marker for liver fibrosis for the prediction of cirrhosis caused by hepatitis C, we aimed to further evaluate the role of autotaxin in liver fibrosis of other aetiologies. Methods Autotaxin antigen was measured in serum samples from 108 patients with chronic hepatitis B and 128 patients with non-alcoholic fatty liver disease who had undergone a liver biopsy as well as healthy subjects and patients with chronic kidney disease, diabetes mellitus, rheumatoid arthritis and cardiac dysfunction. Results When evaluated using receiver operator characteristics curves, the performance of autotaxin for the prediction of significant fibrosis (F2-F4) in chronic hepatitis B patients was better than that of hyaluronic acid or type IV collagen 7S. In non-alcoholic fatty liver disease patients, however, the performance of autotaxin for the prediction of significant fibrosis was poorer than that of hyaluronic acid or type IV collagen 7S. The increase in the serum autotaxin concentrations was less notable than that of hyaluronic acid or type IV collagen in patients with chronic kidney disease, diabetes mellitus, rheumatoid arthritis or cardiac dysfunction. Food intake did not affect the serum autotaxin concentrations. Conclusions Autotaxin is useful as a serum marker for liver fibrosis caused by not only chronic viral hepatitis C but also by hepatitis B, although it was less useful in patients with non-alcoholic fatty liver disease. The increase in serum autotaxin concentrations is fairly specific for liver fibrosis, and the serum autotaxin concentrations can be analysed without consideration of food intake before blood collection.
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Affiliation(s)
- Hitoshi Ikeda
- 1 Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mariko Kobayashi
- 2 Department of Hepatology, Toranomon Hospital, Minato-ku, Tokyo, Japan
| | - Hiromitsu Kumada
- 2 Department of Hepatology, Toranomon Hospital, Minato-ku, Tokyo, Japan
| | - Kenichiro Enooku
- 3 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Kazuhiko Koike
- 3 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Makoto Kurano
- 1 Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masaya Sato
- 1 Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,3 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Takahiro Nojiri
- 4 Department of Clinical Laboratory, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan
| | - Tamaki Kobayashi
- 4 Department of Clinical Laboratory, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan
| | - Ryunosuke Ohkawa
- 5 Analytical Laboratory Chemistry, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Satoshi Shimamoto
- 6 Bioscience Division, Reagent Development Department, AIA Research Group, TOSOH Corporation, Ayase, Kanagawa, Japan
| | - Koji Igarashi
- 6 Bioscience Division, Reagent Development Department, AIA Research Group, TOSOH Corporation, Ayase, Kanagawa, Japan
| | - Junken Aoki
- 7 Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan
| | - Yutaka Yatomi
- 1 Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Farquhar MJ, Humphreys IS, Rudge SA, Wilson GK, Bhattacharya B, Ciaccia M, Hu K, Zhang Q, Mailly L, Reynolds GM, Ashcroft M, Balfe P, Baumert TF, Roessler S, Wakelam MJO, McKeating JA. Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication. J Hepatol 2017; 66:919-929. [PMID: 28126468 DOI: 10.1016/j.jhep.2017.01.009] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 12/09/2016] [Accepted: 01/08/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Chronic hepatitis C is a global health problem with an estimated 170 million hepatitis C virus (HCV) infected individuals at risk of progressive liver disease and hepatocellular carcinoma (HCC). Autotaxin (ATX, gene name: ENPP2) is a phospholipase with diverse roles in the physiological and pathological processes including inflammation and oncogenesis. Clinical studies have reported increased ATX expression in chronic hepatitis C, however, the pathways regulating ATX and its role in the viral life cycle are not well understood. METHODS In vitro hepatocyte and ex vivo liver culture systems along with chimeric humanized liver mice and HCC tissue enabled us to assess the interplay between ATX and the HCV life cycle. RESULTS HCV infection increased hepatocellular ATX RNA and protein expression. HCV infection stabilizes hypoxia inducible factors (HIFs) and we investigated a role for these transcription factors to regulate ATX. In vitro studies show that low oxygen increases hepatocellular ATX expression and transcriptome analysis showed a positive correlation between ATX mRNA levels and hypoxia gene score in HCC tumour tissue associated with HCV and other aetiologies. Importantly, inhibiting ATX-lysophosphatidic acid (LPA) signalling reduced HCV replication, demonstrating a positive role for this phospholipase in the viral life cycle. LPA activates phosphoinositide-3-kinase that stabilizes HIF-1α and inhibiting the HIF signalling pathway abrogates the pro-viral activity of LPA. CONCLUSIONS Our data support a model where HCV infection increases ATX expression which supports viral replication and HCC progression. LAY SUMMARY Chronic hepatitis C is a global health problem with infected individuals at risk of developing liver disease that can progress to hepatocellular carcinoma. Autotaxin generates the biologically active lipid lysophosphatidic acid that has been reported to play a tumorigenic role in a wide number of cancers. In this study we show that hepatitis C virus infection increases autotaxin expression via hypoxia inducible transcription factor and provides an environment in the liver that promotes fibrosis and liver injury. Importantly, we show a new role for lysophosphatidic acid in positively regulating hepatitis C virus replication.
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Affiliation(s)
- Michelle J Farquhar
- Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK
| | - Isla S Humphreys
- Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK
| | | | - Garrick K Wilson
- Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK
| | | | | | - Ke Hu
- Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK
| | | | - Laurent Mailly
- INSERM U1110, University of Strasbourg, 3 Rue Koeberlé, F-67000 Strasbourg, France
| | - Gary M Reynolds
- NIHR Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK
| | | | - Peter Balfe
- Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK
| | - Thomas F Baumert
- INSERM U1110, University of Strasbourg, 3 Rue Koeberlé, F-67000 Strasbourg, France
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Jane A McKeating
- Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK.
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Association of Serum Autotaxin Levels with Liver Fibrosis in Patients with Chronic Hepatitis C. Sci Rep 2017; 7:46705. [PMID: 28425454 PMCID: PMC5397977 DOI: 10.1038/srep46705] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 03/24/2017] [Indexed: 12/31/2022] Open
Abstract
Metabolized by liver sinusoidal endothelial cells, autotaxin (ATX) is a secreted enzyme considered to be associated with liver damage. We sought to clarify the diagnostic ability of ATX for liver fibrosis in 593 biopsy-confirmed hepatitis C virus (HCV)-infected patients. The diagnostic accuracy of ATX was compared with clinical parameters and the established fibrosis biomarkers Wisteria floribunda agglutinin-positive Mac-2-binding protein, FIB-4 index, AST-to-platelet ratio, and Forn’s index. Median ATX levels were consistently higher in female controls and patients than in their male counterparts (P < 0.01). Serum ATX concentration increased significantly according to liver fibrosis stage in overall and both genders (P < 0.001). The cutoff values of ATX for prediction of fibrosis stages ≥F1, ≥F2, ≥F3, and F4 were 0.8, 1.1, 1.3, and 1.7 mg/L, respectively, in male patients and 0.9, 1.7, 1.8, and 2.0 mg/L, respectively, in female patients. The area under the receiver operating characteristic curve for ATX to diagnose fibrosis of ≥F2 (0.861) in male patients was superior to those of FIB-4 index and Forn’s index (P < 0.001), while that in female patients (0.801) was comparable with those of the other markers. ATX therefore represents a novel non-invasive biomarker for liver fibrosis in HCV-infected patients.
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Association between Promoter Hypomethylation and Overexpression of Autotaxin with Outcome Parameters in Biliary Atresia. PLoS One 2017; 12:e0169306. [PMID: 28052132 PMCID: PMC5214988 DOI: 10.1371/journal.pone.0169306] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 12/14/2016] [Indexed: 01/26/2023] Open
Abstract
Objective Biliary atresia (BA) is a progressive fibroinflammatory liver disease. Autotaxin (ATX) has a profibrotic effect resulting from lysophosphatidic acid activity. The purpose of this study was to examine ATX expression and ATX promoter methylation in peripheral blood leukocytes and liver tissues from BA patients and controls and investigate their associations with outcome parameters in BA patients. Methods A total of 130 subjects (65 BA patients and 65 age-matched controls) were enrolled. DNA was extracted from circulating leukocytes and liver tissues of BA patients and from and age-matched controls. ATX promoter methylation status was determined by bisulfite pyrosequencing. ATX expression was analyzed using quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Results Decreased methylation of specific CpGs were observed at the ATX promoter in BA patients. Subsequent analysis revealed that BA patients with advanced stage had lower methylation levels of ATX promoter than those with early stage. ATX promoter methylation levels were found to be associated with hepatic dysfunction in BA. In addition, ATX expression was significantly elevated and correlated with a decrease in ATX promoter methylation in BA patients compared to the controls. Furthermore, promoter hypomethylation and overexpression of ATX were inversely associated with jaundice status, hepatic dysfunction, and liver stiffness in BA patients. Conclusion Accordingly, it has been hypothesized that ATX promoter methylation and ATX expression in peripheral blood may serve as possible biomarkers reflecting the progression of liver fibrosis in postoperative BA. These findings suggest that the promoter hypomethylation and overexpression of ATX might play a contributory role in the pathogenesis of liver fibrosis in BA.
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Bain G, Shannon KE, Huang F, Darlington J, Goulet L, Prodanovich P, Ma GL, Santini AM, Stein AJ, Lonergan D, King CD, Calderon I, Lai A, Hutchinson JH, Evans JF. Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis. J Pharmacol Exp Ther 2017; 360:1-13. [PMID: 27754931 DOI: 10.1124/jpet.116.237156] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 10/14/2016] [Indexed: 03/08/2025] Open
Abstract
Autotaxin (ATX) is a secreted glycoprotein that converts lysophosphatidylcholine (LPC) to the bioactive phospholipid lysophosphatidic acid (LPA) and is the major enzyme generating circulating LPA. Inhibition of LPA signaling has profound antifibrotic effects in multiple organ systems, including lung, kidney, skin, and peritoneum. However, other LPA-generating pathways exist, and the role of ATX in localized tissue LPA production and fibrosis remains unclear and controversial. In this study, we describe the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel small-molecule ATX inhibitor, PAT-505 [3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl) thio)-2-fluorobenzoic acid sodium salt]. PAT-505 is a potent, selective, noncompetitive inhibitor that displays significant inhibition of ATX activity in plasma and liver tissue after oral administration. When dosed therapeutically in a Stelic Mouse Animal Model of nonalcoholic steatohepatitis (NASH), PAT-505 treatment resulted in a small but significant improvement in fibrosis with only minor improvements in hepatocellular ballooning and hepatic inflammation. In a choline-deficient, high-fat diet model of NASH, therapeutic treatment with PAT-505 robustly reduced liver fibrosis with no significant effect on steatosis, hepatocellular ballooning, or inflammation. These data demonstrate that inhibiting autotaxin is antifibrotic and may represent a novel therapeutic approach for the treatment of multiple fibrotic liver diseases, including NASH.
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Affiliation(s)
- Gretchen Bain
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Kristen E Shannon
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Fei Huang
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Janice Darlington
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Lance Goulet
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Patricia Prodanovich
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Gina L Ma
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Angelina M Santini
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Adam J Stein
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Dave Lonergan
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Christopher D King
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Imelda Calderon
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Andiliy Lai
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - John H Hutchinson
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
| | - Jilly F Evans
- PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.)
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Wunsch E, Krawczyk M, Milkiewicz M, Trottier J, Barbier O, Neurath MF, Lammert F, Kremer AE, Milkiewicz P. Serum Autotaxin is a Marker of the Severity of Liver Injury and Overall Survival in Patients with Cholestatic Liver Diseases. Sci Rep 2016; 6:30847. [PMID: 27506882 PMCID: PMC4978954 DOI: 10.1038/srep30847] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 07/08/2016] [Indexed: 02/07/2023] Open
Abstract
Autotaxin (ATX) is involved in the synthesis of lysophosphatidic acid. Both have recently been linked to cholestatic pruritus and liver injury. We aimed to investigate whether ATX is an indicator of cholestatic liver injury, health-related quality of life (HRQoL) and prognosis based on a group of 233 patients, 118 with primary biliary cholangitis (PBC) and 115 with primary sclerosing cholangitis (PSC). Patients were followed for 1–60 months, cumulative survival rates were calculated. ATX activity was significantly higher in both groups than in the 103 controls, particularly in patients with cirrhosis and in patients with longer disease duration. Ursodeoxycholic acid (UDCA) non-responders with PBC exhibited increased ATX activity. ATX activity was correlated with liver biochemistry, MELD, Mayo Risk scores and was associated with worse disease-specific HRQoL aspects. In both groups, Cox model analysis indicated that ATX was a negative predictor of survival. Increased ATX levels were associated with a 4-fold higher risk of death/liver transplantation in patients with PBC and a 2.6-fold higher risk in patients with PSC. We conclude that in patients with cholestatic conditions, ATX is not only associated with pruritus but also indicates impairment of other HRQoL aspects, liver dysfunction, and can serve as a predictor of survival.
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Affiliation(s)
- Ewa Wunsch
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, 66421 Homburg, Germany.,Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Malgorzata Milkiewicz
- Department of Medical Biology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland
| | - Jocelyn Trottier
- Laboratory of Molecular Pharmacology, CHU-de-Québec &Faculty of Pharmacy, Laval University, 2705 Québec, QC, Canada
| | - Olivier Barbier
- Laboratory of Molecular Pharmacology, CHU-de-Québec &Faculty of Pharmacy, Laval University, 2705 Québec, QC, Canada
| | - Markus F Neurath
- Department of Medicine I, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, 66421 Homburg, Germany
| | - Andreas E Kremer
- Department of Medicine I, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Piotr Milkiewicz
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland.,Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery of the Medical University of Warsaw, 02-097 Warsaw, Poland
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Clark AM, Ma B, Taylor DL, Griffith L, Wells A. Liver metastases: Microenvironments and ex-vivo models. Exp Biol Med (Maywood) 2016; 241:1639-52. [PMID: 27390264 DOI: 10.1177/1535370216658144] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The liver is a highly metastasis-permissive organ, tumor seeding of which usually portends mortality. Its unique and diverse architectural and cellular composition enable the liver to undertake numerous specialized functions, however, this distinctive biology, notably its hemodynamic features and unique microenvironment, renders the liver intrinsically hospitable to disseminated tumor cells. The particular focus for this perspective is the bidirectional interactions between the disseminated tumor cells and the unique resident cell populations of the liver; notably, parenchymal hepatocytes and non-parenchymal liver sinusoidal endothelial, Kupffer, and hepatic stellate cells. Understanding the early steps in the metastatic seeding, including the decision to undergo dormancy versus outgrowth, has been difficult to study in 2D culture systems and animals due to numerous limitations. In response, tissue-engineered biomimetic systems have emerged. At the cutting-edge of these developments are ex vivo 'microphysiological systems' (MPS) which are cellular constructs designed to faithfully recapitulate the structure and function of a human organ or organ regions on a milli- to micro-scale level and can be made all human to maintain species-specific interactions. Hepatic MPSs are particularly attractive for studying metastases as in addition to the liver being a main site of metastatic seeding, it is also the principal site of drug metabolism and therapy-limiting toxicities. Thus, using these hepatic MPSs will enable not only an enhanced understanding of the fundamental aspects of metastasis but also allow for therapeutic agents to be fully studied for efficacy while also monitoring pharmacologic aspects and predicting toxicities. The review discusses some of the hepatic MPS models currently available and although only one MPS has been validated to relevantly modeling metastasis, it is anticipated that the adaptation of the other hepatic models to include tumors will not be long in coming.
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Affiliation(s)
- Amanda M Clark
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Bo Ma
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - D Lansing Taylor
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA University of Pittsburgh Cancer Institute, University of Pittsburgh, PA 15213, USA
| | - Linda Griffith
- Department of Biological Engineering, MIT, Cambridge, MA 02139, USA
| | - Alan Wells
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA Pittsburgh VA Medical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA
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Bolier R, Tolenaars D, Kremer AE, Saris J, Parés A, Verheij J, Bosma PJ, Beuers U, Oude Elferink RP. Enteroendocrine cells are a potential source of serum autotaxin in men. Biochim Biophys Acta Mol Basis Dis 2016; 1862:696-704. [DOI: 10.1016/j.bbadis.2016.01.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 12/22/2015] [Accepted: 01/12/2016] [Indexed: 12/26/2022]
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