|
1
|
Wang C, Tang L, Luo H, Liang J, Huang Y, Guo K, Liu R, He Y, Gao Y, Lei M. Abnormally high expression of CHI3L1 in peripheral blood mononuclear cells and serum and their potential diagnosis and prediction from lymphoma patients. Front Immunol 2025; 16:1557802. [PMID: 40260255 PMCID: PMC12009859 DOI: 10.3389/fimmu.2025.1557802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 03/17/2025] [Indexed: 04/23/2025] Open
Abstract
Aim This study aimed to investigate the expression of CHI3L1 in aggressive lymphomas and assess its potential as a diagnostic and prognostic biomarker. Methodology This study investigates the expression of CHI3L1 protein in the peripheral blood of patients with aggressive lymphoma and healthy controls using enzyme-linked immunosorbent assay (ELISA). The prognostic significance of CHI3L1 was assessed through Cox regression and Kaplan-Meier survival analyses. The differences in CHI3L1 expression between lymphoma and control samples were analyzed using the lymphoma-related gene expression datasets GSE25638 and GSE56315, as well as their combined dataset (GSE25638 and GSE56315). Subsequently, a prognostic analysis of CHI3L1 was conducted using the lymphoma tissue sample gene expression dataset GSE31312. Weighted gene co-expression network analysis (WGCNA) identified genes co-expressed with CHI3L1, and a protein-protein interaction (PPI) network was constructed. RT-qPCR was used to further validate CHI3L1 expression in peripheral blood mononuclear cells (PBMCs) from lymphoma patients. Results The serum CHI3L1 protein expression in patients with aggressive lymphoma was significantly higher than that in healthy controls (p<0.001). Moreover, CHI3L1 levels were significantly elevated in stage III~IV patients compared to stage I~II patients (P = 0.001). One-way Cox regression and Kaplan-Meier analyses further demonstrated that high CHI3L1 expression was closely associated with shorter overall survival (p<0.001). Bioinformatics analysis revealed that CHI3L1 expression was significantly elevated in lymphoma samples compared to normal controls (p < 0.05), with diagnostic AUC values of 0.92, 0.99, and 0.93, indicating high diagnostic accuracy. Furthermore, patients with high CHI3L1 expression exhibited significantly shorter overall survival (p < 0.05), suggesting a potential association with poor prognosis. Co-expression analysis identified 605 genes associated with key biological processes, including the inflammatory response, signal transduction, and apoptosis. These genes were enriched in functional pathways such as mineral uptake and the Toll-like receptor signaling pathway. Validation experiments confirmed that CHI3L1 gene expression in PBMCs of patients with aggressive lymphoma was significantly higher than that in healthy individuals (p<0.01). Conclusion This study demonstrates that elevated CHI3L1 expression is strongly associated with lymphoma onset, progression, severity, and poor prognosis, underscoring its potential as both a diagnostic and prognostic biomarker. Moreover, CHI3L1 may contribute to lymphoma progression by regulating key biological processes.
Collapse
Affiliation(s)
- Chao Wang
- Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
| | - Langui Tang
- Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
| | - Haibing Luo
- Department of Clinical Laboratory, The Fourth People’s Hospital of Changde, Changde, China
| | - Juan Liang
- Hengyang Medical College, University of South China, Hengyang, China
| | - Yanzhao Huang
- Hengyang Medical College, University of South China, Hengyang, China
| | - Kaiyun Guo
- Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
| | - Rong Liu
- Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
| | - Yuxing He
- Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
| | - Yan Gao
- Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
| | - Ming Lei
- Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
| |
Collapse
|
|
2
|
Liu D, Hu X, Ding X, Li M, Ding L. Inflammatory Effects and Regulatory Mechanisms of Chitinase-3-like-1 in Multiple Human Body Systems: A Comprehensive Review. Int J Mol Sci 2024; 25:13437. [PMID: 39769202 PMCID: PMC11678640 DOI: 10.3390/ijms252413437] [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: 10/13/2024] [Revised: 11/29/2024] [Accepted: 12/13/2024] [Indexed: 01/03/2025] Open
Abstract
Chitinase-3-like-1 (Chi3l1), also known as YKL-40 or BRP-39, is a highly conserved mammalian chitinase with a chitin-binding ability but no chitinase enzymatic activity. Chi3l1 is secreted by various cell types and induced by several inflammatory cytokines. It can mediate a series of cell biological processes, such as proliferation, apoptosis, migration, differentiation, and polarization. Accumulating evidence has verified that Chi3l1 is involved in diverse inflammatory conditions; however, a systematic and comprehensive understanding of the roles and mechanisms of Chi3l1 in almost all human body system-related inflammatory diseases is still lacking. The human body consists of ten organ systems, which are combinations of multiple organs that perform one or more physiological functions. Abnormalities in these human systems can trigger a series of inflammatory environments, posing serious threats to the quality of life and lifespan of humans. Therefore, exploring novel and reliable biomarkers for these diseases is highly important, with Chi3l1 being one such parameter because of its physiological and pathophysiological roles in the development of multiple inflammatory diseases. Reportedly, Chi3l1 plays an important role in diagnosing and determining disease activity/severity/prognosis related to multiple human body system inflammation disorders. Additionally, many studies have revealed the influencing factors and regulatory mechanisms (e.g., the ERK and MAPK pathways) of Chi3l1 in these inflammatory conditions, identifying potential novel therapeutic targets for these diseases. In this review, we comprehensively summarize the potential roles and underlying mechanisms of Chi3l1 in inflammatory disorders of the respiratory, digestive, circulatory, nervous, urinary, endocrine, skeletal, muscular, and reproductive systems, which provides a more systematic understanding of Chi3l1 in multiple human body system-related inflammatory diseases. Moreover, this article summarizes potential therapeutic strategies for inflammatory diseases in these systems on the basis of the revealed roles and mechanisms mediated by Chi3l1.
Collapse
Affiliation(s)
- Dong Liu
- School of Life Sciences, Yunnan University, Kunming 650500, China;
| | - Xin Hu
- Yunnan Key Laboratory of Soil Erosion Prevention and Green Development, Institute of International Rivers and Ecosecurity, Yunnan University, Kunming 650500, China;
| | - Xiao Ding
- Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China;
| | - Ming Li
- School of Life Sciences, Yunnan University, Kunming 650500, China;
| | - Lei Ding
- School of Life Sciences, Yunnan University, Kunming 650500, China;
| |
Collapse
|
|
3
|
Mesaros O, Onciul M, Matei E, Joldes C, Jimbu L, Neaga A, Serban O, Zdrenghea M, Nanut AM. Macrophages as Potential Therapeutic Targets in Acute Myeloid Leukemia. Biomedicines 2024; 12:2306. [PMID: 39457618 PMCID: PMC11505058 DOI: 10.3390/biomedicines12102306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 09/15/2024] [Accepted: 09/20/2024] [Indexed: 10/28/2024] Open
Abstract
Acute myeloid leukemia (AML) is a heterogenous malignant hemopathy, and although new drugs have emerged recently, current treatment options still show limited efficacy. Therapy resistance remains a major concern due to its contribution to treatment failure, disease relapse, and increased mortality among patients. The underlying mechanisms of resistance to therapy are not fully understood, and it is crucial to address this challenge to improve therapy. Macrophages are immune cells found within the bone marrow microenvironment (BMME), of critical importance for leukemia development and progression. One defining feature of macrophages is their plasticity, which allows them to adapt to the variations in the microenvironment. While this adaptability is advantageous during wound healing, it can also be exploited in cancer scenarios. Thus, clinical and preclinical investigations that target macrophages as a therapeutic strategy appear promising. Existing research indicates that targeting macrophages could enhance the effectiveness of current AML treatments. This review addresses the importance of macrophages as therapeutic targets including relevant drugs investigated in clinical trials such as pexidartinib, magrolimab or bexmarilimab, but also provides new insights into lesser-known therapies, like macrophage receptor with a collagenous structure (MACRO) inhibitors and Toll-like receptor (TLR) agonists.
Collapse
Affiliation(s)
- Oana Mesaros
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania
| | - Madalina Onciul
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania
| | - Emilia Matei
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania
- Department of Pathology, Ion Chiricuta Oncology Institute, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania
| | - Corina Joldes
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania
- Octavian Fodor” Regional Institute of Gastroenterology and Hepatology, 19-21 Croitorilor Str., 400162 Cluj-Napoca, Romania
| | - Laura Jimbu
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania
| | - Alexandra Neaga
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania
| | - Oana Serban
- Regina Maria” Regional Laboratory in Cluj-Napoca, 109 Observatorului Str., 400363 Cluj-Napoca, Romania
| | - Mihnea Zdrenghea
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania
| | - Ana Maria Nanut
- Regina Maria” Regional Laboratory in Cluj-Napoca, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania
| |
Collapse
|
|
4
|
Bartaula-Brevik S, Leitch C, Hernandez-Valladares M, Aasebø E, Berven FS, Selheim F, Brenner AK, Rye KP, Hagen M, Reikvam H, McCormack E, Bruserud Ø, Tvedt THA. Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity. J Clin Med 2023; 12:5546. [PMID: 37685612 PMCID: PMC10488188 DOI: 10.3390/jcm12175546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/20/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
Vacuolar ATPase (V-ATPase) is regarded as a possible target in cancer treatment. It is expressed in primary acute myeloid leukemia cells (AML), but the expression varies between patients and is highest for patients with a favorable prognosis after intensive chemotherapy. We therefore investigated the functional effects of two V-ATPase inhibitors (bafilomycin A1, concanamycin A) for primary AML cells derived from 80 consecutive patients. The V-ATPase inhibitors showed dose-dependent antiproliferative and proapoptotic effects that varied considerably between patients. A proteomic comparison of primary AML cells showing weak versus strong antiproliferative effects of V-ATPase inhibition showed a differential expression of proteins involved in intracellular transport/cytoskeleton functions, and an equivalent phosphoproteomic comparison showed a differential expression of proteins that regulate RNA processing/function together with increased activity of casein kinase 2. Patients with secondary AML, i.e., a heterogeneous subset with generally adverse prognosis and previous cytotoxic therapy, myeloproliferative neoplasia or myelodysplastic syndrome, were characterized by a strong antiproliferative effect of V-ATPase inhibition and also by a specific mRNA expression profile of V-ATPase interactome proteins. Furthermore, the V-ATPase inhibition altered the constitutive extracellular release of several soluble mediators (e.g., chemokines, interleukins, proteases, protease inhibitors), and increased mediator levels in the presence of AML-supporting bone marrow mesenchymal stem cells was then observed, especially for patients with secondary AML. Finally, animal studies suggested that the V-ATPase inhibitor bafilomycin had limited toxicity, even when combined with cytarabine. To conclude, V-ATPase inhibition has antileukemic effects in AML, but this effect varies between patients.
Collapse
Affiliation(s)
- Sushma Bartaula-Brevik
- Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; (S.B.-B.); (M.H.-V.); (E.A.); (A.K.B.); (K.P.R.); (M.H.); (H.R.); (T.H.A.T.)
| | - Calum Leitch
- Department of Clinical Science, Centre for Pharmacy, University of Bergen, 5015 Bergen, Norway; (C.L.); (E.M.)
| | - Maria Hernandez-Valladares
- Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; (S.B.-B.); (M.H.-V.); (E.A.); (A.K.B.); (K.P.R.); (M.H.); (H.R.); (T.H.A.T.)
- The Proteomics Facility of the University of Bergen (PROBE), University of Bergen, 5009 Bergen, Norway; (F.S.B.); (F.S.)
- The Department of Biomedicine, University of Bergen, 5009 Bergen, Norway
- Department of Physical Chemistry, University of Granada, Avenida de la Fuente Nueva S/N, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Elise Aasebø
- Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; (S.B.-B.); (M.H.-V.); (E.A.); (A.K.B.); (K.P.R.); (M.H.); (H.R.); (T.H.A.T.)
- The Proteomics Facility of the University of Bergen (PROBE), University of Bergen, 5009 Bergen, Norway; (F.S.B.); (F.S.)
- The Department of Biomedicine, University of Bergen, 5009 Bergen, Norway
| | - Frode S. Berven
- The Proteomics Facility of the University of Bergen (PROBE), University of Bergen, 5009 Bergen, Norway; (F.S.B.); (F.S.)
- The Department of Biomedicine, University of Bergen, 5009 Bergen, Norway
| | - Frode Selheim
- The Proteomics Facility of the University of Bergen (PROBE), University of Bergen, 5009 Bergen, Norway; (F.S.B.); (F.S.)
- The Department of Biomedicine, University of Bergen, 5009 Bergen, Norway
| | - Annette K. Brenner
- Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; (S.B.-B.); (M.H.-V.); (E.A.); (A.K.B.); (K.P.R.); (M.H.); (H.R.); (T.H.A.T.)
| | - Kristin Paulsen Rye
- Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; (S.B.-B.); (M.H.-V.); (E.A.); (A.K.B.); (K.P.R.); (M.H.); (H.R.); (T.H.A.T.)
| | - Marie Hagen
- Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; (S.B.-B.); (M.H.-V.); (E.A.); (A.K.B.); (K.P.R.); (M.H.); (H.R.); (T.H.A.T.)
| | - Håkon Reikvam
- Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; (S.B.-B.); (M.H.-V.); (E.A.); (A.K.B.); (K.P.R.); (M.H.); (H.R.); (T.H.A.T.)
- Section for Hematology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway
| | - Emmet McCormack
- Department of Clinical Science, Centre for Pharmacy, University of Bergen, 5015 Bergen, Norway; (C.L.); (E.M.)
| | - Øystein Bruserud
- Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; (S.B.-B.); (M.H.-V.); (E.A.); (A.K.B.); (K.P.R.); (M.H.); (H.R.); (T.H.A.T.)
- Section for Hematology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway
| | - Tor Henrik Anderson Tvedt
- Acute Leukemia Research Group, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; (S.B.-B.); (M.H.-V.); (E.A.); (A.K.B.); (K.P.R.); (M.H.); (H.R.); (T.H.A.T.)
- Section for Hematology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway
| |
Collapse
|
|
5
|
Guetta-Terrier C, Karambizi D, Akosman B, Zepecki JP, Chen JS, Kamle S, Fajardo JE, Fiser A, Singh R, Toms SA, Lee CG, Elias JA, Tapinos N. Chi3l1 Is a Modulator of Glioma Stem Cell States and a Therapeutic Target in Glioblastoma. Cancer Res 2023; 83:1984-1999. [PMID: 37101376 PMCID: PMC10267676 DOI: 10.1158/0008-5472.can-21-3629] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 06/24/2022] [Accepted: 04/18/2023] [Indexed: 04/28/2023]
Abstract
Chitinase 3-like 1 (Chi3l1) is a secreted protein that is highly expressed in glioblastoma. Here, we show that Chi3l1 alters the state of glioma stem cells (GSC) to support tumor growth. Exposure of patient-derived GSCs to Chi3l1 reduced the frequency of CD133+SOX2+ cells and increased the CD44+Chi3l1+ cells. Chi3l1 bound to CD44 and induced phosphorylation and nuclear translocation of β-catenin, Akt, and STAT3. Single-cell RNA sequencing and RNA velocity following incubation of GSCs with Chi3l1 showed significant changes in GSC state dynamics driving GSCs towards a mesenchymal expression profile and reducing transition probabilities towards terminal cellular states. ATAC-seq revealed that Chi3l1 increases accessibility of promoters containing a Myc-associated zinc finger protein (MAZ) transcription factor footprint. Inhibition of MAZ downregulated a set of genes with high expression in cellular clusters that exhibit significant cell state transitions after treatment with Chi3l1, and MAZ deficiency rescued the Chi3L-induced increase of GSC self-renewal. Finally, targeting Chi3l1 in vivo with a blocking antibody inhibited tumor growth and increased the probability of survival. Overall, this work suggests that Chi3l1 interacts with CD44 on the surface of GSCs to induce Akt/β-catenin signaling and MAZ transcriptional activity, which in turn upregulates CD44 expression in a pro-mesenchymal feed-forward loop. The role of Chi3l1 in regulating cellular plasticity confers a targetable vulnerability to glioblastoma. SIGNIFICANCE Chi3l1 is a modulator of glioma stem cell states that can be targeted to promote differentiation and suppress growth of glioblastoma.
Collapse
Affiliation(s)
- Charlotte Guetta-Terrier
- Laboratory of Cancer Epigenetics and Plasticity, Brown University, Rhode Island Hospital, Providence, Rhode Island
| | - David Karambizi
- Laboratory of Cancer Epigenetics and Plasticity, Brown University, Rhode Island Hospital, Providence, Rhode Island
| | - Bedia Akosman
- Laboratory of Cancer Epigenetics and Plasticity, Brown University, Rhode Island Hospital, Providence, Rhode Island
- Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island
| | - John P. Zepecki
- Laboratory of Cancer Epigenetics and Plasticity, Brown University, Rhode Island Hospital, Providence, Rhode Island
| | - Jia-Shu Chen
- Laboratory of Cancer Epigenetics and Plasticity, Brown University, Rhode Island Hospital, Providence, Rhode Island
| | - Suchitra Kamle
- Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island
| | - J. Eduardo Fajardo
- Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York
| | - Andras Fiser
- Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York
| | - Ritambhara Singh
- Department of Computer Science, Brown University, Providence, Rhode Island
| | - Steven A. Toms
- Department of Neurosurgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Chun Geun Lee
- Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island
| | - Jack A. Elias
- Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island
- Department of Internal Medicine, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Nikos Tapinos
- Laboratory of Cancer Epigenetics and Plasticity, Brown University, Rhode Island Hospital, Providence, Rhode Island
- Department of Neurosurgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| |
Collapse
|
|
6
|
Li J, Li H, Wang Y, Zhao X, Wang S, Li L. CHI3L1 in the CSF is a potential biomarker for anti-leucine-rich glioma inactivated 1 encephalitis. Front Immunol 2023; 13:1071219. [PMID: 36685530 PMCID: PMC9849687 DOI: 10.3389/fimmu.2022.1071219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 12/16/2022] [Indexed: 01/06/2023] Open
Abstract
Objective Anti-leucine-rich glioma inactivated 1(LGI1) encephalitis is one rare autoimmune encephalitis which is accompanied by inflammatory responses. (Anti-leucine-rich glioma inactivated 1 (anti-LGI1) encephalitis is an autoimmune disease mediated by inflammatory responses.)This study aimed to investigate the Chitinase 3-like 1(CHI3L1) in anti-LGI1encephalitis patients and evaluate its association with modified Rankin Scale (mRS) score in anti-LGI1 encephalitis at admission and 6 months follow-up.(This study looked into the relationship between Chitinase 3-like 1 (CHI3L1) and the modified Ranking Scale (mRS) score in anti-LGI1 encephalitis patients at admission and 6 months later.). Methods Thirty-five patients with anti-LGI1 encephalitis and 22 patients with non-inflammatory neurological disease were enrolled in this study. (We enrolled 35 patients with anti-LGI1 encephalitis and 22 patients with non-inflammatory neurological disease.)Cerebrospinal fluid (CSF) and serum levels of CHI3L1 were measured by enzyme-linked immunosorbent assay. (We quantified CHI3L1 in the serum and cerebrospinal fluid (CSF) by performing an enzyme-linked immunosorbent assay.)Patients were evaluated for mRS score at admission and at 6 months follow-up.(We recorded the mRS score of the patients at admission and 6 months later.). Results CHI3L1 levels in CSF and serum were highly elevated in patients with anti-LGI1 encephalitis at admission compared those with the controls.(At admission, patients with anti-LGI1 encephalitis had elevated CHI3L1 levels in the CSF and serum.) Additionally, patients presenting with cognitive impairment had significantly higher CSF CHI3L1 levels and mRS scores than those without cognitive impairment symptoms. Patients presenting with only faciobrachial dystonic seizures at admission had lower CSF CHI3L1 levels than those with other symptoms. Finally, CSF CHI3L1 levels were positively correlated with CSF lactate levels. Conclusion CHI3L1 level in CSF is correlated with the severity and prognosis of anti-LGI1 encephalitis. (CSF CHI3L1 levels are correlated with the severity and prognosis of anti-LGI1 encephalitis.).
Collapse
Affiliation(s)
- Jinyi Li
- Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Hongyan Li
- Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, China
| | - Yunhuan Wang
- Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiuhe Zhao
- Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Shengjun Wang
- Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China,*Correspondence: Shengjun Wang, ; Ling Li,
| | - Ling Li
- Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, China,*Correspondence: Shengjun Wang, ; Ling Li,
| |
Collapse
|
|
7
|
Huang J, Gu Z, Xu Y, Jiang L, Zhu W, Wang W. CHI3L1 (Chitinase 3 Like 1) upregulation is associated with macrophage signatures in esophageal cancer. Bioengineered 2021; 12:7882-7892. [PMID: 34612767 PMCID: PMC8806503 DOI: 10.1080/21655979.2021.1974654] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Chitinase-3 like-protein-1 (CHI3L1) has been found to be overexpressed in many cancers and increased CHI3L1 level in serum seems to correlate with a poor prognosis in patients with metastatic cancer. However, the expression of CHI3L1 and its potential role in esophageal cancer remains unclear. We retrieved publicly available RNA-seq datasets of esophageal cancer tissues and normal esophageal tissues. We analyzed the correlation between CHI3L1 expression with different clinical parameters (such as T stages, N stage, response to treatment and tumor residues after treatment), the relationship between CHI3L1 expression level and prognosis, and the relationship between CHI3L1 expression and different immune cell signatures in esophageal cancer tissues. A transgenic mouse model of esophageal carcinoma was used to validate CHI3L1 expression and its association with macrophage signature gene expression. The effect of recombinant CHI3L1 on macrophage polarization was assessed in cell model. We showed the upregulation of CHI3L1 in esophageal cancer tissues in comparison to normal esophageal tissues, and its upregulation was positively associated with tumor size. The analysis of immunological signatures and CHI3L1 expression indicated that CHI3L1 level was highly correlated with increased expression of macrophage signature genes in esophageal tumor tissues. CHI3L1 was also upregulated in the esophagus dysplasia tissues in a transgenic mouse model. Recombinant CHI3L1 treatment favored M2 gene expression in LPS-stimulated RAW 264.7 macrophage cell line. CHI3L1 overexpression may favor macrophage recruitment in esophageal tumor tissues. Future studies are needed to delineate the mechanisms of CHI3L1-mediated macrophage recruitment and polarization in tumor tissues.
Collapse
Affiliation(s)
- Jing Huang
- Department of Radiation Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Zhenlin Gu
- Department of Vascular Surgery, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Yingying Xu
- Department of Radiation Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Lei Jiang
- Department of Radiation Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Weiguo Zhu
- Department of Radiation Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian, China
| | - Wanwei Wang
- Department of Radiation Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian, China
| |
Collapse
|
|
8
|
Miari KE, Guzman ML, Wheadon H, Williams MTS. Macrophages in Acute Myeloid Leukaemia: Significant Players in Therapy Resistance and Patient Outcomes. Front Cell Dev Biol 2021; 9:692800. [PMID: 34249942 PMCID: PMC8264427 DOI: 10.3389/fcell.2021.692800] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/04/2021] [Indexed: 12/19/2022] Open
Abstract
Acute Myeloid Leukaemia (AML) is a commonly occurring severe haematological malignancy, with most patients exhibiting sub-optimal clinical outcomes. Therapy resistance significantly contributes towards failure of traditional and targeted treatments, disease relapse and mortality in AML patients. The mechanisms driving therapy resistance in AML are not fully understood, and approaches to overcome therapy resistance are important for curative therapies. To date, most studies have focused on therapy resistant mechanisms inherent to leukaemic cells (e.g., TP53 mutations), overlooking to some extent, acquired mechanisms of resistance through extrinsic processes. In the bone marrow microenvironment (BMME), leukaemic cells interact with the surrounding bone resident cells, driving acquired therapy resistance in AML. Growing evidence suggests that macrophages, highly plastic immune cells present in the BMME, play a role in the pathophysiology of AML. Leukaemia-supporting macrophage subsets (CD163+CD206+) are elevated in preclinical in vivo models of AML and AML patients. However, the relationship between macrophages and therapy resistance in AML warrants further investigation. In this review, we correlate the potential links between macrophages, the development of therapy resistance, and patient outcomes in AML. We specifically focus on macrophage reprogramming by AML cells, macrophage-driven activation of anti-cell death pathways in AML cells, and the association between macrophage phenotypes and clinical outcomes in AML, including their potential prognostic value. Lastly, we discuss therapeutic targeting of macrophages, as a strategy to circumvent therapy resistance in AML, and discuss how emerging genomic and proteomic-based approaches can be utilised to address existing challenges in this research field.
Collapse
Affiliation(s)
- Katerina E. Miari
- Charles Oakley Laboratories, Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, United Kingdom
| | - Monica L. Guzman
- Department of Hematology & Medical Oncology, Graduate School of Medical Sciences, Cornell University, New York, NY, United States
| | - Helen Wheadon
- Paul O’Gorman Leukaemia Research Centre, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Mark T. S. Williams
- Charles Oakley Laboratories, Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, United Kingdom
| |
Collapse
|
|
9
|
Rivas-Alarcón AA, Gómez-Gómez Y, Organista-Nava J, Jiménez-López MA, Rivera-Ramírez AB, Ibarra-Sierra E, Saavedra-Herrera MV, Illades-Aguiar B, Leyva-Vázquez MA. Plasma levels of YKL-40 as a prognostic factor in childhood acute lymphoblastic leukemia. Mol Clin Oncol 2021; 15:168. [PMID: 34194746 PMCID: PMC8237154 DOI: 10.3892/mco.2021.2330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 01/27/2021] [Indexed: 11/05/2022] Open
Abstract
YKL-40, also known as chitinase-3-like protein 1 (CHI3L1), is an inflammatory glycoprotein secreted by different types of cells, such as inflammatory cells. The levels of this protein are elevated in the serum or plasma of patients with different types of cancer, and high concentrations are associated with poor prognosis and short survival in patients with liver, breast, lung, bladder and endometrial cancers. In Mexico, acute lymphoblastic leukemia (ALL) is the most common type of cancer affecting the pediatric population. The prognosis of patients with ALL is difficult to establish. Hence, the objective of the present study was to analyze the plasma levels of YKL-40 in Mexican children with ALL and investigate its role as a prognostic factor. A case-control study was performed in a population of 90 children aged 1-18 years, among whom 45 had ALL and 45 were hematologically healthy. The levels of YKL-40 in plasma samples were measured using ELISA and were found to be significantly higher in children with ALL compared with those in controls (P<0.0001). Children with ALL who had high plasma levels of YKL-40 (≥36.34 ng/ml) had shorter survival compared with those with low levels (<36.34 ng/ml; P<0.05). The findings of the present study revealed that the YKL-40 plasma level, age/initial leukocyte count and central nervous system invasion were associated with the prognosis of children with ALL [odds ratio (OR)=6.06, 95% confidence interval (CI): 1.1-31.6, P=0.03; OR=8.53, 95% CI: 1.2-58.2, P=0.03; and OR=6.45, 95% CI: 1.01-41.2, P=0.04, respectively]. Therefore, YKL-40 plasma levels may serve as a prognostic biomarker in pediatric patients with ALL.
Collapse
Affiliation(s)
- Alinne Ayulieth Rivas-Alarcón
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero 39070, México
| | - Yazmin Gómez-Gómez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero 39070, México
| | - Jorge Organista-Nava
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero 39070, México
| | - Marco Antonio Jiménez-López
- Departamento de Investigación, Instituto Estatal de Cancerología 'Arturo Beltrán Ortega', Acapulco, Guerrero 39570, México
| | - Ana Berta Rivera-Ramírez
- Departamento de Investigación, Instituto Estatal de Cancerología 'Arturo Beltrán Ortega', Acapulco, Guerrero 39570, México
| | - Eloisa Ibarra-Sierra
- Departamento de Investigación, Instituto Estatal de Cancerología 'Arturo Beltrán Ortega', Acapulco, Guerrero 39570, México
| | | | - Berenice Illades-Aguiar
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero 39070, México
| | - Marco Antonio Leyva-Vázquez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero 39070, México
| |
Collapse
|
|
10
|
CHI3L1 promotes Staphylococcus aureus-induced osteomyelitis by activating p38/MAPK and Smad signaling pathways. Exp Cell Res 2021; 403:112596. [PMID: 33826950 DOI: 10.1016/j.yexcr.2021.112596] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/21/2021] [Accepted: 04/01/2021] [Indexed: 12/26/2022]
Abstract
AIMS Staphylococcus aureus (S. aureus) is the most common causative bacterial pathogen involved in promoting infection-induced osteomyelitis, a disease resulting in severe bone degradation. In this study, we aimed to identify the mechanism behind inhibition of osteoclast survival and differentiation by CHI3L1, a lectin previously reported to regulate S. aureus-induced osteomyelitis. MAIN METHODS The role of CHI3L1 in osteoclast survival, proliferation, and differentiation was studied ex vivo using primary human bone marrow derived stem cells (HBMSCs) and transducing them with lentiviral expression vectors or shRNA knockdown constructs. Cell apoptosis was analyzed by flow cytometry using annexin V-fluorescein isothiocyanate/propidium iodide staining. Cell proliferation was assessed using alkaline phosphatase, Alcian Blue, and TRAP staining. The qRT-PCR was used to measure mRNA levels of osteoclast maturation markers, and western blotting was used to analyze protein expression. An in vivo murine model for osteomyelitis and microcomputed tomography analyses of infected femurs were used to study the effects of CHI3L1 on bone erosion. KEY FINDINGS Overexpression of CHI3L1 significantly reduced HBMSC cell viability, proliferation, and differentiation, and knockdown improved these effects in the presence of S. aureus infection. More specifically, CHI3L1 constitutively activated the p38/MAPK pathway to promote apoptosis. Furthermore, CHI3L1 induced activation of the Smad pathway by promoting phosphorylation of Smad-1/5 proteins. Finally, overexpression of CHI3L1 significantly induced bone erosion upon S. aureus infection in a murine osteomyelitis model, and knockdown of CHI3L1 significantly alleviated this effect. SIGNIFICANCE CHI3L1 played a vital role in osteoblast differentiation and proliferation by regulating the p38/MAPK and Smad signaling pathways to promote S. aureus-induced osteomyelitis.
Collapse
|
|
11
|
Krečak I, Gverić-Krečak V, Lapić I, Rončević P, Gulin J, Fumić K, Krečak F, Holik H, Duraković N. Circulating YKL-40 in Philadelphia-negative myeloproliferative neoplasms. Acta Clin Belg 2021; 76:32-39. [PMID: 31455178 DOI: 10.1080/17843286.2019.1659467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Objectives: Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF), are characterized by clonal myeloproliferation and a strong inflammatory atmosphere. YKL-40, expressed in granulocytes, macrophages, megakaryocytes and malignant cells, is an acute phase reactant with an important role in tissue remodeling and atherosclerotic inflammation. The aim of this study was to investigate serum YKL-40 levels in MPNs and to assess its clinical correlations. Methods: ELISA test was used to measure serum YKL-40 levels in 111 MPN patients and in 32 healthy controls. Results: Serum YKL-40 levels were higher in ET, post-ET MF, PV, post-PV MF and primary MF patients, when compared to healthy controls (p < 0.001). Higher serum YKL-40 levels were associated with parameters indicative of the increased inflammatory state (higher C-reactive protein, poor performance status, presence of constitutional symptoms and cardiovascular risk factors). Additionally, higher serum YKL-40 levels in MF patients were associated with blast phase disease, lower hemoglobin and higher Dynamic International Prognostic Scoring System score. In the multivariate Cox regression models, higher serum YKL-40 levels in ET and PV patients were independently associated with an increased risk of thrombosis (HR 4.64, p = 0.031) and impaired survival in MF patients (HR 4.31, p = 0.038). Conclusion: These results indicate that higher circulating YKL-40 levels in MPNs might have a pathophysiological role in disease progression and thrombosis development. Assessing circulating YKL-40 could help in identification of ET and PV patients at a high risk of future cardiovascular events and has a good potential for improving prognostication of MF patients.
Collapse
Affiliation(s)
- Ivan Krečak
- Department of Internal Medicine, General Hospital of Sibenik-Knin County, Sibenik, Croatia
| | - Velka Gverić-Krečak
- Department of Internal Medicine, General Hospital of Sibenik-Knin County, Sibenik, Croatia
| | - Ivana Lapić
- Department of Laboratory Diagnostics of Inborn Errors of Metabolism, Clinical Department of Laboratory Diagnostics, University Hospital Center Zagreb, Zagreb, Croatia
| | - Pavle Rončević
- Division of Hematology, Department of Internal Medicine, University Hospital Center Zagreb, Zagreb, Croatia
| | - Josipa Gulin
- Department of Laboratory Diagnostics of Inborn Errors of Metabolism, Clinical Department of Laboratory Diagnostics, University Hospital Center Zagreb, Zagreb, Croatia
| | - Ksenija Fumić
- Division of Hematology, Department of Internal Medicine, University Hospital Center Zagreb, Zagreb, Croatia
- Faculty of Pharmacy and Biochemistry, University Hospital Center Zagreb, Zagreb, Croatia
| | - Filip Krečak
- School of Medicine, University of Split, Split, Croatia
| | - Hrvoje Holik
- Department of Internal Medicine, “Dr. Josip Bencevic” General Hospital, Slavonski Brod, Croatia
| | - Nadira Duraković
- Division of Hematology, Department of Internal Medicine, University Hospital Center Zagreb, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| |
Collapse
|
|
12
|
Zhao T, Su Z, Li Y, Zhang X, You Q. Chitinase-3 like-protein-1 function and its role in diseases. Signal Transduct Target Ther 2020; 5:201. [PMID: 32929074 PMCID: PMC7490424 DOI: 10.1038/s41392-020-00303-7] [Citation(s) in RCA: 301] [Impact Index Per Article: 60.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 07/28/2020] [Accepted: 08/20/2020] [Indexed: 12/12/2022] Open
Abstract
Non-enzymatic chitinase-3 like-protein-1 (CHI3L1) belongs to glycoside hydrolase family 18. It binds to chitin, heparin, and hyaluronic acid, and is regulated by extracellular matrix changes, cytokines, growth factors, drugs, and stress. CHI3L1 is synthesized and secreted by a multitude of cells including macrophages, neutrophils, synoviocytes, chondrocytes, fibroblast-like cells, smooth muscle cells, and tumor cells. It plays a major role in tissue injury, inflammation, tissue repair, and remodeling responses. CHI3L1 has been strongly associated with diseases including asthma, arthritis, sepsis, diabetes, liver fibrosis, and coronary artery disease. Moreover, following its initial identification in the culture supernatant of the MG63 osteosarcoma cell line, CHI3L1 has been shown to be overexpressed in a wealth of both human cancers and animal tumor models. To date, interleukin-13 receptor subunit alpha-2, transmembrane protein 219, galectin-3, chemo-attractant receptor-homologous 2, and CD44 have been identified as CHI3L1 receptors. CHI3L1 signaling plays a critical role in cancer cell growth, proliferation, invasion, metastasis, angiogenesis, activation of tumor-associated macrophages, and Th2 polarization of CD4+ T cells. Interestingly, CHI3L1-based targeted therapy has been increasingly applied to the treatment of tumors including glioma and colon cancer as well as rheumatoid arthritis. This review summarizes the potential roles and mechanisms of CHI3L1 in oncogenesis and disease pathogenesis, then posits investigational strategies for targeted therapies.
Collapse
Affiliation(s)
- Ting Zhao
- Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou, China
| | - Zhongping Su
- Department of Biotherapy, Department of Geriatrics, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yingchang Li
- Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
| | - Xiaoren Zhang
- Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
| | - Qiang You
- Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou, China.
- Department of Biotherapy, Department of Geriatrics, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China.
| |
Collapse
|
|
13
|
Kjaergaard AD, Helby J, Johansen JS, Nordestgaard BG, Bojesen SE. Elevated plasma YKL-40 and risk of infectious disease: a prospective study of 94665 individuals from the general population. Clin Microbiol Infect 2020; 26:1411.e1-1411.e9. [PMID: 31972315 DOI: 10.1016/j.cmi.2020.01.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 01/06/2020] [Accepted: 01/11/2020] [Indexed: 01/08/2023]
Abstract
OBJECTIVES YKL-40 is an acute phase protein elevated in patients with infectious and inflammatory diseases. We tested the hypothesis that baseline elevated YKL-40 is associated with increased risk of future infectious disease in healthy individuals in the general population. METHODS We prospectively followed 94 665 individuals from the Danish general population for up to 23 years and analysed for plasma YKL-40 levels (n = 21 584) and CHI3L1 rs4950928 genotype (n = 94 184). Endpoints were any infection, bacterial pneumonia, urinary tract infection, skin infection, sepsis, diarrhoeal disease, and other infections. RESULTS For YKL-40 percentile category 91-100% versus 0-33%, the multifactorially and C-reactive protein (CRP) adjusted hazard ratios were 1.71 (95% confidence interval 1.50-1.96; p 4 × 10-14) for any infection, 1.97 (1.64-2.37; p 4 × 10-13) for bacterial pneumonia, 1.62 (1.24-2.11; p 0.002) for urinary tract infection, 1.74 (1.31-2.32; p 2 × 10-4) for skin infection, 1.76 (1.25-2.46; p 0.004) for sepsis, 1.90 (1.29-2.78; p 0.002) for diarrhoeal disease and 2.71 (1.38-5.35; p 0.01) for other infections. In multifactorially and CRP-adjusted models, a twofold increase in YKL-40 was associated with increased risk of all infectious disease endpoints. Mendelian randomization did not support causality, as CHI3L1 rs4950928 was associated with 94% and 190% higher YKL-40 levels (for CG and CC versus GG genotype), but not with increased risk of any infectious disease endpoint. DISCUSSION Baseline elevated plasma YKL-40 was not a cause but a strong marker of increased risk of future infectious diseases in individuals in the general population.
Collapse
Affiliation(s)
- A D Kjaergaard
- Department of Clinical Epidemiology and Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
| | - J Helby
- Department of Clinical Biochemistry, Department of Internal Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
| | - J S Johansen
- Department of Oncology and Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Herlev, Denmark
| | - B G Nordestgaard
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Herlev, Denmark
| | - S E Bojesen
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Herlev, Denmark
| |
Collapse
|
|
14
|
Cheng KC, Lee JJ, Wang SL, Lin CY, Tseng CT, Lin CS, Liao AT. Elevated plasma YKL-40 level is found in the dogs with cancer and is related to poor prognosis. J Vet Sci 2020; 20:e53. [PMID: 31565896 PMCID: PMC6769324 DOI: 10.4142/jvs.2019.20.e53] [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: 04/10/2019] [Revised: 06/24/2019] [Accepted: 08/15/2019] [Indexed: 11/20/2022] Open
Abstract
YKL-40, a secreted glycoprotein, may serve as an autoantigen, which mediates multiple inflammatory diseases and cancers. A high YKL-40 serum level is correlated with metastasis and poor survival in a variety of human cancers. However, the role of YKL-40 in dogs is still under evaluation. Herein, we examined the associations between plasma YKL-40 level and YKL-40 autoantibody (YAA) titers with malignancy and prognosis in canine cancer. Plasma levels of YKL-40 in healthy dogs (n = 20) and in dogs (n = 82) with cancer were evaluated using enzyme-linked immunosorbent assay. Our results indicated that plasma YKL-40 levels were significantly higher (p < 0.01) in dogs with cancer than in healthy dogs. A significant decrease in the YAA titers was detected in the dogs with cancer when compared with those of the healthy dogs (p < 0.05), although the change was not correlated with the YKL-40 levels. Among the dogs with cancer, plasma YKL-40 levels in the dogs that later relapsed or had metastasis were significantly higher than in the dogs with no signs of relapse (p < 0.01) or metastasis (p <0.05). The relapse and metastasis rates were significantly higher in the high YKL-40 group (> 180 pg/mL) than in the low YKL-40 group (< 180 pg/mL). The results imply that plasma YKL-40 levels might have the potential to be developed as a marker of malignancy progression and prognosis in canine cancers.
Collapse
Affiliation(s)
- Kai Chung Cheng
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan, ROC
| | - Jih Jong Lee
- Institute of Veterinary Clinical Science, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan, ROC.,Animal Cancer Center, College of Bioresources and Agriculture, National Taiwan University, Taipei 10617, Taiwan, ROC
| | - Shang Lin Wang
- Institute of Veterinary Clinical Science, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan, ROC.,Animal Cancer Center, College of Bioresources and Agriculture, National Taiwan University, Taipei 10617, Taiwan, ROC
| | - Chun Yu Lin
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan, ROC
| | - Ching Tien Tseng
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan, ROC
| | - Chen Si Lin
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan, ROC.,Animal Cancer Center, College of Bioresources and Agriculture, National Taiwan University, Taipei 10617, Taiwan, ROC
| | - Albert Taiching Liao
- Department of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan, ROC.,Animal Cancer Center, College of Bioresources and Agriculture, National Taiwan University, Taipei 10617, Taiwan, ROC.
| |
Collapse
|
|
15
|
Suzuki H, Boki H, Kamijo H, Nakajima R, Oka T, Shishido-Takahashi N, Suga H, Sugaya M, Sato S, Miyagaki T. YKL-40 Promotes Proliferation of Cutaneous T-Cell Lymphoma Tumor Cells through Extracellular Signal-Regulated Kinase Pathways. J Invest Dermatol 2019; 140:860-868.e3. [PMID: 31622598 DOI: 10.1016/j.jid.2019.09.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 08/28/2019] [Accepted: 09/12/2019] [Indexed: 01/19/2023]
Abstract
YKL-40, one of the chitinase-like proteins, is associated with the pathogenesis of a wide variety of human diseases through modulation of inflammation and tissue remodeling by its diverse roles in cell proliferation, differentiation, and survival. Emerging evidence shows that aberrantly expressed YKL-40 promotes the development of malignancies by inducing proliferation of tumor cells, cytokine production, and angiogenesis by acting on various stromal cells, immune cells, and tumor cells. In this study, we investigated the expression and function of YKL-40 in cutaneous T-cell lymphoma (CTCL). We first revealed that serum YKL-40 levels were increased in patients with CTCL and correlated with disease severity markers. We also found that YKL-40 was expressed by epidermal keratinocytes and tumor cells in lesional skin of CTCL by immunohistochemistry. Although YKL-40 did not affect cytokine production from CTCL cell lines, YKL-40 promoted the proliferation of Hut78 cells and HH cells in vitro, which was dependent on extracellular signal-regulated kinase 1/2 pathways. Moreover, exogenous YKL-40 administration enhanced tumor growth of HH cells in vivo. Our study has suggested that YKL-40 produced from epidermal keratinocytes and CTCL cells promoted the proliferation of CTCL cells through extracellular signal-regulated kinase 1/2 pathways in autocrine and paracrine manners, leading to development of CTCL.
Collapse
Affiliation(s)
- Hideko Suzuki
- Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Hikari Boki
- Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Hiroaki Kamijo
- Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Rina Nakajima
- Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Tomonori Oka
- Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Naomi Shishido-Takahashi
- Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Department of Dermatology, International University of Health and Welfare Faculty of Medicine, Chiba, Japan
| | - Hiraku Suga
- Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Makoto Sugaya
- Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Department of Dermatology, International University of Health and Welfare Faculty of Medicine, Chiba, Japan
| | - Shinichi Sato
- Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Tomomitsu Miyagaki
- Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
| |
Collapse
|
|
16
|
Abstract
Previous studies have shown that interleukin-24 (IL-24) has tumor-suppressing activity by multiple pathways. However, the immunogenicity moderation effect of IL-24 on malignant cells has not been explored extensively. In this study, we investigated the role of IL-24 in immunogenicity modulation of the myelogenous leukemia cells. Data show that myelogenous leukemia cells express low levels of immunogenicity molecules. Treatment with IL-24 could enhance leukemia cell immunogenicity, predominantly regulate leukemia cells to produce immune-associated cytokines, and improve the cytotoxic sensitivity of these cells to immune effector cells. IL-24 expression could retard transplanted leukemia cell tumor growth in vivo in athymic nude mice. Moreover, IL-24 had marked effects on downregulating the expression of angiogenesis-related proteins vascular endothelial growth factor, cluster of differentiation (CD) 31, CD34, collagen IV and metastasis-related factors CD147, membrane type-1 matrix metalloproteinase (MMP), and MMP-2 and MMP-9 in transplanted tumors. These findings indicated novel functions of this antitumor gene and characterized IL-24 as a promising agent for further clinical trial for hematologic malignancy immunotherapy.
Collapse
|
|
17
|
Karataş S, Şal V, Kahramanoğlu İ, Demirkıran F, Beşe T, Arvas M, Sofiyeva N, Güralp O, Uzun H. Ykl-40 and cancer antigen 72-4 as new and promising diagnostic and prognostic markers for endometrial cancer. Turk J Obstet Gynecol 2019; 15:235-242. [PMID: 30693139 PMCID: PMC6334238 DOI: 10.4274/tjod.77906] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 09/03/2018] [Indexed: 12/14/2022] Open
Abstract
Objective: To determine the predictive role of serum levels of YKL-40 and cancer antigen (CA) 72-4 in the diagnosis of endometrial cancer (EC). Materials and Methods: Forty-one patients with EC and 21 women with uterine polyps were evaluated between January and December 2015 in a prospective study. Results: Age, body mass index, preoperative serum YKL-40 and CA 72-4 levels were significantly higher in the malignant group compared with the control group. Serum YKL-40 levels were significantly higher in patients with superficial myometrial invasion and no lymph node involvement (p=0.042; p=0.004). No relationship between clinicopathologic factors and serum CA 72-4 levels was found. Conclusion: Serum CA 72-4 and YKL-40 levels are increased in women with EC compared with uterine polyps. Preoperative serum YKL-40 levels may be associated with favorable prognostic factors. The determination of YKL-40 before surgery may be helpful in the evaluation of the regional lymph nodes.
Collapse
Affiliation(s)
- Suat Karataş
- İstanbul Şişli Hamidiye Etfal Training and Research Hospital, Clinic of Obstetrics and Gynecology, İstanbul, Turkey
| | - Veysel Şal
- İstanbul Şişli Hamidiye Etfal Training and Research Hospital, Clinic of Obstetrics and Gynecology, İstanbul, Turkey
| | - İlker Kahramanoğlu
- İstanbul University Cerrahpaşa Faculty of Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, İstanbul, Turkey
| | - Fuat Demirkıran
- İstanbul University Cerrahpaşa Faculty of Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, İstanbul, Turkey
| | - Tugan Beşe
- İstanbul University Cerrahpaşa Faculty of Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, İstanbul, Turkey
| | - Macit Arvas
- İstanbul University Cerrahpaşa Faculty of Medicine, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, İstanbul, Turkey
| | - Nigar Sofiyeva
- Yale University Faculty of Medicine, Department of Obstetrics and Gynecology and Reproductive Sciences, New Haven, CT, USA
| | - Onur Güralp
- Klinikum Oldenburg University Hospital, Clinic of Obstetrics and Gynecology, Oldenburg, Germany
| | - Hafize Uzun
- İstanbul University Cerrahpaşa Faculty of Medicine, Department of Biochemistry, İstanbul,Turkey
| |
Collapse
|
|
18
|
Fuksiewicz M, Kotowicz B, Rutkowski A, Achinger-Kawecka J, Wagrodzki M, Kowalska MM. The Assessment of Clinical Usage and Prognostic Value of YKL-40 Serum Levels in Patients With Rectal Cancer Without Distant Metastasis. Technol Cancer Res Treat 2018; 17:1533033818765209. [PMID: 29642772 PMCID: PMC5900806 DOI: 10.1177/1533033818765209] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Colorectal cancer is one of the most common and significant malignancies in the world. YKL-40 (chitinase-3-like protein 1) is involved in cell proliferation, migration, inflammation, and tissue remodeling; and serum levels of YKL-40 are associated with patient outcome in various cancers. The aim of this study was to assess the potential clinical usage of YKL-40 pretreatment serum levels as a prognostic biomarker in rectal cancer. METHODS Concentrations of YKL-40 and standard tumor marker-Carcinoembryonic antigen (CEA)-were assessed in serum of 83 patients with rectal cancer without distant metastasis, and association with clinicopathological characteristics and disease-free and overall survival was evaluated. RESULTS Concentration of YKL-40 was significantly higher in serum of patients with rectal cancer compared to healthy controls ( P = .0001), and YKL-40 levels were able to predict rectal cancer (area under the Receiver Operating Characteristic [ROC] curve = .769) with higher accuracy than CEA (area under the ROC curve = .728) in patients with early stage disease. Increased YKL-40 levels were significantly associated with age ( P = .001); however, no association with other clinicopathological characteristics was observed. Finally, in patients with recurrence, the percentage of cases with increased concentration of YKL-40 was significantly higher than in patients without recurrence ( P = .041), and Kaplan-Meier analysis demonstrated that elevated YKL-40 concentration is a predictor of poor overall survival in patients with rectal cancer. CONCLUSION Pretreatment serum levels of YKL-40 may be a novel prognostic factor of overall and disease-free survival in patients with nonmetastatic colorectal cancer.
Collapse
Affiliation(s)
- Malgorzata Fuksiewicz
- 1 Laboratory of Tumor Markers, Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | - Beata Kotowicz
- 1 Laboratory of Tumor Markers, Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | - Andrzej Rutkowski
- 2 Department of Oncological Gastroenterology, Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Joanna Achinger-Kawecka
- 3 Genomics and Epigenetics Division, Garvan Institute of Medical Research, Epigenetics Research Laboratory, Darlinghurst, New South Wales, Australia.,4 Faculty of Medicine, St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia
| | - Michal Wagrodzki
- 5 Laboratory of Pathology, Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Maria M Kowalska
- 1 Laboratory of Tumor Markers, Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| |
Collapse
|
|
19
|
Zadi Heydarabad M, Baharaghdam S, Azimi A, Mohammadi H, Eivazi Ziaei J, Yazdanpanah B, Zak MS, Farahani ME, Dohrabpour A, Partash N, Talebi M. The role of tumor suppressor of resveratrol and prednisolone by downregulation of YKL-40 expression in CCRF-CEM cell line. J Cell Biochem 2018; 120:3773-3779. [PMID: 30426549 DOI: 10.1002/jcb.27659] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 08/21/2018] [Indexed: 01/11/2023]
Abstract
BACKGROUND Acute lymphoblastic leukemia (ALL) is characterized by excessive accumulation of lymphoblast and progenitors. Leukemia is the most common cancer in children and ALL is the most common subtype. Many studies have shown that the YKL-40 gene is one of the most widely expressed genes in tumors, including leukemia, but not in healthy blood cells. Clinical studies have shown that serum YKL-40 levels have a positive correlation with tumor expansion, in addition to being a prognostic agent independent of a short relapse-free interval, as well as a brief overall survival in patients with various cancers. The previous study shows that YKL-40 is closely related to the degree of pathology or degree of human leukemia pathology and plays an important role in cell proliferation. Hence, the YKL-40 can be an attractive target in designing anticancer therapies. METHODS CCRF-CEM cells were treated with resveratrol and prednisolone. For analysis of YKL-40 expression changes under medication, real-time polymerase chain reaction (PCR) and Western blot techniques were used at resonating intervals of 24 and 48 hours. RESULTS The effect of 15, 50, and 100 μM resveratrol and 700 μM of prednisolone on CCRF-CEM cells reduced YKL-40. The YKL-40 gene was quantitatively measured using RT-PCR. The Western blot method was used to evaluate changes in the expression of YKL-40 protein. CONCLUSION In this study, we first evaluated YKL-40 expression and resveratrol and prednisolone effect on YKL-40 in ALL. This finding supports the idea of targeting YKL-40 as a new drug treatment of ALL and extends the use of resveratrol in antileukemia research.
Collapse
Affiliation(s)
| | - Sina Baharaghdam
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ako Azimi
- Department of Basic Sciences, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Hamed Mohammadi
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Jamal Eivazi Ziaei
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behruz Yazdanpanah
- Department of Laboratory Sciences, School Paramedics, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mohsen Sharif Zak
- Clinical Biochemistry and Laboratory, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Aghdas Dohrabpour
- Department of Microbiology, Yasuj Branch, Islamic Azad University, Tehran, Iran
| | - Nasim Partash
- Department of Nursing, School of Nursing and Midwifery, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Mehdi Talebi
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran.,Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
20
|
Bereman MS, Beri J, Enders JR, Nash T. Machine Learning Reveals Protein Signatures in CSF and Plasma Fluids of Clinical Value for ALS. Sci Rep 2018; 8:16334. [PMID: 30397248 PMCID: PMC6218542 DOI: 10.1038/s41598-018-34642-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 10/23/2018] [Indexed: 11/14/2022] Open
Abstract
We use shotgun proteomics to identify biomarkers of diagnostic and prognostic value in individuals diagnosed with amyotrophic lateral sclerosis. Matched cerebrospinal and plasma fluids were subjected to abundant protein depletion and analyzed by nano-flow liquid chromatography high resolution tandem mass spectrometry. Label free quantitation was used to identify differential proteins between individuals with ALS (n = 33) and healthy controls (n = 30) in both fluids. In CSF, 118 (p-value < 0.05) and 27 proteins (q-value < 0.05) were identified as significantly altered between ALS and controls. In plasma, 20 (p-value < 0.05) and 0 (q-value < 0.05) proteins were identified as significantly altered between ALS and controls. Proteins involved in complement activation, acute phase response and retinoid signaling pathways were significantly enriched in the CSF from ALS patients. Subsequently various machine learning methods were evaluated for disease classification using a repeated Monte Carlo cross-validation approach. A linear discriminant analysis model achieved a median area under the receiver operating characteristic curve of 0.94 with an interquartile range of 0.88–1.0. Three proteins composed a prognostic model (p = 5e-4) that explained 49% of the variation in the ALS-FRS scores. Finally we investigated the specificity of two promising proteins from our discovery data set, chitinase-3 like 1 protein and alpha-1-antichymotrypsin, using targeted proteomics in a separate set of CSF samples derived from individuals diagnosed with ALS (n = 11) and other neurological diseases (n = 15). These results demonstrate the potential of a panel of targeted proteins for objective measurements of clinical value in ALS.
Collapse
Affiliation(s)
- Michael S Bereman
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, 27695, USA. .,Department of Chemistry, North Carolina State University, Raleigh, NC, 27695, USA. .,Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA.
| | - Joshua Beri
- Department of Chemistry, North Carolina State University, Raleigh, NC, 27695, USA
| | - Jeffrey R Enders
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA
| | - Tara Nash
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA
| |
Collapse
|
|
21
|
Pouyafar A, Heydarabad MZ, Mahboob S, Mokhtarzadeh A, Rahbarghazi R. Angiogenic potential of YKL-40 in the dynamics of tumor niche. Biomed Pharmacother 2018; 100:478-485. [PMID: 29477911 DOI: 10.1016/j.biopha.2018.02.050] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 02/09/2018] [Accepted: 02/13/2018] [Indexed: 12/20/2022] Open
Abstract
A multitude of clinical studies showed the elevation of YKL-40 in subjects with different kinds of tumors. It is predicted that an inherent correlation exists between survivals of cancer patients with total YKL-40 serum levels, making this factor as a potential novel biomarker. However, the crucial role of YKL-40 in the dynamics of cancers, especially angiogenesis, has not yet been completely addressed. In this review, we highlighted the various facets of YKL-40 and its importance in cancer biology as a bio-shuttle in gene therapy.
Collapse
Affiliation(s)
- Ayda Pouyafar
- Department of Biochemistry, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Milad Zadi Heydarabad
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soltanali Mahboob
- Department of Biochemistry, Higher Education Institute of Rab-Rashid, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Department of Biochemistry, Higher Education Institute of Rab-Rashid, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
22
|
Shantha Kumara HMC, Gaita D, Miyagaki H, Yan X, Hearth SAC, Njoh L, Cekic V, Whelan RL. Plasma chitinase 3-like 1 is persistently elevated during first month after minimally invasive colorectal cancer resection. World J Gastrointest Oncol 2016; 8:607-614. [PMID: 27574553 PMCID: PMC4980651 DOI: 10.4251/wjgo.v8.i8.607] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 03/03/2016] [Accepted: 06/03/2016] [Indexed: 02/05/2023] Open
Abstract
AIM: To assess blood chitinase 3-like 1 (CHi3L1) levels for 2 mo after minimally invasive colorectal resection (MICR) for colorectal cancer (CRC).
METHODS: CRC patients in an Institutional Review Board approved data/plasma bank who underwent elective MICR for whom preoperative (PreOp), early postoperative (PostOp), and 1 or more late PostOp samples [postoperative day (POD) 7-27] available were included. Plasma CHi3L1 levels (ng/mL) were determined in duplicate by enzyme linked immunosorbent assay.
RESULTS: PreOp and PostOp plasma sample were available for 80 MICR cancer patients for the study. The median PreOp CHi3L1 level was 56.8 CI: 41.9-78.6 ng/mL (n = 80). Significantly elevated (P < 0.001) median plasma levels (ng/mL) over PreOp levels were detected on POD1 (667.7 CI: 495.7, 771.7; n = 79), POD 3 (132.6 CI: 95.5, 173.7; n = 76), POD7-13 (96.4 CI: 67.7, 136.9; n = 62), POD14-20 (101.4 CI: 80.7, 287.4; n = 22), and POD 21-27 (98.1 CI: 66.8, 137.4; n = 20, P = 0.001). No significant difference in plasma levels were noted on POD27-41.
CONCLUSION: Plasma CHi3L1 levels were significantly elevated for one month after MICR. Persistently elevated plasma CHi3L1 may support the growth of residual tumor and metastasis.
Collapse
|
|
23
|
Kornblit B, Wang T, Lee SJ, Spellman SR, Zhu X, Fleischhauer K, Müller C, Verneris MR, Müller K, Johansen JS, Vindelov L, Garred P. YKL-40 in allogeneic hematopoietic cell transplantation after AML and myelodysplastic syndrome. Bone Marrow Transplant 2016; 51:1556-1560. [PMID: 27427920 DOI: 10.1038/bmt.2016.192] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Revised: 06/09/2016] [Accepted: 06/13/2016] [Indexed: 11/09/2022]
Abstract
YKL-40, also called chitinase-3-like-1 protein, is an inflammatory biomarker that has been associated with disease severity in inflammatory and malignant diseases, including AML, multiple myeloma and lymphomas. The objective of the current study was to assess the prognostic value of pretransplant recipient and donor plasma YKL-40 concentrations in patients with AML (n=624) or myelodysplastic syndrome (n=157) treated with allogeneic hematopoietic cell transplantation (HCT). In recipients, the plasma YKL-40 concentrations were increased when the HCT-comorbidity index was ⩾5 (P=0.028). There were no significant associations between plasma YKL-40 concentrations in recipients and any outcome measures. In donors with YKL-40 plasma concentrations above the age-adjusted 95th percentile, a trend toward increased grade II-IV acute GvHD in recipients was observed (adjusted hazard ratio 1.39 (95% confidence interval 1.00-1.94), P=0.050), with no significant associations with overall survival, treatment-related mortality or relapse. In conclusion, our study shows that YKL-40 does not aid risk stratification of patients undergoing allogeneic HCT, but suggests that YKL-40 may aid donor selection when multiple, otherwise equal, donors are available.
Collapse
Affiliation(s)
- B Kornblit
- The Allogeneic Hematopoietic Cell Transplantation Laboratory, Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - T Wang
- Division of Biostatistics, Institute for Health & Society, Medical College of Wisconsin, Milwaukee, WI, USA.,Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA
| | - S J Lee
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA
| | - S R Spellman
- Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA
| | - X Zhu
- Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA
| | - K Fleischhauer
- Institute for Experimental Cellular Therapy, Universitatsklinikum Essen KMT, Essen, Germany
| | - C Müller
- Zentrales Knochenmarkspender-Register Deutschland, Ulm, Germany
| | - M R Verneris
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
| | - K Müller
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - J S Johansen
- Department of Oncology and Medicine, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - L Vindelov
- The Allogeneic Hematopoietic Cell Transplantation Laboratory, Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - P Garred
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Laboratory of Molecular Medicine, Department of Clinical Immunology - Section 7631, Rigshospitalet, Copenhagen, Denmark
| |
Collapse
|
|
24
|
Duraković N, Krečak I, Perić Z, Milošević M, Desnica L, Pulanić D, Pusic I, Kušec V, Vrhovac R, Pavletic SZ, Nemet D. Glycoprotein YKL-40: a novel biomarker of chronic graft-vs-host disease activity and severity? Croat Med J 2016; 57:239-46. [PMID: 27374825 PMCID: PMC4937225 DOI: 10.3325/cmj.2016.57.239] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
AIM To investigate whether increased YKL-40 levels positively correlate with graft-vs-host disease (cGVHD) activity and severity and if YKL-40 could serve as a disease biomarker. METHODS This case-control study was conducted at the University Hospital Centre Zagreb from July 2013 to October 2015. 56 patients treated with hematopoietic stem cell transplantation (HSCT) were included: 35 patients with cGVHD and 21 without cGVHD. There was no difference between groups in age, sex, median time from transplant to study enrollment, intensity of conditioning, type of donor, or source of stem cells. Blood samples were collected at study enrollment and YKL-40 levels were measured with ELISA. Disease activity was estimated using Clinician's Impression of Activity and Intensity of Immunosuppression scales and disease severity using Global National Institutes of Health (NIH) score. RESULTS YKL-40 levels were significantly higher in cGVHD patients than in controls (P=0.003). The difference remained significant when patients with myelofibrosis were excluded from the analysis (P=0.017). YKL-40 level significantly positively correlated with disease severity (P<0.001; correlation coefficient 0.455), and activity estimated using Clinician's Impression of Activity (P=0.016; correlation coefficient 0.412) but not using Intensity of Immunosuppression (P=0.085; correlation coefficient 0.296). CONCLUSION YKL-40 could be considered a biomarker of cGVHD severity and activity. However, validation in a larger group of patients is warranted, as well as longitudinal testing of YKL-40 levels in patients at risk of developing cGVHD.
Collapse
Affiliation(s)
- Nadira Duraković
- Nadira Duraković, University Hospital Centre Zagreb, Dept of Internal Medicine, Division of Hematology, Kišpatićeva 12, 10000 Zagreb, Croatia,
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Kemik P, Saatli B, Yıldırım N, Kemik VD, Deveci B, Terek MC, Koçtürk S, Koyuncuoğlu M, Saygılı U. Diagnostic and prognostic values of preoperative serum levels of YKL-40, HE-4 and DKK-3 in endometrial cancer. Gynecol Oncol 2015; 140:64-9. [PMID: 26607777 DOI: 10.1016/j.ygyno.2015.11.020] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 11/10/2015] [Accepted: 11/18/2015] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The objective of this study is to determine the efficiency of YKL-40, HE-4 and DKK-3 levels in early diagnosis of patients with endometrial cancer and in the pre-operative estimation of the prognostic parameters such as stage, grade and the extension of the disease. METHODS In this prospective study, 50 patients diagnosed with endometrial cancer and 50 women as a control group, who applied to Dokuz Eylul University and Ege University Faculties of Medicine, Obstetrics and Gynecology Clinics between May 2011-May 2012 were included. CA125, HE-4, YKL-40 and DKK-3 serum levels were measured by ELISA and compared between two groups. The relation between serum levels and histopathological results, extension of disease and prognostic factors were analyzed. RESULTS Preoperative serum CA125, HE-4 and YKL-40 levels were significantly higher in endometrial cancer group (p<0.001). Serum HE-4 levels were significantly higher in advanced stages (p=0.004). When we examined early stage patients, YKL-40 levels were significantly higher in non-endometrioid histology compared with endometrioid adenocarcinoma (p=0.022). We also examined the relation between the markers and prognostic factors. Different from other markers, HE-4 levels were significantly higher in endometrial cancer patients who had lymphovascular space involvement, lower uterine segment involvement, endocervical stromal involvement, and deep myometrial invasion. CONCLUSION YKL-40 and HE-4 were significantly higher in patients with endometrial cancer. HE-4 seems to be superior to YKL-40 in discriminating early and advanced stages. Additionally, HE4 is significantly correlated with prognostic factors. HE-4 and YKL-40 may be successful in early determination of endometrial cancer and in detection of high risk subsets before surgery.
Collapse
Affiliation(s)
- Pınar Kemik
- Fatma Hatun Hospital, Department of Obstetrics and Gynecology, Bolu, Turkey.
| | - Bahadır Saatli
- Dokuz Eylül University, Faculty of Medicine, Department of Obstetrics and Gynecology, Izmir, Turkey.
| | - Nuri Yıldırım
- Ege University, Faculty of Medicine, Department of Obstetrics and Gynecology, Izmir, Turkey.
| | - Vahit Doğu Kemik
- Cagsu Hospital, Department of Obstetrics and Gynecology, Bolu, Turkey.
| | - Banu Deveci
- Buca Children and Women Hospital, Department of Biochemistry, Izmir, Turkey.
| | - Mustafa Coşan Terek
- Ege University, Faculty of Medicine, Department of Obstetrics and Gynecology, Izmir, Turkey.
| | - Semra Koçtürk
- Dokuz Eylül University, Faculty of Medicine, Department of Biochemistry, Izmir, Turkey.
| | - Meral Koyuncuoğlu
- Dokuz Eylül University, Faculty of Medicine, Department of Pathology, Izmir, Turkey.
| | - Uğur Saygılı
- Dokuz Eylül University, Faculty of Medicine, Department of Obstetrics and Gynecology, Izmir, Turkey.
| |
Collapse
|
|
26
|
CHI3L1 nuclear localization in monocyte derived dendritic cells. Immunobiology 2015; 221:347-56. [PMID: 26466985 DOI: 10.1016/j.imbio.2015.09.023] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 09/03/2015] [Accepted: 09/30/2015] [Indexed: 02/07/2023]
Abstract
Chitinase-3-like-1 protein (CHI3L1) is a glycosyl hydrolase (GH) highly expressed in a variety of inflammatory diseases at infectious and non-infectious etiology. CHI3L1 is produced by a wide variety of cells including monocyte-derived macrophages cell lines such as polarized M1 and M2 type macrophages, osteoclasts and Kupffer cells. In this study we have examined the expression of CHI3L1 during the differentiation and maturation of dendritic cells. Magnetically-isolated peripheral blood monocytes were differentiated toward immature DCs (iDC) and mature DCs (mDCs) through a combination of factors and cytokines. Our result showed, for the first time, that CHI3L1 is expressed during the process of differentiation and maturation of dendritic cells in time dependent manner. Furthermore, the CHI3L1 is evenly distributed in cytoplasm and in the nucleus of both the iDCs and mDCs. These results suggest that CHI3L1 may play crucial role in the DCs immunoresponse.
Collapse
|
|
27
|
Jeet V, Tevz G, Lehman M, Hollier B, Nelson C. Elevated YKL40 is associated with advanced prostate cancer (PCa) and positively regulates invasion and migration of PCa cells. Endocr Relat Cancer 2014; 21:723-37. [PMID: 24981110 PMCID: PMC4134518 DOI: 10.1530/erc-14-0267] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Chitinase 3-like 1 (CHI3L1 or YKL40) is a secreted glycoprotein highly expressed in tumours from patients with advanced stage cancers, including prostate cancer (PCa). The exact function of YKL40 is poorly understood, but it has been shown to play an important role in promoting tumour angiogenesis and metastasis. The therapeutic value and biological function of YKL40 are unknown in PCa. The objective of this study was to examine the expression and function of YKL40 in PCa. Gene expression analysis demonstrated that YKL40 was highly expressed in metastatic PCa cells when compared with less invasive and normal prostate epithelial cell lines. In addition, the expression was primarily limited to androgen receptor-positive cell lines. Evaluation of YKL40 tissue expression in PCa patients showed a progressive increase in patients with aggressive disease when compared with those with less aggressive cancers and normal controls. Treatment of LNCaP and C4-2B cells with androgens increased YKL40 expression, whereas treatment with an anti-androgen agent decreased the gene expression of YKL40 in androgen-sensitive LNCaP cells. Furthermore, knockdown of YKL40 significantly decreased invasion and migration of PCa cells, whereas overexpression rendered them more invasive and migratory, which was commensurate with an enhancement in the anchorage-independent growth of cells. To our knowledge, this study characterises the role of YKL40 for the first time in PCa. Together, these results suggest that YKL40 plays an important role in PCa progression and thus inhibition of YKL40 may be a potential therapeutic strategy for the treatment of PCa.
Collapse
Affiliation(s)
- Varinder Jeet
- Australian Prostate Cancer Research Centre - QueenslandInstitute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, AustraliaDepartment of Urologic SciencesVancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada
| | - Gregor Tevz
- Australian Prostate Cancer Research Centre - QueenslandInstitute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, AustraliaDepartment of Urologic SciencesVancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada
| | - Melanie Lehman
- Australian Prostate Cancer Research Centre - QueenslandInstitute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, AustraliaDepartment of Urologic SciencesVancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, CanadaAustralian Prostate Cancer Research Centre - QueenslandInstitute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, AustraliaDepartment of Urologic SciencesVancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada
| | - Brett Hollier
- Australian Prostate Cancer Research Centre - QueenslandInstitute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, AustraliaDepartment of Urologic SciencesVancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada
| | - Colleen Nelson
- Australian Prostate Cancer Research Centre - QueenslandInstitute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, AustraliaDepartment of Urologic SciencesVancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, CanadaAustralian Prostate Cancer Research Centre - QueenslandInstitute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, AustraliaDepartment of Urologic SciencesVancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada
| |
Collapse
|
|
28
|
Kros JM, Mustafa DM, Dekker LJM, Sillevis Smitt PAE, Luider TM, Zheng PP. Circulating glioma biomarkers. Neuro Oncol 2014; 17:343-60. [PMID: 25253418 DOI: 10.1093/neuonc/nou207] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Accepted: 07/13/2014] [Indexed: 02/06/2023] Open
Abstract
Validated biomarkers for patients suffering from gliomas are urgently needed for standardizing measurements of the effects of treatment in daily clinical practice and trials. Circulating body fluids offer easily accessible sources for such markers. This review highlights various categories of tumor-associated circulating biomarkers identified in blood and cerebrospinal fluid of glioma patients, including circulating tumor cells, exosomes, nucleic acids, proteins, and oncometabolites. The validation and potential clinical utility of these biomarkers is briefly discussed. Although many candidate circulating protein biomarkers were reported, none of these have reached the required validation to be introduced for clinical practice. Recent developments in tracing circulating tumor cells and their derivatives as exosomes and circulating nuclear acids may become more successful in providing useful biomarkers. It is to be expected that current technical developments will contribute to the finding and validation of circulating biomarkers.
Collapse
Affiliation(s)
- Johan M Kros
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., P.-P.Z.); Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands (L.J.M.D., P.A.E.S.S., T.M.L.); Brain Tumor Center Rotterdam, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., L.J.M.D., P.A.E.S.S., T.M.L., P.-P.Z.)
| | - Dana M Mustafa
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., P.-P.Z.); Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands (L.J.M.D., P.A.E.S.S., T.M.L.); Brain Tumor Center Rotterdam, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., L.J.M.D., P.A.E.S.S., T.M.L., P.-P.Z.)
| | - Lennard J M Dekker
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., P.-P.Z.); Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands (L.J.M.D., P.A.E.S.S., T.M.L.); Brain Tumor Center Rotterdam, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., L.J.M.D., P.A.E.S.S., T.M.L., P.-P.Z.)
| | - Peter A E Sillevis Smitt
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., P.-P.Z.); Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands (L.J.M.D., P.A.E.S.S., T.M.L.); Brain Tumor Center Rotterdam, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., L.J.M.D., P.A.E.S.S., T.M.L., P.-P.Z.)
| | - Theo M Luider
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., P.-P.Z.); Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands (L.J.M.D., P.A.E.S.S., T.M.L.); Brain Tumor Center Rotterdam, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., L.J.M.D., P.A.E.S.S., T.M.L., P.-P.Z.)
| | - Ping-Pin Zheng
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., P.-P.Z.); Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands (L.J.M.D., P.A.E.S.S., T.M.L.); Brain Tumor Center Rotterdam, Erasmus Medical Center, Rotterdam, The Netherlands (J.M.K., D.M.M., L.J.M.D., P.A.E.S.S., T.M.L., P.-P.Z.)
| |
Collapse
|
|
29
|
Libreros S, Garcia-Areas R, Iragavarapu-Charyulu V. CHI3L1 plays a role in cancer through enhanced production of pro-inflammatory/pro-tumorigenic and angiogenic factors. Immunol Res 2014; 57:99-105. [PMID: 24222276 DOI: 10.1007/s12026-013-8459-y] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Elevated serum levels of a glycoprotein known as chitinase-3-like protein 1 (CHI3L1) have been correlated with poor prognosis and shorter survival of patients with cancer and inflammatory diseases. The biological and physiological functions of CHI3L1 in cancer have not yet been completely elucidated. In this review, we describe the role of CHI3L1 in inducing pro-inflammatory/pro-tumorigenic and angiogenic factors that could promote tumor growth and metastasis.
Collapse
Affiliation(s)
- Stephania Libreros
- Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA
| | | | | |
Collapse
|
|
30
|
Andersen CL, Bjørn ME, McMullin MF, Harrison C, Samuelsson J, Ejerblad E, Zweegman S, Fernandes S, Bareford D, Knapper S, Löfvenberg E, Linder O, Andreasson B, Ahlstrand E, Jensen MK, Bjerrum OW, Vestergaard H, Larsen H, Klausen TW, Mourits-Andersen T, Skov V, Thomassen M, Kruse T, Grønbæk K, Hasselbalch HC. Circulating YKL-40 in patients with essential thrombocythemia and polycythemia vera treated with the novel histone deacetylase inhibitor vorinostat. Leuk Res 2014; 38:816-21. [DOI: 10.1016/j.leukres.2014.04.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 04/02/2014] [Accepted: 04/04/2014] [Indexed: 11/26/2022]
|
|
31
|
Bjørn ME, Andersen CL, Jensen MK, Hasselbalch HC. Circulating YKL-40 in myelofibrosis a potential novel biomarker of disease activity and the inflammatory state. Eur J Haematol 2014; 93:224-8. [DOI: 10.1111/ejh.12332] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2014] [Indexed: 01/12/2023]
Affiliation(s)
- Mads Emil Bjørn
- Institute for Inflammation Research; Department of Infectious Diseases and Rheumatology; Copenhagen University Hospital; Rigshospitalet Denmark
| | | | - Morten Krogh Jensen
- Department of Hematology; Århus Hospital; Århus University Hospital; Århus Denmark
| | - Hans C. Hasselbalch
- Department of Hematology; Roskilde Hospital; Copenhagen University Hospital; Roskild Denmark
| |
Collapse
|
|
32
|
Shao R. YKL-40 acts as an angiogenic factor to promote tumor angiogenesis. Front Physiol 2013; 4:122. [PMID: 23755018 PMCID: PMC3664773 DOI: 10.3389/fphys.2013.00122] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Accepted: 05/10/2013] [Indexed: 01/28/2023] Open
Abstract
A secreted glycoprotein YKL-40 also named chitinase-3-like-1 is normally expressed by multiple cell types such as macrophages, chondrocytes, and vascular smooth muscle cells. However, a prominently high level of YKL-40 was found in a wide spectrum of human diseases including cancers and chronic inflammatory diseases where it was strongly expressed by cancerous cells and infiltrating macrophages. Here, we summarized recent important findings of YKL-40 derived from cancerous cells and smooth muscle cells during tumor angiogenesis and development. YKL-40 is a potent angiogenic factor capable of stimulating tumor vascularization mediated by endothelial cells and maintaining vascular integrity supported by smooth muscle cells. In addition, YKL-40 induces FAK-MAPK signaling and up-regulates VEGF receptor 2 in endothelial cells; but a neutralizing antibody (mAY) against YKL-40 inhibits its angiogenic activity. While YKL-40 is essential for angiogenesis, little is known about its functional role in tumor-associated macrophage (TAM)-mediated tumor development. Therefore, significant efforts are urgently needed to identify pathophysiological function of YKL-40 in the dynamic interaction between tumor cells and TAMs in the tumor microenvironment, which may offer substantial mechanistic insights into tumor angiogenesis and metastasis, and also point to a therapeutic target for treatment of cancers and other diseases.
Collapse
Affiliation(s)
- Rong Shao
- Molecular and Cellular Biology Program, Morrill Science Center, University of Massachusetts Amherst, MA, USA ; Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, MA, USA
| |
Collapse
|
|
33
|
Francescone R, Ngernyuang N, Yan W, Bentley B, Shao R. Tumor-derived mural-like cells coordinate with endothelial cells: role of YKL-40 in mural cell-mediated angiogenesis. Oncogene 2013; 33:2110-22. [PMID: 23665676 PMCID: PMC3926897 DOI: 10.1038/onc.2013.160] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2012] [Revised: 03/08/2013] [Accepted: 03/14/2013] [Indexed: 12/23/2022]
Abstract
Tumor neo-vasculature is characterized by spatial coordination of endothelial cells with mural cells, which delivers oxygen and nutrients. Here, we explored a key role of the secreted glycoprotein YKL-40, a mesenchymal marker, in the interaction between endothelial cells and mesenchymal mural-like cells for tumor angiogenesis. Xenotransplantation of tumor-derived mural-like cells (GSDCs) expressing YKL-40 in mice developed extensive and stable blood vessels covered with more GSDCs than those in YKL-40 gene knockdown tumors. YKL-40 expressed by GSDCs was associated with increased interaction of neural cadherin/β-catenin/smooth muscle alpha actin; thus, mediating cell-cell adhesion and permeability. YKL-40 also induced the interaction of vascular endothelial cadherin/β-catenin/actin in endothelial cells (HMVECs). In cell co-culture systems, YKL-40 enhanced both GSDC and HMVEC contacts, restricted vascular leakage, and stabilized vascular networks. Collectively, the data inform new mechanistic insights into the cooperation of mural cells with endothelial cells induced by YKL-40 during tumor angiogenesis, and also enhance our understanding of YKL-40 in both mural and endothelial cell biology.
Collapse
Affiliation(s)
- R Francescone
- Molecular and Cellular Biology Program, Morrill Science Center, University of Massachusetts, Amherst, MA, USA
| | - N Ngernyuang
- Graduate School, Khon Khaen University, Khon Khaen, Thailand
| | - W Yan
- Pioneer Valley Life Sciences Institute, Springfield, MA, USA
| | - B Bentley
- Pioneer Valley Life Sciences Institute, Springfield, MA, USA
| | - R Shao
- 1] Molecular and Cellular Biology Program, Morrill Science Center, University of Massachusetts, Amherst, MA, USA [2] Pioneer Valley Life Sciences Institute, Springfield, MA, USA [3] Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, USA
| |
Collapse
|
|
34
|
Sanchez-Correa B, Bergua JM, Campos C, Gayoso I, Arcos MJ, Bañas H, Morgado S, Casado JG, Solana R, Tarazona R. Cytokine profiles in acute myeloid leukemia patients at diagnosis: Survival is inversely correlated with IL-6 and directly correlated with IL-10 levels. Cytokine 2013; 61:885-91. [DOI: 10.1016/j.cyto.2012.12.023] [Citation(s) in RCA: 152] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2012] [Revised: 12/19/2012] [Accepted: 12/22/2012] [Indexed: 11/27/2022]
|
|
35
|
Kastrup J. Can YKL-40 be a new inflammatory biomarker in cardiovascular disease? Immunobiology 2012; 217:483-91. [DOI: 10.1016/j.imbio.2011.04.007] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2010] [Revised: 02/08/2011] [Accepted: 04/21/2011] [Indexed: 12/28/2022]
|
|
36
|
Inhibitory activity of YKL-40 in mammary epithelial cell differentiation and polarization induced by lactogenic hormones: a role in mammary tissue involution. PLoS One 2011; 6:e25819. [PMID: 21991364 PMCID: PMC3185048 DOI: 10.1371/journal.pone.0025819] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2011] [Accepted: 09/11/2011] [Indexed: 12/11/2022] Open
Abstract
We previously reported that a secreted glycoprotein YKL-40 acts as an angiogenic factor to promote breast cancer angiogenesis. However, its functional role in normal mammary gland development is poorly understood. Here we investigated its biophysiological activity in mammary epithelial development and mammary tissue morphogenesis. YKL-40 was expressed exclusively by ductal epithelial cells of parous and non-parous mammary tissue, but was dramatically up-regulated at the beginning of involution. To mimic ductal development and explore activity of elevated YKL-40 during mammary tissue regression in vivo, we grew a mammary epithelial cell line 76N MECs in a 3-D Matrigel system in the presence of lactogenic hormones including prolactin, hydrocortisone, and insulin. Treatment of 76N MECs with recombinant YKL-40 significantly inhibited acinar formation, luminal polarization, and secretion. YKL-40 also suppressed expression of E-cadherin but increased MMP-9 and cell motility, the crucial mechanisms that mediate mammary tissue remodeling during involution. In addition, engineering of 76N MECs with YKL-40 gene to express ectopic YKL-40 recapitulated the same activities as recombinant YKL-40 in the inhibition of cell differentiation. These results suggest that YKL-40-mediated inhibition of cell differentiation and polarization in the presence of lactogenic hormones may represent its important function during mammary tissue involution. Identification of this biophysiological property will enhance our understanding of its pathologic role in the later stage of breast cancer that is developed from poorly differentiated and highly invasive cells.
Collapse
|
|
37
|
Breast cancer expression of YKL-40 correlates with tumour grade, poor differentiation, and other cancer markers. Br J Cancer 2011; 105:1203-9. [PMID: 21934681 PMCID: PMC3208489 DOI: 10.1038/bjc.2011.347] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Background: Serum levels of a secreted glycoprotein YKL-40 are elevated in patients with a wide range of cancers including breast, colorectal, and ovarian cancers. Furthermore, these increased levels correlate with poorer survival of cancer patients, suggesting that serum levels of YKL-40 might be a prognostic biomarker. However, the tissue expression of YKL-40 and its relationship with clinical outcomes and other potential markers are poorly understood. Methods: Tissue samples from invasive breast cancers, breast ductal carcinoma in situ (DCIS), and cancer-free reduction mammoplasty were enrolled. YKL-40 expression was measured using immunohistochemistry and evaluated by a semi-quantification assay. Statistical analyses explored the relationship of YKL-40 with clinical outcome and other breast cancer biomarkers. Results: Breast ductal carcinoma in situ expressed low and moderate levels of YKL-40. In the subset of 203 patients with invasive cancer, YKL-40 levels were positively correlated with tumour grade (P<0.0001) and Her2/neu (P<0.01), but negatively correlated with oestrogen (P<0.0001) and progesterone receptor (P<0.0001). YKL-40 levels were inversely correlated with expressions of GATA3 (P=0.0137) and E-cadherin (P=0.0417). Conclusion: These data demonstrate that expression levels of YKL-40 are associated with tumour grade, poor differentiation, and other breast cancer markers, highlighting that tissue levels of YKL-40 serve as a valuable biomarker for breast cancer diagnosis and prognosis.
Collapse
|
|
38
|
Iwamoto FM, Hottinger AF, Karimi S, Riedel E, Dantis J, Jahdi M, Panageas KS, Lassman AB, Abrey LE, Fleisher M, DeAngelis LM, Holland EC, Hormigo A. Serum YKL-40 is a marker of prognosis and disease status in high-grade gliomas. Neuro Oncol 2011; 13:1244-51. [PMID: 21831900 DOI: 10.1093/neuonc/nor117] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The objective of this study was to evaluate whether longitudinal levels of serum YKL-40 correlate with disease status or survival in adults with gliomas. Patients with histologically confirmed gliomas were eligible for this longitudinal study. Serum samples were collected prospectively and concurrently with MRI scans at multiple time points during the course of the disease. YKL-40 levels determined by ELISA were correlated with radiographic disease status and survival. We performed a multivariate survival analysis including well-known prognostic factors such as age, performance status, and extent of surgical resection. Three hundred and forty-three patients with gliomas (41 low-grade, 105 anaplastic, and 197 glioblastoma) were accrued. Two-year survival from registration was 29% for glioblastomas, 62% for anaplastic gliomas, and 83% for low-grade gliomas. A total of 1740 serum samples were collected, and 95.6% of samples had matching MRI scans. Serum YKL-40 level was significantly lower in patients with no radiographic disease compared with patients with radiographic disease in both the anaplastic glioma (P= .0008) and the glioblastoma (P= .0006) cohorts. Serum levels of YKL-40 in patients with low-grade gliomas were not associated with radiographic disease status. Increases in YKL-40 were independently associated with worse survival in anaplastic gliomas (hazard ratio [HR] = 1.4, P= .01) and glioblastomas (HR = 1.4, P< .0001). Longitudinal increases in serum YKL-40 are associated with increased risk of death in patients with glioblastomas and anaplastic gliomas. YKL-40 is also a putative indicator of disease status in these patients.
Collapse
Affiliation(s)
- Fabio M Iwamoto
- The Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Stawerski P, Wągrowska-Danilewicz M, Stasikowska-Kanicka O, Danilewicz M. Increased tissue immunoexpression of YKL-40 protein in high grade serous ovarian cancers. Pathol Res Pract 2011; 207:573-6. [PMID: 21820815 DOI: 10.1016/j.prp.2011.06.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2011] [Revised: 06/06/2011] [Accepted: 06/15/2011] [Indexed: 12/01/2022]
Abstract
YKL-40 is a glycoprotein secreted by numerous human cells, such as cartilage, synovial, and endothelial cells. The biological role of YKL-40 has not yet been fully unveiled, however, its participation is perceived in angiogenesis, growth, proliferation, differentiation, and remodeling processes. The primary goal of our study was to evaluate possible differences in tissue immunoexpression of YKL-40, assumed between high grade and low-grade ovarian cancers and between the above-mentioned cancer types and benign lesions. Another purpose was to find out whether immunoexpression of the studied protein could correlate with the tumor proliferation process, evaluated by Ki-67 immunoexpression. The analysis comprised 45 women, diagnosed and treated for epithelial ovarian tumors at the Medical University of Lodz between 1997 and 2002. YKL-40 protein immunoexpression was semiquantitatively assessed, whereas immunoexpression of Ki-67 was evaluated using a computer image analysis system. Significantly higher immunoexpression values of both examined proteins were observed in high-grade serous ovarian cancers vs. low-grade and benign tumors. Moreover, a significant positive correlation was identified between the immunoexpressions of YKL-40 and Ki-67 proteins in the studied groups of tumors. In conclusion, the obtained data suggest an overt prominence of TKL-40 tissue immunoexpression of YKL-40 in high-grade serous ovarian tumors, which could then be approached as a helpful, additional marker to identify more aggressive ovarian cancers.
Collapse
Affiliation(s)
- Paweł Stawerski
- Department of Nephropathology, Medical University of Lodz, ul. Pomorska 251, 92-213 Lodz, Poland.
| | | | | | | |
Collapse
|
|
40
|
Itik V, Kemik O, Kemik A, Dulger AC, Sümer A, Soyoral YU, Begenik H, Purisa S, Kotan C. Serum YKL-40 Levels in Patients with Gastric Cancer. BIOMARKERS IN CANCER 2011; 3:25-30. [PMID: 24179388 PMCID: PMC3791919 DOI: 10.4137/bic.s7154] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Aims and background YKL-40 is secreted by several types of tumors. Increased serum YKL-40 levels have been reported in prostate, glioblastoma, breast and colorectal cancers. Determination of YKL-40 levels may serve as a valuable biomarker for the diagnosis and treatment of gastric cancer. The purpose of this study was to determine the serum YKL-40 levels expressed in gastric carcinomas. Methods Between 2009 and 2011, we retrospectively reviewed 100 patients with gastric cancer and compared their serum samples to 75 healthy volunteers. YKL-40 levels were determined by an enzyme-linked immunosorbent assay (ELISA). Results We found significantly higher serum levels of YKL-40 in patients with gastric cancer compared to the healthy population (P < 0.0001). We also found significant differences in serum YKL-40 levels between female and male patients with gastric cancer (P < 0.01). Conclusions YKL-40 is over-expressed in gastric cancer, suggesting a more aggressive phenotype. YKL-40 may be a useful serum biomarker for gastric cancer identification, and future studies should focus on the role of YKL-40 in the tumorigenesis of gastric cancer and responsiveness toward treatment.
Collapse
Affiliation(s)
- Veyis Itik
- Department of General Surgery, Yuzuncu Yil University Medical Faculty, Van, Turkey
| | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Faibish M, Francescone R, Bentley B, Yan W, Shao R. A YKL-40-neutralizing antibody blocks tumor angiogenesis and progression: a potential therapeutic agent in cancers. Mol Cancer Ther 2011; 10:742-51. [PMID: 21357475 PMCID: PMC3091949 DOI: 10.1158/1535-7163.mct-10-0868] [Citation(s) in RCA: 129] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Accumulating evidence has indicated that expression levels of YKL-40, a secreted glycoprotein, were elevated in multiple advanced human cancers. Recently, we have identified an angiogenic role of YKL-40 in cancer development. However, blockade of the function of YKL-40, which implicates therapeutic value, has not been explored yet. Our current study sought to establish a monoclonal anti-YKL-40 antibody as a neutralizing antibody for the purpose of blocking tumor angiogenesis and metastasis. A mouse monoclonal anti-YKL-40 antibody (mAY) exhibited specific binding with recombinant YKL-40 and with YKL-40 secreted from osteoblastoma cells MG-63 and brain tumor cells U87. In the functional analysis, we found that mAY inhibited tube formation of microvascular endothelial cells in Matrigel induced by conditioned medium of MG-63 and U87 cells, as well as recombinant YKL-40. mAY also abolished YKL-40-induced activation of the membrane receptor VEGF receptor 2 (Flk-1/KDR) and intracellular signaling mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (Erk) 1 and Erk 2. In addition, mAY enhanced cell death response of U87 line to γ-irradiation through decreased expression of pAKT and AKT and accordingly, abrogated angiogenesis induced by the conditioned medium of U87 cells in which YKL-40 levels were elevated by treatment with γ-irradiation. Furthermore, treatment of xenografted tumor mice with mAY restrained tumor growth, angiogenesis, and progression. Taken together, this study has shown the therapeutic use for the mAY in treatment of tumor angiogenesis and metastasis.
Collapse
MESH Headings
- Adipokines
- Angiogenesis Inhibitors/pharmacology
- Animals
- Antibodies, Neutralizing/metabolism
- Antibodies, Neutralizing/pharmacology
- Antineoplastic Agents/pharmacology
- Cell Death/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Chitinase-3-Like Protein 1
- Disease Progression
- Endothelial Cells/metabolism
- Gene Expression Regulation, Neoplastic
- Glycoproteins/genetics
- Glycoproteins/immunology
- Glycoproteins/metabolism
- Humans
- Lectins/genetics
- Lectins/immunology
- Lectins/metabolism
- Mice
- Mice, SCID
- Neoplasms/pathology
- Neoplasms/therapy
- Neovascularization, Pathologic/pathology
- RNA Interference
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors
- Receptors, Vascular Endothelial Growth Factor/metabolism
- Signal Transduction/drug effects
- Xenograft Model Antitumor Assays
Collapse
Affiliation(s)
- Michael Faibish
- Molecular and Cellular Biology Program, Morrill Science Center, University of Massachusetts, Amherst, MA 01003
| | - Ralph Francescone
- Molecular and Cellular Biology Program, Morrill Science Center, University of Massachusetts, Amherst, MA 01003
| | - Brooke Bentley
- Pioneer Valley Life Sciences Institute, 3601 Main Street, Springfield, MA 01199
| | - Wei Yan
- Pioneer Valley Life Sciences Institute, 3601 Main Street, Springfield, MA 01199
| | - Rong Shao
- Molecular and Cellular Biology Program, Morrill Science Center, University of Massachusetts, Amherst, MA 01003
- Pioneer Valley Life Sciences Institute, 3601 Main Street, Springfield, MA 01199
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003
| |
Collapse
|
|
42
|
Francescone RA, Scully S, Faibish M, Taylor SL, Oh D, Moral L, Yan W, Bentley B, Shao R. Role of YKL-40 in the angiogenesis, radioresistance, and progression of glioblastoma. J Biol Chem 2011; 286:15332-43. [PMID: 21385870 PMCID: PMC3083166 DOI: 10.1074/jbc.m110.212514] [Citation(s) in RCA: 204] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2010] [Revised: 02/28/2011] [Indexed: 01/17/2023] Open
Abstract
Glioblastoma is one of the most fatal cancers, characterized by a strong vascularized phenotype. YKL-40, a secreted glycoprotein, is overexpressed in patients with glioblastomas and has potential as a novel tumor biomarker. The molecular mechanisms of YKL-40 in glioblastoma development, however, are poorly understood. Here, we aimed to elucidate the role YKL-40 plays in the regulation of VEGF expression, tumor angiogenesis, and radioresistance. YKL-40 up-regulated VEGF expression in glioblastoma cell line U87, and both YKL-40 and VEGF synergistically promote endothelial cell angiogenesis. Interestingly, long term inhibition of VEGF up-regulated YKL-40. YKL-40 induced coordination of membrane receptor syndecan-1 and integrin αvβ5, and triggered a signaling cascade through FAK(397) to ERK-1 and ERK-2, leading to elevated VEGF and enhanced angiogenesis. In addition, γ-irradiation of U87 cells increased YKL-40 expression that protects cell death through AKT activation and also enhances endothelial cell angiogenesis. Blockade of YKL-40 activity or expression decreased tumor growth, angiogenesis, and metastasis in xenografted animals. Immunohistochemical analysis of human glioblastomas revealed a correlation between YKL-40, VEGF, and patient survival. These findings have shed light on the mechanisms by which YKL-40 promotes tumor angiogenesis and malignancy, and thus provide a therapeutic target for tumor treatment.
Collapse
Affiliation(s)
| | - Steve Scully
- From the Molecular and Cellular Biology Program, Morrill Science Center, and
- the Pioneer Valley Life Sciences Institute, University of Massachusetts Amherst, Springfield, Massachusetts 01107, and
| | - Michael Faibish
- From the Molecular and Cellular Biology Program, Morrill Science Center, and
| | | | | | - Luis Moral
- Pathology, Baystate Medical Center, Tufts University, Springfield, Massachusetts 01199
| | - Wei Yan
- From the Molecular and Cellular Biology Program, Morrill Science Center, and
| | - Brooke Bentley
- the Pioneer Valley Life Sciences Institute, University of Massachusetts Amherst, Springfield, Massachusetts 01107, and
| | - Rong Shao
- From the Molecular and Cellular Biology Program, Morrill Science Center, and
- the Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, Massachusetts 01003
- the Pioneer Valley Life Sciences Institute, University of Massachusetts Amherst, Springfield, Massachusetts 01107, and
| |
Collapse
|
|
43
|
Yilmaz O, Kemik O, Kemik A, Sumer A, Dülger AC, Hasirci I, Almali N, Purisa S, Kotan Q. Serum YKL-40 Levels in Patients with Esophageal Squamous Cell Carcinoma. CANCER GROWTH AND METASTASIS 2011. [DOI: 10.4137/cgm.s7046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Aims and Background YKL-40 is a glycoprotein secreted by macrophages, neutrophils and malignant tumor cells. YKL-40 is expressed and secreted by several types of tumors. The aim of this study examined the clinical usefulness of YKL-40 for detection in esophageal squamous cell carcinoma (ESCC). Methods Using ELISA kits, we measured the concentration of YKL-40 in serum from 100 patients with ESCC and compared this concentration with healthy population. Results We found significantly higher serum levels of YKL-40 in patients with ESCC compared to the healthy population ( P < 0.0001). Conclusions These results suggested that regarding serum YKL-40 as a tumor marker could be benefical in the early clinical diagnosis.
Collapse
Affiliation(s)
- Ozkan Yilmaz
- Department of General Surgery, Medical Faculty, University of Yuzuncu Yil, Van, Turkey
| | - Ozgur Kemik
- Department of General Surgery, Medical Faculty, University of Yuzuncu Yil, Van, Turkey
| | - Ahu Kemik
- Department of Biochemistry, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey
| | - Aziz Sumer
- Department of General Surgery, Medical Faculty, University of Yuzuncu Yil, Van, Turkey
| | - A. Cumhur Dülger
- Department of Gastroenterology, Medical Faculty, University of Yüzüncü Yil, Van, Turkey
| | - Ismail Hasirci
- Department of General Surgery, Medical Faculty, University of Yuzuncu Yil, Van, Turkey
| | - Nejat Almali
- Department of General Surgery, Medical Faculty, University of Yuzuncu Yil, Van, Turkey
| | - Sevim Purisa
- Department of Biostatistics, Istanbul Medical Faculty, University of Istanbul, Istanbul, Turkey
| | - Qetin Kotan
- Department of General Surgery, Medical Faculty, University of Yuzuncu Yil, Van, Turkey
| |
Collapse
|
|
44
|
Serum YKL-40 Predicts Adverse Clinical Outcomes in Patients With Chronic Heart Failure. J Card Fail 2010; 16:873-9. [DOI: 10.1016/j.cardfail.2010.05.029] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2010] [Revised: 05/03/2010] [Accepted: 05/28/2010] [Indexed: 11/17/2022]
|
|
45
|
Thöm I, Andritzky B, Schuch G, Burkholder I, Edler L, Johansen JS, Bokemeyer C, Schumacher U, Laack E. Elevated pretreatment serum concentration of YKL-40-An independent prognostic biomarker for poor survival in patients with metastatic nonsmall cell lung cancer. Cancer 2010; 116:4114-21. [PMID: 20564116 DOI: 10.1002/cncr.25196] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND The glycoprotein YKL-40 is synthesized both by cancer cells and by tumor-associated macrophages and plays a functional role in tumor progression. Consequently, high serum YKL-40 levels have been associated with a poor prognosis in patients with several cancer types. However, the role of YKL-40 has not been established in nonsmall cell lung cancer (NSCLC). METHODS Pretreatment serum levels of YKL-40 were determined in 189 patients with NSCLC (143 men and 46 women; median age, 62 years;, age range, 41-76 years). Twelve percent of patients had stage IIIB disease, and 88% had stage IV disease. Ninety-eight patients received combined gemcitabine and vinorelbine, and 91 received combined gemcitabine, vinorelbine, and cisplatin as first-line chemotherapy. The median overall survival was 37 weeks. RESULTS Patients had a median serum YKL-40 level of 209 ng/mL (range, 19-2153 ng/mL). No correlation was observed between overall survival and the type of chemotherapy regimen used, tumor stage, sex, or histologic types. Patients with high serum YKL-40 levels (greater than the median level for all patients [209 ng/mL]) had a significantly shorter survival than patients with serum YKL-40 levels below the median (median survival, 32 weeks vs 41 weeks; P = .007). In multivariate analysis, the serum YKL-40 level, the presence of bone lesions, and the serum lactate dehydrogenase level were independent, statistically significant prognostic factors. CONCLUSIONS The pretreatment serum YKL-40 level was identified as a new, independent prognostic biomarker in patients with metastatic NSCLC and may help to determine the individual prognosis of these patients.
Collapse
Affiliation(s)
- Ina Thöm
- Department of Oncology, Hematology, and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumor Center, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Mathiasen AB, Henningsen KMA, Harutyunyan MJ, Mygind ND, Kastrup J. YKL-40: a new biomarker in cardiovascular disease? Biomark Med 2010; 4:591-600. [DOI: 10.2217/bmm.10.58] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Cardiovascular disease in the form of coronary artery disease is the most common cause of death in western countries. Early treatment with stabilizing drugs and mechanical revascularization by percutaneous coronary intervention or coronary bypass surgery has reduced the mortality significantly. But in spite of improved treatments, many patients are still plagued by a high frequency of angina symptoms, hospitalizations and a poor prognosis. There is a need for new independent or supplementary biomarkers that can help to predict cardiovascular disease and cardiovascular events earlier and more precisely, and thus accompany existing biomarkers in both primary and secondary cardiovascular prevention. One such potential new biomarker is the protein YKL-40. As an independent biomarker in both cardiovascular diseases and noncardiovascular diseases, current evidence suggests YKL-40 to be most useful as a marker of disease severity, prognosis and short survival. However, future studies will evaluate whether YKL-40 can be used for monitoring of the treatment effect in different patient populations with a distinct disease diagnosis. In this article we explore present knowledge on YKL-40 as a biomarker in cardiovascular disease.
Collapse
Affiliation(s)
- Anders Bruun Mathiasen
- Cardiac Catheterization Laboratory 2014, The Heart Centre, Rigshospitalet, Copenhagen University Hospital and Faculty of Health Sciences, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
| | - Kristoffer Mads Aaris Henningsen
- Cardiac Catheterization Laboratory 2014, The Heart Centre, Rigshospitalet, Copenhagen University Hospital and Faculty of Health Sciences, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
| | - Marina Jurjevna Harutyunyan
- Cardiac Catheterization Laboratory 2014, The Heart Centre, Rigshospitalet, Copenhagen University Hospital and Faculty of Health Sciences, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
| | - Naja Dam Mygind
- Cardiac Catheterization Laboratory 2014, The Heart Centre, Rigshospitalet, Copenhagen University Hospital and Faculty of Health Sciences, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
| | - Jens Kastrup
- Cardiac Catheterization Laboratory 2014, The Heart Centre, Rigshospitalet, Copenhagen University Hospital and Faculty of Health Sciences, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
| |
Collapse
|
|
47
|
YKL-40-A Protein in the Field of Translational Medicine: A Role as a Biomarker in Cancer Patients? Cancers (Basel) 2010; 2:1453-91. [PMID: 24281168 PMCID: PMC3837317 DOI: 10.3390/cancers2031453] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2010] [Revised: 07/01/2010] [Accepted: 07/09/2010] [Indexed: 02/07/2023] Open
Abstract
YKL-40 is a 40 kDa glycoprotein produced by cancer cells, inflammatory cells and stem cells. It probably has a role in cell proliferation and differentiation, inflammation, protection against apoptosis, stimulation of angiogenesis, and regulation of extracellular tissue remodelling. Plasma levels of YKL-40 are often elevated in patients with localized or advanced cancer compared to age-matched healthy subjects. Several studies have demonstrated that high plasma YKL-40 is an independent prognostic biomarker of short survival in patients with different types of cancer. However, there is not yet sufficient data to support determination of plasma YKL-40 outside research projects as a biomarker for screening of gastrointestinal cancer and determination of treatment response and poor prognosis before or during treatment and follow-up. Plasma YKL-40 is also elevated in patients with other diseases than cancer, e.g., severe infections, cardiovascular disease, diabetes, chronic obstructive lung disease, asthma, liver fibrosis and rheumatoid arthritis. Co-morbidity should therefore always be considered in patients with cancer, since other sources than cancer cells can increase plasma YKL-40 levels. Future focused translational research projects combining basic and clinical research are needed in a joint effort to answer questions of the complex function and regulation of YKL-40 and the question if plasma YKL-40 is a clinical useful biomarker in patients with cancer.
Collapse
|
|
48
|
Ohi K, Hashimoto R, Yasuda Y, Yoshida T, Takahashi H, Iike N, Iwase M, Kamino K, Ishii R, Kazui H, Fukumoto M, Takamura H, Yamamori H, Azechi M, Ikezawa K, Tanimukai H, Tagami S, Morihara T, Okochi M, Yamada K, Numata S, Ikeda M, Tanaka T, Kudo T, Ueno SI, Yoshikawa T, Ohmori T, Iwata N, Ozaki N, Takeda M. The chitinase 3-like 1 gene and schizophrenia: evidence from a multi-center case-control study and meta-analysis. Schizophr Res 2010; 116:126-32. [PMID: 20051317 DOI: 10.1016/j.schres.2009.12.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2009] [Revised: 10/30/2009] [Accepted: 12/03/2009] [Indexed: 01/07/2023]
Abstract
The chitinase 3-like 1 (CHI3L1) gene acts as a cellular survival factor in response to several environmental and psychosocial stresses. The expression level of CHI3L1 was increased in the hippocampus and prefrontal cortex regions of patients with schizophrenia. Genetic variants of the CHI3L1 gene have been significantly associated with schizophrenia in two distinct ethnic groups, the Chinese and Irish populations. The aims of this study are to confirm the association between the CHI3L1 gene and schizophrenia in a Japanese population using the largest sample size to date (1463 cases and 1795 controls) and perform a meta-analysis of the combined samples (3005 cases, 3825 controls and 601 trios). We found significant associations between single nucleotide polymorphism (SNP) 4/rs4950928 (p=0.009), which is located in the promoter region of the CHI3L1 gene, and haplotypes including this SNP and schizophrenia (the most significant global p<0.001). As the meta-analysis of the combined samples showed significant heterogeneity among studies of SNP3/rs10399805 (p=0.026) and SNP4 (p<0.001), we performed meta-analyses separately in the Japanese (2033 cases and 2365 controls) and Chinese populations (412 cases, 464 controls and 601 trios), the major groups analyzed in association studies of the CHI3L1 gene. The meta-analysis in Japanese populations showed stronger evidence for the association of schizophrenia with SNP4 (p=0.003), while the meta-analysis in Chinese populations showed an association with a different variant (SNP3) (p=0.003). We conclude that the genetic variants in the CHI3L1 gene have ethnic heterogeneity and confer a susceptibility to schizophrenia in Asian populations.
Collapse
Affiliation(s)
- Kazutaka Ohi
- Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Johansen JS, Schultz NA, Jensen BV. Plasma YKL-40: a potential new cancer biomarker? Future Oncol 2009; 5:1065-82. [PMID: 19792974 DOI: 10.2217/fon.09.66] [Citation(s) in RCA: 127] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
YKL-40, a 40-kDa secreted glycoprotein, with its gene located on chromosome 1q32.1, is produced by cancer cells and inflammatory cells and has a role in inflammation, cell proliferation, differentiation, protection against apoptosis, stimulation of angiogenesis and regulation of extracellular tissue remodeling. Plasma levels of YKL-40 are elevated in a subgroup of patients with primary or advanced cancer compared with age-matched healthy subjects, but also in patients with many different diseases characterized by inflammation. Elevated plasma YKL-40 levels are an independent prognostic biomarker of short survival. There is still insufficient evidence to support its value outside of clinical trials as a screening tool, prognosticator of survival, predictor of treatment response and as a monitoring tool in the routine management of individual patients with cancer or diseases characterized by inflammation. Large prospective, longitudinal clinical cancer studies are needed to determine if plasma YKL-40 is a new cancer biomarker, or is mainly a biomarker of inflammation.
Collapse
Affiliation(s)
- Julia S Johansen
- Department of Medicine O, Herlev Hospital, Herlev Ringvej 75, DK-2730, Herlev, Denmark.
| | | | | |
Collapse
|
|
50
|
Abstract
Tumor angiogenesis is of paramount importance in solid tumor development. Elevated serum levels of YKL-40, a secreted heparin-binding glycoprotein have been associated with a worse prognosis from a variety of advanced human cancers. Yet the role of YKL-40 activity in these cancers is still missing. Here, we have shown that ectopic expression of YKL-40 in MDA-MB-231 breast cancer cells and HCT-116 colon cancer cells led to larger tumor formation with an extensive angiogenic phenotype than did control cancer cells in mice. Affinity purified recombinant YKL-40 protein promoted vascular endothelial cell angiogenesis in vitro, the effects similar to the activities observed using MDA-MB-231 and HCT-116 cell conditioned medium after transfection with YKL-40. Further, YKL-40 was found to induce the coordination of membrane-bound receptor syndecan-1 and integrin αvβ3 and activate an intracellular signaling cascade including focal adhesion kinase and MAP kinase Erk1/2 in endothelial cells. Also, blockade of YKL-40 using siRNA gene knockdown suppressed tumor angiogenesis in vitro and in vivo. Immunohistochemical analysis of human breast cancer revealed a correlation between YKL-40 expression and blood vessel density. These findings provide novel insights into angiogenic activities and molecular mechanisms of YKL-40 in cancer development.
Collapse
|