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Wang CY, Wang M, Zhao CY, Zhou Q, Zhang XY, Wang FX, Dong JM, Du CP, Zhang CL, Dang Y, Yang AJ, Dong JF, Li M. ADAMTS-13 Prevents VWF-Mediated Gastric Cancer Metastasis. Arterioscler Thromb Vasc Biol 2025. [PMID: 40336476 DOI: 10.1161/atvbaha.125.322553] [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: 01/28/2025] [Accepted: 04/17/2025] [Indexed: 05/09/2025]
Abstract
BACKGROUND Gastric cancer invades local tissue extensively and metastasizes through the circulation to remote organs. Patients with metastasized gastric cancer have poor clinical outcomes. The vasculature in the cancer niche is developed poorly, thus allowing cancer cells to be released into the circulation. However, it is poorly understood how cancer cells adhere to and transmigrate through the fully developed endothelium in remote organs and what key adhesive ligands are involved in the process. Here, we report results from a study designed to investigate the role of hyperadhesive VWF (von Willebrand factor) in promoting the pulmonary metastasis of gastric cancer. METHODS We used mouse models to investigate the roles of hyperadhesive VWF in the pulmonary metastasis of gastric cancer. The findings from these mouse models were validated through in vitro experiments that specifically examined how VWF promoted gastric cancer-derived extracellular vesicles to activate endothelial cells and analyzed established databases of patients with gastric cancer. RESULTS VWF in cancer-bearing mice became hyperadhesive and mediated the adhesion of gastric cancer-derived extracellular vesicles to the endothelium, where gastric cancer-derived extracellular vesicles caused endothelial permeability and promoted the transmigration of cancer cells to the interstitial tissue of the lungs. Reducing VWF adhesive activity by the metalloprotease ADAMTS-13 (A disintegrin and metalloprotease with thrombospondin type motifs, type 13) prevented the pulmonary metastasis of gastric cancer cells in mice. We further validated the findings in mice through targeted in vitro experiments and by associating VWF with the outcomes of patients with gastric cancer through established databases of patients with gastric cancer using bioinformatics tools. CONCLUSIONS We show how VWF becomes hyperadhesive to promote the pulmonary metastasis of gastric cancer through its interaction with gastric cancer-derived extracellular vesicles and that the hyperadhesive activity of VWF is reduced by ADAMTS-13 to prevent the metastasis.
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Affiliation(s)
- Chen-Yu Wang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, China. (C.-y.W., M.W., C.-y.Z., Q.Z., X.-y.Z., J.-m.D., C.-p.D., C.-l.Z., Y.D., A.-j.Y., M.L.)
| | - Min Wang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, China. (C.-y.W., M.W., C.-y.Z., Q.Z., X.-y.Z., J.-m.D., C.-p.D., C.-l.Z., Y.D., A.-j.Y., M.L.)
- Experimental Teaching Center of Basic Medicine, School of Basic Medical Science, Lanzhou University, China. (M.W.)
| | - Chan-Yuan Zhao
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, China. (C.-y.W., M.W., C.-y.Z., Q.Z., X.-y.Z., J.-m.D., C.-p.D., C.-l.Z., Y.D., A.-j.Y., M.L.)
| | - Quan Zhou
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, China. (C.-y.W., M.W., C.-y.Z., Q.Z., X.-y.Z., J.-m.D., C.-p.D., C.-l.Z., Y.D., A.-j.Y., M.L.)
| | - Xiao-Yu Zhang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, China. (C.-y.W., M.W., C.-y.Z., Q.Z., X.-y.Z., J.-m.D., C.-p.D., C.-l.Z., Y.D., A.-j.Y., M.L.)
| | | | - Jia-Ming Dong
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, China. (C.-y.W., M.W., C.-y.Z., Q.Z., X.-y.Z., J.-m.D., C.-p.D., C.-l.Z., Y.D., A.-j.Y., M.L.)
| | - Cun-Pu Du
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, China. (C.-y.W., M.W., C.-y.Z., Q.Z., X.-y.Z., J.-m.D., C.-p.D., C.-l.Z., Y.D., A.-j.Y., M.L.)
| | - Chen-Li Zhang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, China. (C.-y.W., M.W., C.-y.Z., Q.Z., X.-y.Z., J.-m.D., C.-p.D., C.-l.Z., Y.D., A.-j.Y., M.L.)
| | - Yun Dang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, China. (C.-y.W., M.W., C.-y.Z., Q.Z., X.-y.Z., J.-m.D., C.-p.D., C.-l.Z., Y.D., A.-j.Y., M.L.)
- Gansu Provincial Maternity and Child-Care Hospital, Lanzhou, China (Y.D.)
| | - Ai-Jun Yang
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, China. (C.-y.W., M.W., C.-y.Z., Q.Z., X.-y.Z., J.-m.D., C.-p.D., C.-l.Z., Y.D., A.-j.Y., M.L.)
| | - Jing-Fei Dong
- Bloodworks Research Institute, Seattle, WA (J.-f.D.)
- Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle (J.-f.D.)
| | - Min Li
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, China. (C.-y.W., M.W., C.-y.Z., Q.Z., X.-y.Z., J.-m.D., C.-p.D., C.-l.Z., Y.D., A.-j.Y., M.L.)
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, China. (M.L.)
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Ma H, Srivastava S, Ho SWT, Xu C, Lian BSX, Ong X, Tay ST, Sheng T, Lum HYJ, Abdul Ghani SAB, Chu Y, Huang KK, Goh YT, Lee M, Hagihara T, Ng CSY, Tan ALK, Zhang Y, Ding Z, Zhu F, Ng MSW, Joseph CRC, Chen H, Li Z, Zhao JJ, Rha SY, Teh M, Yeong J, Yong WP, So JBY, Sundar R, Tan P. Spatially Resolved Tumor Ecosystems and Cell States in Gastric Adenocarcinoma Progression and Evolution. Cancer Discov 2025; 15:767-792. [PMID: 39774838 PMCID: PMC11962405 DOI: 10.1158/2159-8290.cd-24-0605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 10/17/2024] [Accepted: 01/06/2025] [Indexed: 01/11/2025]
Abstract
SIGNIFICANCE Integration of spatial transcriptomic (GeoMx Digital Spatial Profiler) and single-cell RNA sequencing data from multiple gastric cancers identifies spatially resolved expression-based intratumoral heterogeneity, associated with distinct immune microenvironments. We uncovered two separate evolutionary trajectories associated with specific molecular subtypes, clinical prognoses, stromal neighborhoods, and genetic drivers. Tumor-stroma interfaces emerged as a unique state of tumor ecology.
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Affiliation(s)
- Haoran Ma
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Supriya Srivastava
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Shamaine Wei Ting Ho
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Chang Xu
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | | | - Xuewen Ong
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Su Ting Tay
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Taotao Sheng
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | | | | | - Yunqiang Chu
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Kie Kyon Huang
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Yeek Teck Goh
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Minghui Lee
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Takeshi Hagihara
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Clara Shi Ya Ng
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Angie Lay Keng Tan
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Yanrong Zhang
- Department of Information Systems and Analytics, School of Computing, National University of Singapore, Singapore, Singapore
| | - Zichen Ding
- School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Feng Zhu
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Michelle Shu Wen Ng
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
| | - Craig Ryan Cecil Joseph
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Hui Chen
- MGI Tech Singapore Pte. Ltd., Singapore, Singapore
| | - Zhen Li
- MGI Tech Singapore Pte. Ltd., Singapore, Singapore
| | - Joseph J. Zhao
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - Sun Young Rha
- Yonsei Cancer Center, Yonsei University Health System, Seoul, Republic of Korea
- Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ming Teh
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Joe Yeong
- Department of Pathology, National University Hospital, Singapore, Singapore
- Bioinformatics Institute, Agency for Science, Technology and Research, Singapore, Singapore
| | - Wei Peng Yong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Singapore Gastric Cancer Consortium, Singapore, Singapore
| | - Jimmy Bok-Yan So
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Singapore Gastric Cancer Consortium, Singapore, Singapore
- Department of Surgery, University Surgical Cluster, National University Health System, Singapore, Singapore
- Division of Surgical Oncology, National University Cancer Institute, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Raghav Sundar
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
- Singapore Gastric Cancer Consortium, Singapore, Singapore
- The N.1 Institute for Health, National University of Singapore, Singapore, Singapore
| | - Patrick Tan
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Singapore Gastric Cancer Consortium, Singapore, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore
- Singhealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore, Singapore
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Wang R, Liu G, Wang K, Pan Z, Pei Z, Hu X. Hypoxia signature derived from tumor-associated endothelial cells predict prognosis in gastric cancer. Front Cell Dev Biol 2025; 13:1515681. [PMID: 39901877 PMCID: PMC11788339 DOI: 10.3389/fcell.2025.1515681] [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: 10/23/2024] [Accepted: 01/03/2025] [Indexed: 02/05/2025] Open
Abstract
Background A hypoxic metabolism environment in the tumors is often associated with poor prognostic events such as tumor progression and treatment resistance. In gastric cancer, the mechanism of how hypoxia metabolism affects the tumor microenvironment and immunotherapy efficacy remains to be elucidated. Methods We used the bulk-mapping method to analyze the signatures correlated with the response of immunotherapy in the single-cell dataset. Cellular, pathway, and gene were systematically analyzed in both single-cell and bulk validation datasets. Results The most significant cell proportion difference between the response and non-response groups was in endothelial cells, which represent the malignant cells. VWF was specifically overexpressed in endothelial cells and was the hub gene of differential genes. EPAS1 was a VWF trans-regulated gene and highly positively correlated with VWF in expression. Knockdown experiments demonstrated that siVWF reduced the expression of VWF, EPAS1, and HIF1A, as well as the synthesis of lactate and adenosine which are indicators of hypoxic metabolism. These results suggest that the overexpression of core malign endothelial genes such as VWF drives hypoxic metabolism in tumors and creates an immunosuppressive environment that reduces the efficacy of immunotherapy. The adverse prognosis of the hypoxia signature was validated in the bulk cohort and significance was further enhanced after selecting core genes and combined survival weight scoring. Conclusion In summary, high expression of the malignant endothelial cell driver genes VWF and EPAS1 enhances hypoxic metabolism, and malignant cell-immune cell interactions suppress the immune response. Therefore, the two core genes of hypoxic metabolism might represent potential therapeutic and predicting biomarkers for immunotherapy of gastric cancer in the future.
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Affiliation(s)
- Ruiheng Wang
- Surgical Ward, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Guijun Liu
- Heilongjiang University of Chinese Medicine, Harbin, China
- Department of administrative, The Fourth Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Ke Wang
- Endoscopy Room, First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Zhanglei Pan
- Surgical Ward, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Zhihua Pei
- Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, China
| | - Xijiao Hu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
- Postdoctoral Research Station of Heilongjiang Academy of Traditional Chinese Medicine, Harbin, China
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Ma Q, Gao J, Hui Y, Zhang ZM, Qiao YJ, Yang BF, Gong T, Zhao DM, Huang BR. Single-cell RNA-sequencing and genome-wide Mendelian randomisation along with abundant machine learning methods identify a novel B cells signature in gastric cancer. Discov Oncol 2025; 16:11. [PMID: 39760915 PMCID: PMC11703799 DOI: 10.1007/s12672-025-01759-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/02/2025] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) has a poor prognosis, considerable cellular heterogeneity, and ranks fifth among malignant tumours. Understanding the tumour microenvironment (TME) and intra-tumor heterogeneity (ITH) may lead to the development of novel GC treatments. METHODS The single-cell RNA sequencing (scRNA-seq) dataset was obtained from the Gene Expression Omnibus (GEO) database, where diverse immune cells were isolated and re-annotated based on cell markers established in the original study to ascertain their individual characteristics. We conducted a weighted gene co-expression network analysis (WGCNA) to identify genes with a significant correlation to GC. Utilising bulk RNA sequencing data, we employed machine learning integration methods to train specific biomarkers for the development of novel diagnostic combinations. A two-sample Mendelian randomisation study was performed to investigate the causal effect of biomarkers on gastric cancer (GC). Ultimately, we utilised the DSigDB database to acquire associations between signature genes and pharmaceuticals. RESULTS The 18 genes that made up the signature were as follows: ZFAND2A, PBX4, RAMP2, NNMT, RNASE1, CD93, CDH5, NFKBIE, VWF, DAB2, FAAH2, VAT1, MRAS, TSPAN4, EPAS1, AFAP1L1, DNM3. Patients were categorised into high-risk and low-risk groups according to their risk scores. Individuals in the high-risk cohort exhibited a dismal outlook. The Mendelian randomisation study demonstrated that individuals with a genetic predisposition for elevated NFKBIE levels exhibited a heightened likelihood of acquiring GC. Molecular docking indicates that gemcitabine and chloropyramine may serve as effective therapeutics against NFKBIE. CONCLUSIONS We developed and validated a signature utilising scRNA-seq and bulk sequencing data from gastric cancer patients. NFKBIE may function as a novel biomarker and therapeutic target for GC.
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Affiliation(s)
- Qi Ma
- Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, 730050, China
| | - Jie Gao
- Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Yuan Hui
- Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, 730050, China
| | - Zhi-Ming Zhang
- Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, 730050, China
| | - Yu-Jie Qiao
- Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, 730050, China
| | - Bin-Feng Yang
- Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, 730050, China
| | - Ting Gong
- Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, 730050, China
| | - Duo-Ming Zhao
- Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, 730050, China
| | - Bang-Rong Huang
- Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, 730050, China.
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Millapán T, Gutiérrez Á, Rosas K, Buchegger K, Ili CG, Brebi P. In Silico Insights Reveal Fibronectin 1 as a Theranostic Marker in Gastric Cancer. Int J Mol Sci 2024; 25:11113. [PMID: 39456895 PMCID: PMC11507984 DOI: 10.3390/ijms252011113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 10/09/2024] [Accepted: 10/10/2024] [Indexed: 10/28/2024] Open
Abstract
Gastric cancer (GC) is a complex and highly variable disease, ranking among the top five cancers diagnosed globally, and a leading cause of cancer-related deaths. Emerging from stomach lining cells amid chronic inflammation, it often advances to preneoplastic stages. Late-stage diagnoses and treatment challenges highlight the critical need for early detection and innovative biomarkers, motivating this study's focus on identifying theranostic markers through gene ontology analysis. By exploring deregulated biological processes, this study aims to uncover insights into cancer progression and associated markers, potentially identifying novel theranostic candidates in GC. Using public data from The Human Protein Atlas, this study pinpointed 299 prognostic genes, delineating 171 with unfavorable prognosis and 128 with favorable prognosis. Functional enrichment and protein-protein interaction analyses, supported by RNAseq results and conducted via Metascape and Cytoscape, highlighted five genes (vWF, FN1, THBS1, PCDH7, and F5) with promising theranostic potential. Notably, FN1 and THBS1 exhibited significant promise, with FN1 showing a 370% expression increase in cancerous tissue, and it is possible that FN1 can also indicate the stratification status in GC. While further validation is essential, these findings provide new insights into molecular alterations in GC and potential avenues for clinical application of theranostic markers.
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Affiliation(s)
- Tatiana Millapán
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (T.M.)
- Millennium Institute on Immunology and Immunotherapy, Santiago 8331150, Chile
| | - Álvaro Gutiérrez
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (T.M.)
- Millennium Institute on Immunology and Immunotherapy, Santiago 8331150, Chile
- Doctoral Program in Sciences with a Specialization in Applied Cellular and Molecular Biology, Universidad de La Frontera, Temuco 4810296, Chile
| | - Krisnna Rosas
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (T.M.)
- Biotechnology Engineering Program, Universidad de La Frontera, Temuco 4810296, Chile
| | - Kurt Buchegger
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (T.M.)
- Millennium Institute on Immunology and Immunotherapy, Santiago 8331150, Chile
- BMRC, Biomedical Research Consortium, Santiago 8331150, Chile
- Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4810296, Chile
| | - Carmen Gloria Ili
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (T.M.)
- Millennium Institute on Immunology and Immunotherapy, Santiago 8331150, Chile
- BMRC, Biomedical Research Consortium, Santiago 8331150, Chile
| | - Priscilla Brebi
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (T.M.)
- Millennium Institute on Immunology and Immunotherapy, Santiago 8331150, Chile
- BMRC, Biomedical Research Consortium, Santiago 8331150, Chile
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Zhao Y, He M, Cui L, Zhang M, Zhao T, Yang X, Xu Y, Dong J, He K, Zhang H, Chen L. Systematic screening of protein-coding gene expression identified VWF as a potential key regulator in anthracycline-based chemotherapy-exacerbated metastasis of breast cancer. BMC Cancer 2024; 24:1243. [PMID: 39379897 PMCID: PMC11462902 DOI: 10.1186/s12885-024-12999-9] [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: 07/15/2024] [Accepted: 09/27/2024] [Indexed: 10/10/2024] Open
Abstract
BACKGROUND Breast cancer is the most commonly diagnosed cancer worldwide. Although major treatments represented by chemotherapy have shown effectiveness at the initial period, recurrence and metastasis still occur later after treatments. The alternation of the tumor microenvironment by chemotherapy is confirmed as a trigger of the elevated proliferation and migration of the remaining tumor cells. METHODS Using bioinformatic methods, differential gene expression analysis was used to determine DEGs between post-chemotherapy and pre-chemotherapy samples of breast cancer patients, followed by survival analysis and ELISA analysis of the potential key genes. An in vitro model of 2 breast cancer cells lines was used to demonstrate the role of VWF in the evasion and migration of breast cancer cells, using cell migration, evasion and wound healing assays, PCR and molecular docking analysis. RESULTS 19 hub genes were further identified using GO and KEGG pathway analyses and WGCNA. The 5 secreted protein-coding genes with reported carcinogenesis effects (VWF, SVEP1, DPT, ADIPOQ, and LPL) were further analyzed in breast cancer patients and VWF was identified as a potential key regulator in the anthracycline-based chemotherapy-exacerbated metastasis. It was further confirmed that anthracycline-based chemotherapeutics doxorubicin exacerbated VWF upregulation and the evasion and migration of breast cancer cells. Based on molecular docking analysis and previous study, berberine was used as an inhibitor of VWF, and showed an effective inhibition of the doxorubicin-exacerbated VWF upregulation, migration and evasion in breast cancer. CONCLUSIONS Doxorubicin-exacerbated evasion and migration through VWF upregulation. Berberine as an inhibitor of VWF was able to reversed the doxorubicin-exacerbated VWF upregulation and evasion and migration in breast cancer cells.
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Affiliation(s)
- Yawei Zhao
- Department of Pharmacology, Nanomedicine Engineering Laboratory of Jilin Province, College of Basic Medical Sciences, Jilin University, No. 126 Xinmin Street, Changchun, 130021, China
| | - Meihui He
- Department of Pharmacology, Nanomedicine Engineering Laboratory of Jilin Province, College of Basic Medical Sciences, Jilin University, No. 126 Xinmin Street, Changchun, 130021, China
- Changchun Medical College, Changchun, 130031, China
| | - Lianzhi Cui
- Clinical Laboratory, Jilin Cancer Hospital, Changchun, 130012, China
| | - Min Zhang
- Department of Pharmacology, Nanomedicine Engineering Laboratory of Jilin Province, College of Basic Medical Sciences, Jilin University, No. 126 Xinmin Street, Changchun, 130021, China
| | - Tianyu Zhao
- Department of Pharmacology, Nanomedicine Engineering Laboratory of Jilin Province, College of Basic Medical Sciences, Jilin University, No. 126 Xinmin Street, Changchun, 130021, China
| | - Xuehan Yang
- Department of Pharmacology, Nanomedicine Engineering Laboratory of Jilin Province, College of Basic Medical Sciences, Jilin University, No. 126 Xinmin Street, Changchun, 130021, China
| | - Yang Xu
- Department of Pharmacology, Nanomedicine Engineering Laboratory of Jilin Province, College of Basic Medical Sciences, Jilin University, No. 126 Xinmin Street, Changchun, 130021, China
| | - Jianhua Dong
- Department of Pharmacology, Nanomedicine Engineering Laboratory of Jilin Province, College of Basic Medical Sciences, Jilin University, No. 126 Xinmin Street, Changchun, 130021, China
| | - Kan He
- Department of Pharmacology, Nanomedicine Engineering Laboratory of Jilin Province, College of Basic Medical Sciences, Jilin University, No. 126 Xinmin Street, Changchun, 130021, China
| | - Hansi Zhang
- Department of Pharmacology, Nanomedicine Engineering Laboratory of Jilin Province, College of Basic Medical Sciences, Jilin University, No. 126 Xinmin Street, Changchun, 130021, China.
| | - Li Chen
- Department of Pharmacology, Nanomedicine Engineering Laboratory of Jilin Province, College of Basic Medical Sciences, Jilin University, No. 126 Xinmin Street, Changchun, 130021, China.
- School of Nursing, Jilin University, Changchun, 130021, China.
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Philippe A, Günther S, Rancic J, Cavagna P, Renaud B, Gendron N, Mousseaux E, Hua-Huy T, Reverdito G, Planquette B, Sanchez O, Gaussem P, Salmon D, Diehl JL, Smadja DM. VEGF-A plasma levels are associated with impaired DLCO and radiological sequelae in long COVID patients. Angiogenesis 2024; 27:51-66. [PMID: 37526809 DOI: 10.1007/s10456-023-09890-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 07/21/2023] [Indexed: 08/02/2023]
Abstract
BACKGROUND Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is characterized by persistent clinical symptoms following COVID-19. OBJECTIVE To correlate biomarkers of endothelial dysfunction with persistent clinical symptoms and pulmonary function defects at distance from COVID-19. METHODS Consecutive patients with long COVID-19 suspicion were enrolled. A panel of endothelial biomarkers was measured in each patient during clinical evaluation and pulmonary function test (PFT). RESULTS The study included 137 PASC patients, mostly male (68%), with a median age of 55 years. A total of 194 PFTs were performed between months 3 and 24 after an episode of SARS-CoV-2 infection. We compared biomarkers evaluated in PASC patients with 20 healthy volunteers (HVs) and acute hospitalized COVID-19 patients (n = 88). The study found that angiogenesis-related biomarkers and von Willebrand factor (VWF) levels were increased in PASC patients compared to HVs without increased inflammatory or platelet activation markers. Moreover, VEGF-A and VWF were associated with persistent lung CT scan lesions and impaired diffusing capacity of the lungs for carbon monoxide (DLCO) measurement. By employing a Cox proportional hazards model adjusted for age, sex, and body mass index, we further confirmed the accuracy of VEGF-A and VWF. Following adjustment, VEGF-A emerged as the most significant predictive factor associated with persistent lung CT scan lesions and impaired DLCO measurement. CONCLUSION VEGF-A is a relevant predictive factor for DLCO impairment and radiological sequelae in PASC. Beyond being a biomarker, we hypothesize that the persistence of angiogenic disorders may contribute to long COVID symptoms.
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Affiliation(s)
- Aurélien Philippe
- University Paris Cité, Innovative Therapies in Hemostasis, INSERM, 75006, Paris, France
- Hematology Department, AP-HP.Centre, Université Paris Cité, Georges Pompidou European Hospital, 75015, Paris, France
| | - Sven Günther
- University Paris Cité, Innovative Therapies in Hemostasis, INSERM, 75006, Paris, France
- Unité d'Explorations Fonctionnelles Respiratoires et du Sommeil, AP-HP, Georges Pompidou European Hospital, 75015, Paris, France
| | - Jeanne Rancic
- University Paris Cité, Innovative Therapies in Hemostasis, INSERM, 75006, Paris, France
| | - Pauline Cavagna
- Pharmacy Department, Pitié-Salpêtrière Hospital, AP-HP Sorbonne University, Paris, France
- Université Paris Cité, INSERM, PARCC, 75015, Paris, France
| | - Bertrand Renaud
- Unité d'Explorations Fonctionnelles Respiratoires et du Sommeil, AP-HP, Georges Pompidou European Hospital, 75015, Paris, France
| | - Nicolas Gendron
- University Paris Cité, Innovative Therapies in Hemostasis, INSERM, 75006, Paris, France
- Hematology Department, AP-HP.Centre, Université Paris Cité, Georges Pompidou European Hospital, 75015, Paris, France
| | - Elie Mousseaux
- Paris-Cardiovascular Research Center INSERM 970, Université de Paris, Paris, France
- Department of Radiology, Georges Pompidou European Hospital, 75015, Paris, France
| | - Thông Hua-Huy
- Unité d'Explorations Fonctionnelles Respiratoires et du Sommeil, AP-HP, Georges Pompidou European Hospital, 75015, Paris, France
| | - Guillaume Reverdito
- Paris-Cardiovascular Research Center INSERM 970, Université de Paris, Paris, France
- Department of Radiology, Georges Pompidou European Hospital, 75015, Paris, France
| | - Benjamin Planquette
- University Paris Cité, Innovative Therapies in Hemostasis, INSERM, 75006, Paris, France
- Respiratory Diseases Department, AP-HP.Centre, Université Paris Cité, Georges Pompidou European Hospital, 75015, Paris, France
| | - Olivier Sanchez
- University Paris Cité, Innovative Therapies in Hemostasis, INSERM, 75006, Paris, France
- Respiratory Diseases Department, AP-HP.Centre, Université Paris Cité, Georges Pompidou European Hospital, 75015, Paris, France
| | - Pascale Gaussem
- University Paris Cité, Innovative Therapies in Hemostasis, INSERM, 75006, Paris, France
- Hematology Department, AP-HP.Centre, Université Paris Cité, Georges Pompidou European Hospital, 75015, Paris, France
| | - Dominique Salmon
- Infectious Diseases and Immunology Department, AP-HP. Centre, Université Paris Cité, Hôtel-Dieu Hospital, 75004, Paris, France
| | - Jean-Luc Diehl
- University Paris Cité, Innovative Therapies in Hemostasis, INSERM, 75006, Paris, France
- Intensive Care Unit, AP-HP. Centre Université Paris Cité, Georges Pompidou European Hospital, 75015, Paris, France
| | - David M Smadja
- University Paris Cité, Innovative Therapies in Hemostasis, INSERM, 75006, Paris, France.
- Hematology Department, AP-HP.Centre, Université Paris Cité, Georges Pompidou European Hospital, 75015, Paris, France.
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8
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Wong SWK, Tey SK, Mao X, Fung HL, Xiao Z, Wong DKH, Mak L, Yuen M, Ng IO, Yun JP, Gao Y, Yam JWP. Small Extracellular Vesicle-Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2302677. [PMID: 37387563 PMCID: PMC10502836 DOI: 10.1002/advs.202302677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/07/2023] [Indexed: 07/01/2023]
Abstract
Hepatocellular carcinoma (HCC) is a hypervascular malignancy by which its growth and dissemination are largely driven by the modulation of tumor-derived small extracellular vesicles (sEVs). Proteomic profiling of circulating sEVs of control individuals and HCC patients identifies von Willibrand factor (vWF) to be upregulated progressively along HCC stages. Elevated sEV-vWF levels are found in a larger cohort of HCC-sEV samples and metastatic HCC cell lines compared to their respective normal counterparts. Circulating sEVs of late-stage HCC patients markedly augment angiogenesis, tumor-endothelial adhesion, pulmonary vascular leakiness, and metastasis, which are significantly compromised by anti-vWF antibody. The role of vWF is further corroborated by the enhanced promoting effect of sEVs collected from vWF-overexpressing cells. sEV-vWF modulates endothelial cells through an elevated level of vascular endothelial growth factor A (VEGF-A) and fibroblast growth factor 2 (FGF2). Mechanistically, secreted FGF2 elicits a positive feedback response in HCC via the FGFR4/ERK1 signaling pathway. The co-administration of anti-vWF antibody or FGFR inhibitor significantly improves the treatment outcome of sorafenib in a patient-derived xenograft mouse model. This study reveals mutual stimulation between HCC and endothelial cells by tumor-derived sEVs and endothelial angiogenic factors, facilitating angiogenesis and metastasis. It also provides insights into a new therapeutic strategy involving blocking tumor-endothelial intercellular communication.
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Affiliation(s)
- Samuel Wan Ki Wong
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Sze Keong Tey
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- Department of SurgerySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Xiaowen Mao
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- State Key Laboratory of Liver Research, The University of Hong KongHong Kong
| | - Hiu Ling Fung
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Zhi‐Jie Xiao
- Research CentreThe Seventh Affiliated HospitalSun Yat‐sen University518107ShenzhenP. R. China
| | - Danny Ka Ho Wong
- Department of MedicineSchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Lung‐Yi Mak
- Department of MedicineSchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Man‐Fung Yuen
- Department of MedicineSchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Irene Oi‐Lin Ng
- State Key Laboratory of Liver Research, The University of Hong KongHong Kong
| | - Jing Ping Yun
- Department of PathologySun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Yi Gao
- Department of Hepatobiliary Surgery IIZhuJiang HospitalSouthern Medical UniversityGuangzhouGuangdong510280P. R. China
| | - Judy Wai Ping Yam
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- State Key Laboratory of Liver Research, The University of Hong KongHong Kong
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9
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Cai W, Wang M, Wang CY, Zhao CY, Zhang XY, Zhou Q, Zhao WJ, Yang F, Zhang CL, Yang AJ, Dong JF, Li M. Extracellular vesicles, hyperadhesive von willebrand factor, and outcomes of gastric cancer: a clinical observational study. Med Oncol 2023; 40:140. [PMID: 37031314 DOI: 10.1007/s12032-023-01950-w] [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: 08/23/2022] [Accepted: 01/12/2023] [Indexed: 04/10/2023]
Abstract
Von Willebrand factor (VWF) is an adhesive ligand critical for maintaining hemostasis. However, it has also been increasingly recognized for its role in cancer development because it has been shown to mediate the adhesion of cancer cells to endothelial cells, promote the epithelial-mesenchymal transition, and enhance angiogenesis. We have previously shown that gastric cancer cells synthesize VWF, which mediates the interaction between the cancer and endothelial cells to promote cancer growth. Here, we report results from a clinical observational study that demonstrate the association of VWF in plasma and on the surface of extracellular vesicles (EVs) with the pathological characteristics of gastric cancer. We found that patients with gastric cancer had elevated and intrinsically hyperadhesive VWF in their peripheral blood samples. VWF was detected on the surface of EVs from cancer cells, platelets, and endothelial cells. Higher levels of these VWF-bound EVs were associated with cancer aggression and poor clinical outcomes for patients. These findings suggest that VWF+ EVs from different cell types serve collectively as a new class of biomarkers for the outcome assessment of gastric cancer patients.
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Affiliation(s)
- Wei Cai
- School of Basic Medical Sciences, Institute of Pathology, Lanzhou University, Lanzhou, China
- Gansu Provincial Hospital, Lanzhou, China
| | - Min Wang
- School of Basic Medical Sciences, Institute of Pathology, Lanzhou University, Lanzhou, China
- School of Basic Medical Sciences, Institute of Integrated Traditional Chinese and Western Medicine, Lanzhou University, Lanzhou, China
| | - Chen-Yu Wang
- School of Basic Medical Sciences, Institute of Pathology, Lanzhou University, Lanzhou, China
| | - Chan-Yuan Zhao
- School of Basic Medical Sciences, Institute of Pathology, Lanzhou University, Lanzhou, China
| | - Xiao-Yu Zhang
- School of Basic Medical Sciences, Institute of Pathology, Lanzhou University, Lanzhou, China
| | - Quan Zhou
- School of Basic Medical Sciences, Institute of Pathology, Lanzhou University, Lanzhou, China
| | - Wen-Jie Zhao
- School of Basic Medical Sciences, Institute of Pathology, Lanzhou University, Lanzhou, China
| | - Feng Yang
- School of Basic Medical Sciences, Institute of Pathology, Lanzhou University, Lanzhou, China
| | - Chen-Li Zhang
- School of Basic Medical Sciences, Institute of Pathology, Lanzhou University, Lanzhou, China
| | - Ai-Jun Yang
- School of Basic Medical Sciences, Institute of Pathology, Lanzhou University, Lanzhou, China.
| | - Jing-Fei Dong
- Bloodworks Research Institute, Seattle, WA, USA.
- Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
| | - Min Li
- School of Basic Medical Sciences, Institute of Pathology, Lanzhou University, Lanzhou, China.
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou, China.
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10
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Wu LH, Wang XX, Wang Y, Wei J, Liang ZR, Yan X, Wang J. Construction and validation of a prognosis signature based on the immune microenvironment in gastric cancer. Front Surg 2023; 10:1088292. [PMID: 37066015 PMCID: PMC10102374 DOI: 10.3389/fsurg.2023.1088292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 03/02/2023] [Indexed: 04/03/2023] Open
Abstract
BackgroundGastric cancer (GC) is an aggressive malignant tumor with a high degree of heterogeneity, and its immune microenvironment is closely associated with tumor growth, development and drug resistance. Therefore, a classification system of gastric cancer based explicitly on the immune microenvironment context might enrich the strategy for gastric cancer prognosis and therapy.MethodsA total of 668 GC patients were collected from TCGA-STAD (n = 350), GSE15459 (n = 192), GSE57303 (n = 70) and GSE34942 (n = 56) datasets. Three immune-related subtypes (immunity-H, -M, and -L) were identified by hierarchical cluster analysis based on the ssGSEA score of 29 immune microenvironment-related gene sets. The immune microenvironment-related prognosis signature (IMPS) was constructed via univariate Cox regression, Lasso-Cox regression and multivariate Cox regression, and nomogram model combining IMPS and clinical variables was further constructed by the “rms” package. RT-PCR was applied to validate the expression of 7 IMPS genes between two human GC cell lines (AGS and MKN45) and one normal gastric epithelial cell line (GES-1).ResultsThe patients classified as immunity-H subtype exhibited highly expressed immune checkpoint and HLA-related genes, with enriched naïve B cells, M1 macrophages and CD8 T cells. We further constructed and validated a 7-gene (CTLA4, CLDN6, EMB, GPR15, ENTPD2, VWF and AKR1B1) prognosis signature, termed as IMPS. The patients with higher IMPS expression were more likely to be associated with higher pathology grade, more advanced TNM stages, higher T and N stage, and higher ratio of death. In addition, the prediction values of the combined nomogram in predicting 1-year (AUC = 0.750), 3-year (AUC = 0.764) and 5-year (AUC = 0.802) OS was higher than IMPS and individual clinical characteristics.ConclusionsThe IMPS is a novel prognosis signature associated with the immune microenvironment and clinical characteristics. The IMPS and the combined nomogram model provide a relatively reliable predictive index for predicting the survival outcomes of gastric cancer.
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Affiliation(s)
- Li-Hong Wu
- Xijing 986 Hospital Department, Fourth Military Medical University, Xi’an, China
| | - Xiang-Xu Wang
- Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Yan Wang
- Xijing 986 Hospital Department, Fourth Military Medical University, Xi’an, China
| | - Jing Wei
- Xijing 986 Hospital Department, Fourth Military Medical University, Xi’an, China
| | - Zi-Rong Liang
- Xijing 986 Hospital Department, Fourth Military Medical University, Xi’an, China
| | - Xi Yan
- Xijing 986 Hospital Department, Fourth Military Medical University, Xi’an, China
- Correspondence: Jun Wang Xi Yan
| | - Jun Wang
- Xijing 986 Hospital Department, Fourth Military Medical University, Xi’an, China
- Correspondence: Jun Wang Xi Yan
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11
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Strasenburg W, Jóźwicki J, Durślewicz J, Kuffel B, Kulczyk MP, Kowalewski A, Grzanka D, Drewa T, Adamowicz J. Tumor Cell-Induced Platelet Aggregation as an Emerging Therapeutic Target for Cancer Therapy. Front Oncol 2022; 12:909767. [PMID: 35814405 PMCID: PMC9259835 DOI: 10.3389/fonc.2022.909767] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
Tumor cells have the ability to induce platelet activation and aggregation. This has been documented to be involved in tumor progression in several types of cancers, such as lung, colon, breast, pancreatic, ovarian, and brain. During the process, platelets protect circulating tumor cells from the deleterious effects of shear forces, shield tumor cells from the immune system, and provide growth factors, facilitating metastatic spread and tumor growth at the original site as well as at the site of metastasis. Herein, we present a wider view on the induction of platelet aggregation by specific factors primarily developed by cancer, including coagulation factors, adhesion receptors, growth factors, cysteine proteases, matrix metalloproteinases, glycoproteins, soluble mediators, and selectins. These factors may be presented on the surface of tumor cells as well as in their microenvironment, and some may trigger more than just one simple receptor-ligand mechanism. For a better understanding, we briefly discuss the physiological role of the factors in the platelet activation process, and subsequently, we provide scientific evidence and discuss their potential role in the progression of specific cancers. Targeting tumor cell-induced platelet aggregation (TCIPA) by antiplatelet drugs may open ways to develop new treatment modalities. On the one hand, it may affect patients' prognosis by enhancing known therapies in advanced-stage tumors. On the other hand, the use of drugs that are mostly easily accessible and widely used in general practice may be an opportunity to propose an unparalleled antitumor prophylaxis. In this review, we present the recent discoveries of mechanisms by which cancer cells activate platelets, and discuss new platelet-targeted therapeutic strategies.
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Affiliation(s)
- Wiktoria Strasenburg
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Jakub Jóźwicki
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Justyna Durślewicz
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Błażej Kuffel
- Department of General and Oncological Urology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
| | - Martyna Parol Kulczyk
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Adam Kowalewski
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Tomasz Drewa
- Department of General and Oncological Urology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
| | - Jan Adamowicz
- Department of General and Oncological Urology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
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12
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Eswaran S, Adiga D, Khan G N, S S, Kabekkodu SP. Comprehensive analysis of the exocytosis pathway genes in cervical cancer. Am J Med Sci 2022; 363:526-537. [PMID: 34995576 DOI: 10.1016/j.amjms.2021.12.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/09/2021] [Accepted: 12/29/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cervical cancer (CC) is the fourth most common gynecological malignancy globally. This suggests the need for improved markers for prognosis, better understanding of the molecular mechanism, and targets for therapy. The defective exocytosis pathway is proposed as bona fide drivers of carcinogenesis. This study aimed to identify the exocytosis pathway network and its contribution to CC. METHODS We screened exocytosis genes from the The Cancer Genome Atlas Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA-CESC) dataset and performed differential expression and methylation, Kaplan-Meier survival, and pathway enrichment analysis. We constructed the protein-protein interaction networks (PPIN), predicted the possible metastatic genes, and identified FDA approved drugs to target the exocytosis network in CC. RESULTS Integrated bioinformatics analysis identified 245 differentially methylated genes, including 153 hypermethylated and 92 hypomethylated genes. Further, 89 exocytosis pathway genes were differentially expressed, including 60 downregulated and 29 upregulated genes in CC. The overlapping analysis identified 39 genes as methylation regulated genes and showed an inverse correlation between methylation and expression. The HCMDB database identified nine of the identified genes (GRIK5, PTPN6, GAB2, ATP8B4, HTR2A, SPARC, CLEC3B, VWF, and S100A11) were linked with metastasis in CC. Moreover, the Kaplan-Meier survival analysis identified that high expression of PTPN6 and low expression of CLEC3B were significantly linked with poor overall survival (OS) in patients with CC. The KEGG pathway enrichment analysis identified differentially expressed genes that were mainly involved with proteoglycans in cancer, TGF-beta signaling, PI3K-Akt signaling, MAPK signaling pathway, and others. The PPIN identified 89 nodes, 192 edges with VWF, MMP9, THBS1, IGF1, CLU, A2M, IGF2, SPARC, VAMP2, and FIGF as top 10 hub genes. The drug-gene interaction analysis identified 188 FDA approved drugs targeting 32 genes, including 5 drugs that are already in use for treating CC. CONCLUSIONS In summary, we have identified the exocytosis pathway networks, candidate genes, and novel drugs for better management of CC.
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Affiliation(s)
- Sangavi Eswaran
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Karnataka, India
| | - Divya Adiga
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Karnataka, India
| | - Nadeem Khan G
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Karnataka, India
| | - Sriharikrishnaa S
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Karnataka, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Karnataka, India.
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13
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Mechanism of N-Methyl-N-Nitroso-Urea-Induced Gastric Precancerous Lesions in Mice. JOURNAL OF ONCOLOGY 2022; 2022:3780854. [PMID: 35342404 PMCID: PMC8942688 DOI: 10.1155/2022/3780854] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 02/25/2022] [Accepted: 03/02/2022] [Indexed: 11/17/2022]
Abstract
Early diagnosis and treatment of gastric precancerous lesions (GPL) are key factors for reducing the incidence and morbidity of gastric cancer. The study is aimed at examining GPL in mice induced by N-methyl-N-nitroso-urea (MNU) and to illustrate the underlying mechanisms of tumorigenesis. In this study, we utilized an in vivo MNU-induced GPL mouse model, and histopathological changes of the gastric mucosa were observed by hematoxylin and eosin (H&E-stain) and alcian blue (AB-PAS-stain). The level of miR-194-5p in the gastric mucosa was determined by real-time polymerase chain reaction. We used transmission electron microscopy to observe the effects of MNU on gastric chief cells and parietal cells. We performed immunohistochemical detection of HIF-1α, vWF, Ki-67, and P53, while the changes in the protein expression of key genes in LKB1-AMPK and AKT-FoxO3 signaling pathways were detected by western blot analysis. We demonstrated that the miR-194-5p expression was upregulated under hypoxia in GPL gastric tissues, and that a high miR-194-5p expression level closely related with tumorigenesis. Mechanistically, miR-194-5p exerted the acceleration of activities related to metabolic reprogramming through LKB1-AMPK and AKT-FoxO3 pathways. Furthermore, similar to miR-194-5p, high expression levels of AMPK and AKT were also related to the metabolic reprogramming of GPL. Moreover, we revealed the correlation between the expression levels of miR-194-5p, p-AMPKα, p-AKT, and FoxO3a. These findings suggest that miR-194-5p/FoxO3 pathway is important for the reversal of metabolic reprogramming in GPL. Thus, exploring strategies to regulate the miR-194-5p/FoxO3a pathway may provide an efficient strategy for the prevention and treatment of GPL.
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14
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The Intriguing Connections between von Willebrand Factor, ADAMTS13 and Cancer. Healthcare (Basel) 2022; 10:healthcare10030557. [PMID: 35327035 PMCID: PMC8953111 DOI: 10.3390/healthcare10030557] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/06/2022] [Accepted: 03/14/2022] [Indexed: 12/21/2022] Open
Abstract
von Willebrand factor (VWF) is a complex and large protein that is cleaved by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13), and together they serve important roles in normal hemostasis. Malignancy can result in both a deficiency or excess of VWF, leading to aberrant hemostasis with either increased bleeding or thrombotic complications, as respectively seen with acquired von Willebrand syndrome and cancer-associated venous thromboembolism. There is emerging evidence to suggest VWF also plays a role in inflammation, angiogenesis and tumor biology, and it is likely that VWF promotes tumor metastasis. High VWF levels have been documented in a number of malignancies and in some cases correlate with more advanced disease and poor prognosis. Tumor cells can induce endothelial cells to release VWF and certain tumor cells have the capacity for de novo expression of VWF, leading to a proinflammatory microenvironment that is likely conducive to tumor progression, metastasis and micro-thrombosis. VWF can facilitate tumor cell adhesion to endothelial cells and aids with the recruitment of platelets into the tumor microenvironment, where tumor/platelet aggregates are able to form and facilitate hematogenous spread of cancer. As ADAMTS13 moderates VWF level and activity, it too is potentially involved in the pathophysiology of these events. VWF and ADAMTS13 have been explored as tumor biomarkers for the detection and prognostication of certain malignancies; however, the results are underdeveloped and so currently not utilized for clinical use. Further studies addressing the basic science mechanisms and real word epidemiology are required to better appreciate the intriguing connections between VWF, ADAMTS13 and malignancy. A better understanding of the role VWF and ADAMTS13 play in the promotion and inhibition of cancer and its metastasis will help direct further translational studies to aid with the development of novel cancer prognostic tools and treatment modalities.
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15
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Walker GE, Merlin S, Zanolini D, Vandoni A, Volpe A, Gaidano G, Valente G, Olivero M, Follenzi A. Factor VIII as a potential player in cancer pathophysiology. J Thromb Haemost 2022; 20:648-660. [PMID: 34847278 PMCID: PMC9306727 DOI: 10.1111/jth.15611] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 11/29/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Trousseau sign was the first demonstration of a close relationship between cancer and thrombosis. Currently, venous thromboembolism (VTE) is five to six times more likely to occur in cancer patients, whereas there is a greater risk of cancer diagnoses following thromboses. In considering novel players, factor VIII (FVIII), an essential coagulation cofactor with emerging extracoagulative functions, has been identified as an independent VTE risk factor in cancer; however, the basis of this increase is unknown. OBJECTIVE To investigate the possible direct expression and secretion of FVIII by cancer cells. METHODS Bladder cancer, with a high VTE risk, and normal bladder tissue and epithelium, were used to investigate FVIII. Factor VIII protein and secretion were examined in bladder cancer cell lines. Expanding to other cancers, the Cancer Cell line Encyclopedia database was used to analyze FVIII, tissue factor, FV, FVII, FIX, FX, and von Willebrand factor (VWF) mRNA in 811 cell lines subdivided according to origin. Factor VIII protein synthesis, secretion, and bioactivity were investigated in a profile of cancer cell lines of differing origins. RESULTS AND CONCLUSIONS Although expressed in the normal bladder epithelium, FVIII mRNA and protein were higher in matched bladder neoplasms, with synthesis and secretion of bioactive FVIII evident in bladder cancer cells. This can be extended to other cancer cell lines, with a pattern reflecting the tumor origin, and that is independent of VWF and other relevant players in the coagulation cascade. Here, evidence is provided of a possible independent role for FVIII in cancer-related pathophysiology.
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Affiliation(s)
- Gillian E. Walker
- Department of Health SciencesUniversità del Piemonte OrientaleNovaraItaly
| | - Simone Merlin
- Department of Health SciencesUniversità del Piemonte OrientaleNovaraItaly
| | - Diego Zanolini
- Department of Health SciencesUniversità del Piemonte OrientaleNovaraItaly
| | - Andrea Vandoni
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
| | - Alessandro Volpe
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
| | - Gianluca Gaidano
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
| | - Guido Valente
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
| | - Martina Olivero
- Department of OncologyUniversity of TorinoTorinoItaly
- Candiolo Cancer Institute‐FPOIRCCSCandiolo, TorinoItaly
| | - Antonia Follenzi
- Department of Health SciencesUniversità del Piemonte OrientaleNovaraItaly
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16
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Moreira AM, Ferreira RM, Carneiro P, Figueiredo J, Osório H, Barbosa J, Preto J, Pinto-do-Ó P, Carneiro F, Seruca R. Proteomic Identification of a Gastric Tumor ECM Signature Associated With Cancer Progression. Front Mol Biosci 2022; 9:818552. [PMID: 35340765 PMCID: PMC8942767 DOI: 10.3389/fmolb.2022.818552] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 01/18/2022] [Indexed: 12/12/2022] Open
Abstract
The extracellular matrix (ECM) plays an undisputable role in tissue homeostasis and its deregulation leads to altered mechanical and biochemical cues that impact cancer development and progression. Herein, we undertook a novel approach to address the role of gastric ECM in tumorigenesis, which remained largely unexplored. By combining decellularization techniques with a high-throughput quantitative proteomics approach, we have performed an extensive characterization of human gastric mucosa, uncovering its composition and distribution among tumor, normal adjacent and normal distant mucosa. Our results revealed a common ECM signature composed of 142 proteins and indicated that gastric carcinogenesis encompasses ECM remodeling through alterations in the abundance of 24 components, mainly basement membrane proteins. Indeed, we could only identify one de novo tumor-specific protein, the collagen alpha-1(X) chain (COL10A1). Functional analysis of the data demonstrated that gastric ECM remodeling favors tumor progression by activating ECM receptors and cellular processes involved in angiogenesis and cell-extrinsic metabolic regulation. By analyzing mRNA expression in an independent GC cohort available at the TGCA, we validated the expression profile of 12 differentially expressed ECM proteins. Importantly, the expression of COL1A2, LOX and LTBP2 significantly correlated with high tumor stage, with LOX and LTBP2 further impacting patient overall survival. These findings contribute for a better understanding of GC biology and highlight the role of core ECM components in gastric carcinogenesis and their clinical relevance as biomarkers of disease prognosis.
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Affiliation(s)
- Ana M. Moreira
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Doctoral Program on Cellular and Molecular Biotechnology Applied to Health Sciences, School of Medicine and Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Rui M. Ferreira
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Patrícia Carneiro
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Joana Figueiredo
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - Hugo Osório
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
| | - José Barbosa
- Faculty of Medicine, University of Porto, Porto, Portugal
- Department of General Surgery, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - John Preto
- Faculty of Medicine, University of Porto, Porto, Portugal
- Department of General Surgery, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Perpétua Pinto-do-Ó
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Institute of Biomedical Engineering (INEB), University of Porto, Porto, Portugal
- School of Medicine and Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Fátima Carneiro
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Pathology, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Raquel Seruca
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
- *Correspondence: Raquel Seruca,
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Definition of an Inflammatory Biomarker Signature in Plasma-Derived Extracellular Vesicles of Glioblastoma Patients. Biomedicines 2022; 10:biomedicines10010125. [PMID: 35052804 PMCID: PMC8773644 DOI: 10.3390/biomedicines10010125] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/05/2022] [Accepted: 01/05/2022] [Indexed: 12/12/2022] Open
Abstract
Glioblastoma (GB) is an aggressive type of tumour for which therapeutic options and biomarkers are limited. GB diagnosis mostly relies on symptomatic presentation of the tumour and, in turn, brain imaging and invasive biopsy that can delay its diagnosis. Description of easily accessible and effective biomarkers present in biofluids would thus prove invaluable in GB diagnosis. Extracellular vesicles (EVs) derived from both GB and stromal cells are essential to intercellular crosstalk in the tumour bulk, and circulating EVs have been described as a potential reservoir of GB biomarkers. Therefore, EV-based liquid biopsies have been suggested as a promising tool for GB diagnosis and follow up. To identify GB specific proteins, sEVs were isolated from plasma samples of GB patients as well as healthy volunteers using differential ultracentrifugation, and their content was characterised through mass spectrometry. Our data indicate the presence of an inflammatory biomarker signature comprising members of the complement and regulators of inflammation and coagulation including VWF, FCGBP, C3, PROS1, and SERPINA1. Overall, this study is a step forward in the development of a non-invasive liquid biopsy approach for the identification of valuable biomarkers that could significantly improve GB diagnosis and, consequently, patients’ prognosis and quality of life.
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18
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Popa M, Hecker M, Wagner AH. Inverse Regulation of Confluence-Dependent ADAMTS13 and von Willebrand Factor Expression in Human Endothelial Cells. Thromb Haemost 2021; 122:611-622. [PMID: 34352896 DOI: 10.1055/s-0041-1733800] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is a zinc-containing metalloprotease also known as von Willebrand factor (vWF)-cleaving protease. Low ADAMTS13 plasma levels are associated with an increased risk of arterial thrombosis, including myocardial infarction and cerebrovascular disease. The expression and regulation of this metalloprotease in human endothelial cells have not been systematically investigated. In this study, we demonstrate that ADAMTS13 expression is inhibited by proinflammatory cytokines tumor necrosis factor-α and interferon-γ as well as by CD40 ligand, which was hitherto unknown. Factors protecting against atherosclerosis such as exposure to continuous unidirectional shear stress, interleukin-10, or different HMG-CoA reductase inhibitors like, e.g., simvastatin, atorvastatin, or rosuvastatin, did not influence ADAMTS13 expression. Unidirectional periodic orbital shear stress, mimicking oscillatory flow conditions found at atherosclerosis-prone arterial bifurcations, had also no effect. In contrast, a reciprocal correlation between ADAMTS13 and vWF expression in endothelial cells depending on the differentiation state was noted. ADAMTS13 abundance significantly rose on both the mRNA and intracellular protein level and also tethered to the endothelial glycocalyx with the degree of confluency while vWF protein levels were highest in proliferating cells but significantly decreased upon reaching confluence. This finding could explain the anti-inflammatory and antithrombotic phenotype of dormant endothelial cells mediated by contact inhibition.
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Affiliation(s)
- Miruna Popa
- Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
| | - Markus Hecker
- Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
| | - Andreas H Wagner
- Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
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19
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Bøhn SK, Thune I, Flote VG, Frydenberg H, Bertheussen GF, Husøy A, Fjeldheim F, Brunvoll SH, Hjartåker A, Mowinckel MC, Sandset PM, Iversen PO. Effects of a 1-Year Physical Activity Intervention on Markers of Hemostasis among Breast Cancer Survivors: A Randomized Controlled Trial. TH OPEN 2021; 5:e14-e23. [PMID: 33564742 PMCID: PMC7867414 DOI: 10.1055/s-0040-1721782] [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: 06/04/2020] [Accepted: 11/10/2020] [Indexed: 10/25/2022] Open
Abstract
Introduction Physical activity may reduce the development of breast cancer. Whereas hypercoagulability has been linked to adverse outcomes in breast cancer patients, the effects of physical activity on their hemostatic factors are unknown. The study aimed to assess whether long-term (1 year) physical activity can affect hemostatic factors in breast cancer patients. Methods Fifty-five women (35-75 years) with invasive breast cancer stage I/II were randomized to a physical activity intervention ( n = 29) lasting 1 year or to a control group ( n = 26), and analyzed as intention to treat. Fibrinogen, factor VII antigen, tissue factor pathway inhibitor, and von Willebrand factor (VWF) antigen as well as prothrombin fragment 1 + 2, the endogenous thrombin potential and D-dimer, were measured in plasma before intervention (baseline), and then after 6 and 12 months. Results Maximal oxygen uptake (measure of cardiorespiratory fitness) decreased the first 6 months among the controls, but remained stable in the intervention group. We found no significant differences between the two study groups regarding any of the hemostatic factors, except a significantly higher increase in factor VII antigen in the intervention group. The effect of the intervention on VWF was, however, significantly affected by menopausal stage, and a significant effect of the intervention was found on VWF among postmenopausal women, even after adjustment for dietary intake. Conclusion Long-term physical activity had no effect on the majority of the hemostatic factors measured, but led to increased plasma concentrations of factor VII antigen and prevented an increase in VWF concentration after breast cancer treatment in postmenopausal women. The clinical impact of these findings for risk of vascular thrombosis warrants further studies.
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Affiliation(s)
- Siv Kjølsrud Bøhn
- Faculty of Chemistry, Biotechnology and Food Sciences, Norwegian University of Life Sciences, Ås, Norway
| | - Inger Thune
- Department of Oncology, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
| | | | | | - Gro Falkenér Bertheussen
- Department of Physical Medicine and Rehabilitation, St. Olav University Hospital, Trondheim, Norway.,Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway
| | - Anders Husøy
- Department of Sports Medicine, Norwegian School of Sport Sciences, Oslo, Norway
| | | | | | - Anette Hjartåker
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | | | - Per Morten Sandset
- Department of Haematology, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Per Ole Iversen
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.,Department of Haematology, Oslo University Hospital and University of Oslo, Oslo, Norway
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20
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Schwarz C, Fitschek F, Mittlböck M, Saukel V, Bota S, Ferlitsch M, Ferlitsch A, Bodingbauer M, Kaczirek K. von Willebrand Factor Antigen Predicts Outcomes in Patients after Liver Resection of Hepatocellular Carcinoma. Gut Liver 2021; 14:218-224. [PMID: 30428508 PMCID: PMC7096232 DOI: 10.5009/gnl17115] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 10/26/2017] [Accepted: 11/25/2017] [Indexed: 12/12/2022] Open
Abstract
Background/Aims von Willebrand factor antigen (vWF-Ag) is a noninvasive predictor of portal hypertension that serves as a negative prognostic marker in various malignancies. Increased portal hypertension is associated with higher postoperative morbidity and decreased survival after hepatectomy. The purpose of this study was to determine the correlation between vWF-Ag, postoperative morbidity and oncological outcome. Methods This analysis includes 55 patients who underwent liver resection for hepatocellular carcinoma (HCC) between 2008 and 2015 with available preoperative vWF-Ag levels. The primary endpoints were postoperative complications and long-term outcome, including overall and disease-free survival. Results The median plasma level of vWF-Ag was 191% (range, 162.5% to 277%). There was a significant correlation between vWF-Ag levels and tumor size in the resected specimens (p=0.010, r=0.350). Patients who developed any grade of postoperative complication had significantly higher preoperative vWF-Ag levels (216% [range, 178% to 283.25%] vs 176% [range, 148% to 246%], p=0.041). Median overall survival was 39.8 months in patients with high vWF-Ag levels (≥191%) compared with 73.4 months in patients with low levels (<191%, p=0.007). Of note, there was a remarkable disparity in the number of patients who died of HCC with low versus high vWF-Ag levels (14.8% vs 28.6%, p=0.011). Conclusions vWF-Ag may serve as a prognostic marker for the outcome of patients undergoing liver resection for HCC that is closely connected to tumor size, postoperative complication rate and long-term outcome.
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Affiliation(s)
- Christoph Schwarz
- Department of General Surgery, Medical University Vienna, Vienna, Austria
| | - Fabian Fitschek
- Department of General Surgery, Medical University Vienna, Vienna, Austria
| | - Martina Mittlböck
- Center for Medical Statistics, Informatics, and Intelligent Systems, Section for Clinical Biometrics, Medical University Vienna, Vienna, Austria
| | - Veronika Saukel
- Department of General Surgery, Medical University Vienna, Vienna, Austria
| | - Simona Bota
- Department of Gastroenterology, Hepatology, Nephrology and Endocrinology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Monika Ferlitsch
- Center for Medical Statistics, Informatics, and Intelligent Systems, Section for Clinical Biometrics, Medical University Vienna, Vienna, Austria
| | - Arnulf Ferlitsch
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria
| | - Martin Bodingbauer
- Department of General Surgery, Medical University Vienna, Vienna, Austria
| | - Klaus Kaczirek
- Department of General Surgery, Medical University Vienna, Vienna, Austria
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21
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Patmore S, Dhami SPS, O'Sullivan JM. Von Willebrand factor and cancer; metastasis and coagulopathies. J Thromb Haemost 2020; 18:2444-2456. [PMID: 32573945 DOI: 10.1111/jth.14976] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/05/2020] [Accepted: 06/12/2020] [Indexed: 12/16/2022]
Abstract
Von Willebrand factor (VWF) is a multimeric procoagulant plasma glycoprotein that mediates platelet adhesion along the endothelium. In addition to its role maintaining normal hemostasis, more recently novel biological functions for VWF have been described, including inflammation, angiogenesis, and metastasis. Significantly increased plasma VWF levels have been reported across a variety of cancer patient cohorts. Given that VWF is established as a risk factor for venous thrombosis, this is of direct clinical importance. Moreover, elevated VWF has also been observed localized within the tumor microenvironment, correlating with advanced disease stage and poorer clinical outcome. Critically, evidence suggests that elevated VWF levels in cancer patients may not only contribute to cancer associated coagulopathies but may also mediate cancer progression and metastasis. Studies have shown that VWF can promote pro-inflammatory signaling, regulate angiogenesis and vascular permeability, which may facilitate tumor cell growth and extravasation across the vessel wall. Endothelial secreted VWF multimers contribute to the adhesion and transendothelial migration of tumor cells key for tumor dissemination. In support of this, VWF inhibition attenuated metastasis in vivo. Perhaps most intriguingly, specific tumor cells have been reported to acquire de novo VWF expression which increases tumor-platelet heteroaggregates and confers enhanced metastatic activity. Current knowledge on the roles of VWF in cancer and in particular its contribution to metastasis and cancer associated coagulopathies is summarized in this review.
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Affiliation(s)
- Sean Patmore
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Sukhraj Pal S Dhami
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Jamie M O'Sullivan
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
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22
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Aryal B, Yamakuchi M, Shimizu T, Kadono J, Furoi A, Gejima K, Takenouchi K, Komokata T, Hashiguchi T, Imoto Y. Bivalent property of intra-platelet VWF in liver regeneration and HCC recurrence: A prospective multicenter study. Cancer Biomark 2020; 26:51-61. [PMID: 31322547 DOI: 10.3233/cbm-190168] [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] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS A striking difference has been observed in structure and functional properties between plasma and platelet von Willebrand factor (VWF). While the existing evidence has revealed a clinical relevance of plasma VWF-Ag in liver regeneration (LR) and different cancers, this study was designed to explore the properties of intra-platelet (IP) and serum VWF-Ag in patients with hepatocellular carcinoma (HCC) undergoing partial hepatectomy. METHODS A total of 40 patients undergoing partial hepatectomy were prospectively recruited from 3 institutions. VWF-Ag concentrations were evaluated mainly in serum and platelet extracts. Patients were followed-up for postoperative liver dysfunction and HCC recurrence. RESULTS We observed a post-resection increase in the concentration of VWF-Ag in serum and platelet. Patients with postoperative liver dysfunction had substantially reduced serum and IP VWF-Ag concentrations. After a 2-year follow-up, patients with higher post-resection serum and IP VWF-Ag concentrations were found to develop early HCC recurrence. Likewise, IP VWF-Ag was able to independently predict post-resection early HCC recurrence. CONCLUSION This multicenter, prospective, pilot study demonstrates a bivalent property of IP VWF in LR and oncological outcome; low preoperative VWF appeared to have a negative association on post-resection liver dysfunction, whereas, patients with higher post-resection VWF-Ag concentrations were found to have early HCC recurrence.
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Affiliation(s)
- Bibek Aryal
- Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Munekazu Yamakuchi
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Toshiaki Shimizu
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Jun Kadono
- Department of Surgery, Kirishima Medical Center, Kirishima 899-5112, Japan
| | - Akira Furoi
- Department of Surgery, Kirishima Medical Center, Kirishima 899-5112, Japan
| | - Kentaro Gejima
- Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Kazunori Takenouchi
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Teruo Komokata
- Department of Surgery, Kagoshima Medical Center, National Hospital Organization, Kagoshima 892-0853, Japan
| | - Teruto Hashiguchi
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Yutaka Imoto
- Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
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23
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Takaya H, Namisaki T, Shimozato N, Kaji K, Kitade M, Moriya K, Sato S, Kawaratani H, Akahane T, Matsumoto M, Yoshiji H. ADAMTS13 and von Willebrand factor are useful biomarkers for sorafenib treatment efficiency in patients with hepatocellular carcinoma. World J Gastrointest Oncol 2019; 11:424-435. [PMID: 31139312 PMCID: PMC6522768 DOI: 10.4251/wjgo.v11.i5.424] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 03/26/2019] [Accepted: 04/08/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Many advanced hepatocellular carcinoma (HCC) patients are receiving sorafenib treatment. Sorafenib reportedly improves overall survival (OS) significantly in patients with HCC. Prediction of sorafenib response and prognosis in patients with HCC receiving sorafenib treatment are important due to the potentially serious side effects of sorafenib. A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) and von Willebrand factor (VWF) are associated with the pathophysiology of liver cirrhosis and HCC through their roles in hypercoagulability; they are also associated with angiogenesis via vascular endothelial growth factor (VEGF). The imbalance between ADAMTS13 and VWF was associated with prognosis of various cancers in patients undergoing chemotherapy. AIM To investigate ADAMTS13 and VWF as potential biomarkers for sorafenib response and prognosis in patients with HCC receiving sorafenib treatment. METHODS Forty-one patients with HCC receiving sorafenib treatment were included in this study. The initial daily sorafenib dose was 400 mg in all patients. ADAMTS13 activity (ADAMTS13:AC), VWF antigen (VWF:Ag), VEGF levels were determined by enzyme-linked immunosorbent assay. Univariate and multivariate analyses were used to determine predictive factors for sorafenib response and prognosis in patients with HCC receiving sorafenib treatment. RESULTS ADAMTS13:AC was significantly higher in patients with stable disease (SD), partial response (PR), and complete response (CR) than in those with progressive disease (PD) (P < 0.05). In contrast, VWF:Ag and the VWF:Ag/ADAMTS13:AC ratio were significantly lower in patients with SD, PR, and CR than in those with PD (P < 0.05 for both). Multivariate analysis showed that the VWF:Ag/ADAMTS13:AC ratio was the only predictive factor for sorafenib response and ADAMTS13:AC was the only prognostic factor in patients with HCC receiving sorafenib treatment. The patients with a low ADAMTS13:AC (< 78.0) had significantly higher VEGF levels than those with a high ADAMTS13:AC (≥ 78.0) (P < 0.05). CONCLUSION The VWF:Ag/ADAMTS13:AC ratio and ADAMTS13:AC are potentially useful biomarkers for sorafenib response and prognosis, respectively, in patients with HCC receiving sorafenib treatment.
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Affiliation(s)
- Hiroaki Takaya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Naotaka Shimozato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kosuke Kaji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Mitsuteru Kitade
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Shinya Sato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Takemi Akahane
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Masanori Matsumoto
- Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
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24
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Navone SE, Doniselli FM, Summers P, Guarnaccia L, Rampini P, Locatelli M, Campanella R, Marfia G, Costa A. Correlation of Preoperative Von Willebrand Factor with Magnetic Resonance Imaging Perfusion and Permeability Parameters as Predictors of Prognosis in Glioblastoma. World Neurosurg 2019; 122:e226-e234. [DOI: 10.1016/j.wneu.2018.09.216] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 09/26/2018] [Accepted: 09/28/2018] [Indexed: 10/28/2022]
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25
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Dengue Virus NS1 Exposure Affects von Willebrand Factor Profile and Platelet Adhesion Properties of Cultured Vascular Endothelial Cells. Indian J Hematol Blood Transfus 2018; 35:502-506. [PMID: 31388264 DOI: 10.1007/s12288-018-1058-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 12/03/2018] [Indexed: 10/27/2022] Open
Abstract
Hematological abnormalities and altered vascular permeability are frequently encountered in Dengue virus infected patients, but the mechanisms that alter platelet-endothelium interactions remain incompletely understood. The DENV NS1 protein has been implicated in adverse disease outcomes. In the present study the role of NS1 protein in affecting the expression of vWF and platelet adhesion properties of endothelial cells was studied in vitro. The results suggest that vWF is down regulated in cultured endothelial cells 6 and 24 h after exposure with increase in vWF levels in culture supernatants at corresponding time points. Ultrastructural studies showed distinct evidence of endothelial cell activation morphology and degranulation of Weibel-Palade bodies in NS1 exposed cells that also showed increased platelet activation physiology. The findings suggest that changes in vWF production and secretion may be induced in endothelial cells exposed to DENV NS1 protein; and play a role in bleeding complications of severe DENV disease.
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26
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von Willebrand factor rescued by miR-24 inhibition facilitates the proliferation and migration of osteosarcoma cells in vitro. Biosci Rep 2018; 38:BSR20180372. [PMID: 30279208 PMCID: PMC6240719 DOI: 10.1042/bsr20180372] [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] [Received: 03/12/2018] [Revised: 09/12/2018] [Accepted: 09/17/2018] [Indexed: 11/17/2022] Open
Abstract
von Willebrand factor (vWF) is a major procoagulant molecule that was shown to differentiate between metastatic and primary osteosarcoma (OS) tissues and associated with increased metastasis. However, its functional role in OS progression has been unclear yet. The expression profile of vWF and miR-24 in human OS tissues was characterized using immunofluorescence labeling and quantitative real-time PCR analysis. The interaction between miR-24 and vWF was identified by dual luciferase reporter assay. The effects of vWF and miR-24 on OS cells were assessed by cell proliferation, colony formation, and migration. The clinical significance of miR-24 in OS patients was analyzed using Kaplan–Meier analyses and Pearson’s Chi-squared test. Here, we reported that the expression of vWF was significantly increased, but miR-24 was significantly decreased in OS tissues (n=84). vWF was further validated as the target of miR-24 in MG-63 and U2OS cells. miR-24 obviously suppressed the proliferation and migration of MG-63 and U2OS cells. However, the migration-inhibiting activity of miR-24 was predominantly attenuated by vWF overexpression. Clinically, low miR-24 expression in human OS tissues was significantly associated with tumor metastasis and predicted a poor survival in OS patients. This work demonstrated that vWF, as a downstream effector of miR-24, played an important role in controlling OS cell progression. Target miR-24 or vWF, therefore, promises to be an effective biological target for OS treatment.
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27
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Takaya H, Kawaratani H, Tsuji Y, Nakanishi K, Saikawa S, Sato S, Sawada Y, Kaji K, Okura Y, Shimozato N, Kitade M, Akahane T, Moriya K, Namisaki T, Mitoro A, Matsumoto M, Fukui H, Yoshiji H. von Willebrand factor is a useful biomarker for liver fibrosis and prediction of hepatocellular carcinoma development in patients with hepatitis B and C. United European Gastroenterol J 2018; 6:1401-1409. [PMID: 30386613 PMCID: PMC6206538 DOI: 10.1177/2050640618779660] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 05/05/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Several noninvasive biomarkers are available for diagnosing liver fibrosis stage and predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis and liver cirrhosis. However, these biomarkers are not sufficiently accurate. Recently, von Willebrand factor (VWF) has been related to angiogenesis and apoptosis. Furthermore, VWF is associated with hepatic spare ability and HCC. OBJECTIVE We aimed to determine whether VWF is a potential biomarker for liver fibrosis and HCC development. METHODS Two hundred and twelve patients with chronic hepatitis B and C were recruited. VWF antigen (VWF: Ag) levels in each patient were determined via enzyme-linked immunosorbent assay. Univariable and multivariable analyses were used to determine the risk factor of HCC. RESULTS The VWF: Ag levels were higher in patients with severe liver fibrosis stage and/or HCC development than in those without. The area under the curve of VWF: Ag for diagnosis of severe liver fibrosis stage was 0.721. Multivariable analysis showed that only VWF: Ag was a predictive biomarker for HCC development. CONCLUSIONS VWF: Ag is related to liver fibrosis and may be useful for predicting HCC development. VWF is a potentially useful biomarker to diagnose severe liver fibrosis and predict HCC development.
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Affiliation(s)
- Hiroaki Takaya
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Hideto Kawaratani
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Yuki Tsuji
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Keisuke Nakanishi
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Soichiro Saikawa
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Shinya Sato
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Yasuhiko Sawada
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Kosuke Kaji
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Yasushi Okura
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Naotaka Shimozato
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Mitsuteru Kitade
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Takemi Akahane
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Kei Moriya
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Akira Mitoro
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Masanori Matsumoto
- Department of Blood Transfusion
Medicine,
Nara
Medical University, Kashihara, Japan
| | - Hiroshi Fukui
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine,
Nara
Medical University, Kashihara, Japan
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Linhares P, Viana-Pereira M, Ferreira M, Amorim J, Nabiço R, Pinto F, Costa S, Vaz R, Reis RM. Genetic variants of vascular endothelial growth factor predict risk and survival of gliomas. Tumour Biol 2018; 40:1010428318766273. [PMID: 29584591 DOI: 10.1177/1010428318766273] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The vascular endothelial growth factor regulates angiogenesis that is increased in glioma. VEGF polymorphisms are thought to modulate vascular endothelial growth factor plasma levels and therefore may be implicated in glioma risk. We aimed to clarify the role of VEGF and von Willebrand factor polymorphisms in glioma susceptibility and prognosis. A case-control study of 126 glioma patients and 180 cancer-free controls was performed. Using Sequenom MassARRAY platform, 11 VEGF and 1 VWF polymorphisms were genotyped. Unconditional multivariate logistic regression models were used to calculate odds ratios and 95% confidence intervals. The associations between polymorphisms and survival were evaluated using a Cox regression model. Bonferroni's adjustment was used to correct for multiple testing. The VEGF polymorphism rs833061 was strongly associated with increased risk for glioma (odds ratio = 164.85) and glioblastoma (odds ratio = 155.66), confirmed after Bonferroni correction. Also, the VEGF polymorphisms rs3024994, rs2010963, and particularly the homozygous carriers of rs1005230 were associated with a worse prognosis for glioma and glioblastoma. Our data support a role of VEGF and VWF polymorphisms as glioma biomarkers, with additional potential relevance for molecular stratification of patients for anti-angiogenic therapies.
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Affiliation(s)
- Paulo Linhares
- 1 Department of Neurosurgery, Hospital S. João, Porto, Portugal.,2 Faculty of Medicine, University of Porto, Porto, Portugal
| | - Marta Viana-Pereira
- 3 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,4 ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Mónica Ferreira
- 3 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,4 ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Júlia Amorim
- 5 Department of Oncology, Hospital de Braga, Braga, Portugal
| | - Rui Nabiço
- 5 Department of Oncology, Hospital de Braga, Braga, Portugal
| | - Filipe Pinto
- 3 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,4 ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Sandra Costa
- 3 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,4 ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Rui Vaz
- 1 Department of Neurosurgery, Hospital S. João, Porto, Portugal.,2 Faculty of Medicine, University of Porto, Porto, Portugal
| | - Rui Manuel Reis
- 3 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,4 ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.,6 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil
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29
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Yang AJ, Wang M, Wang Y, Cai W, Li Q, Zhao TT, Zhang LH, Houck K, Chen X, Jin YL, Mu JY, Dong JF, Li M. Cancer cell-derived von Willebrand factor enhanced metastasis of gastric adenocarcinoma. Oncogenesis 2018; 7:12. [PMID: 29362409 PMCID: PMC5833464 DOI: 10.1038/s41389-017-0023-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 11/16/2017] [Indexed: 01/30/2023] Open
Abstract
Cancer prognosis is poor for patients with blood-borne metastasis. Platelets are known to assist cancer cells in transmigrating through the endothelium, but ligands for the platelet-mediated cancer metastasis remain poorly defined. von Willebrand factor (vWF) is a major platelet ligand that has been widely used as a biomarker in cancer and associated inflammation. However, its functional role in cancer growth and metastasis is largely unknown. Here we report that gastric cancer cells from patients and cells from two well-established gastric cancer lines express vWF and secrete it into the circulation, upon which it rapidly becomes cell-bound to mediate cancer-cell aggregation and interaction with platelets and endothelial cells. The vWF-mediated homotypic and heterotypic cell-cell interactions promote the pulmonary graft of vWF-overexpressing gastric cancer BGC823 cells in a mouse model. The metastasis-promoting activity of vWF was blocked by antibodies against vWF and its platelet receptor GP Ibα. It was also reduced by an inhibitory siRNA that suppresses vWF expression. These findings demonstrate a causal role of cancer-cell-derived vWF in mediating gastric cancer metastasis and identify vWF as a new therapeutic target.
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Affiliation(s)
- Ai-Jun Yang
- Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Min Wang
- Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Yan Wang
- Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Gansu Provincial Hospital, Lanzhou, China
| | - Wei Cai
- Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Gansu Provincial Hospital, Lanzhou, China
| | - Qiang Li
- The First Affiliated Hospital of Lanzhou University, Lanzhou, China
| | - Ting-Ting Zhao
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Li-Han Zhang
- Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Katie Houck
- Bloodworks Research Institute, Seattle, Washington, USA
| | - Xu Chen
- Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Gansu Provincial Hospital, Lanzhou, China
| | - Yan-Ling Jin
- Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Ji-Ying Mu
- Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Jing-Fei Dong
- Bloodworks Research Institute, Seattle, Washington, USA. .,Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
| | - Min Li
- Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China. .,Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China. .,Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou, China.
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30
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Dai L, Peng XX, Tan EM, Zhang JY. Tumor-associated antigen CAPERα and microvessel density in hepatocellular carcinoma. Oncotarget 2017; 7:16985-95. [PMID: 26934653 PMCID: PMC4941365 DOI: 10.18632/oncotarget.7707] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 01/31/2016] [Indexed: 02/05/2023] Open
Abstract
PURPOSE CAPERα, a tumor-associated antigen, was identified from a cDNA clone with autoantibody from a patient with hepatocellular carcinoma (HCC). It has been implicated, by way of alternative splicing of VEGF pre-mRNA, in the regulation of microvessel formation in Ewing's sarcoma. In this study, we looked for possible association of alterations in CAPERα with microvessel density in HCC. METHODS Enzyme-linked immunosorbent assay using recombinant CAPERα as antigen were used to detect antibody against CAPERα. Immunohistochemistry (IHC) on liver sections was performed to analyze expression profiles of CAPERα, VEGF and CD34 in HCC and control tissues and was further used to assess the correlation of expression among CAPERα, VEGF and CD34 in HCC development. RESULTS Autoantibody to CAPERα was highest in HCC (22/76, 28.9%), not detected in prostate cancer (0/79) and at 3.4% (3/88) in breast cancer. In immunohistochemical analysis of grades II and III HCC tissues, significantly decreased immunostaining for CAPERα was observed and this correlated directly with decreased immunostaining for VEGF (R=0.534, P=0.0003). Using CD34 immunostaining for detecting newly formed microvessels, strong staining was observed in grades II and III HCC. Normal liver sections, all of which have high expression of CAPERα were totally negative for CD34 immunostaining. A significant inverse correlation was seen between CAPERα and CD34 immunostaining (R=-0.481, P=0.0012). CONCLUSIONS Decreased expression of CAPERα appears to be correlated with appearance of microvessels. It would be of interest to elucidate the cause of altered CAPERα since new formation of microvessels is important in progression of HCC.
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Affiliation(s)
- Liping Dai
- Department of Biological Sciences & NIH-Sponsored Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA
| | - Xuan-Xian Peng
- School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Eng M Tan
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Jian-Ying Zhang
- Department of Biological Sciences & NIH-Sponsored Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968, USA
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31
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Allouh MZ, Al Barbarawi MM, Hiasat MY, Al-Qaralleh MA, Ababneh EI. Glioblastoma and ABO blood groups: further evidence of an association between the distribution of blood group antigens and brain tumours. BLOOD TRANSFUSION = TRASFUSIONE DEL SANGUE 2017; 15:543-547. [PMID: 27416574 PMCID: PMC5649963 DOI: 10.2450/2016.0041-16] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Accepted: 04/28/2016] [Indexed: 01/20/2023]
Abstract
BACKGROUND Glioblastoma is a highly malignant brain tumour that usually leads to death. Several studies have reported a link between the distribution of ABO blood group antigens and a risk of developing specific types of cancer, although no consensus has been reached. This study aims to investigate the relationship between the distribution of ABO blood group antigens and the incidence of glioblastoma. MATERIALS AND METHODS The study cohort consisted of 115 glioblastoma patients who were diagnosed at King Abdullah University Hospital, Jordan, between 2004 and 2015. Three different patient populations made up three control groups and these were selected from among patients at the same institution between 2014 and 2015 as follows: 3,847 healthy blood donors, 654 accidental trauma patients admitted to the Departments of Neurosurgery and Orthopaedics, and 230 age- and sex-matched control subjects recruited blindly from the Departments of Paediatrics and Internal Medicine. RESULTS There was a significant association between the distribution of ABO blood group antigens and the incidence of glioblastoma. Post hoc residual analysis revealed that individuals with group A had a higher than expected chance of developing glioblastoma, while individuals with group O had a lower than expected chance. Furthermore, individuals with group A were found to be at a 1.62- to 2.28-fold increased risk of developing glioblastoma compared to individuals with group O. DISCUSSION In the present study, we demonstrate that, in Jordan, individuals with group A have an increased risk of developing glioblastoma, while individuals with group O have a reduced risk. These findings suggest that the distribution of ABO blood group antigens is associated with a risk of brain tumours and may play an important role in their development. However, further clinical and experimental investigations are required to confirm this association.
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Affiliation(s)
- Mohammed Z. Allouh
- Department of Anatomy, Department of Neuroscience, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Mohammed M. Al Barbarawi
- Division of Neurosurgery, Department of Neuroscience, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Mohammad Y. Hiasat
- Division of Neurosurgery, Department of Neuroscience, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Mohammed A. Al-Qaralleh
- Department of Anatomy, Department of Neuroscience, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Emad I. Ababneh
- Department of Anatomy, Department of Neuroscience, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
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32
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Von Willebrand factor protects against acute CCl 4-induced hepatotoxicity through phospho-p38 MAPK signaling pathway inhibition. Immunol Res 2017; 65:1046-1058. [PMID: 28868583 DOI: 10.1007/s12026-017-8946-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The blood glycoprotein von Willebrand factor (vWF) is involved in coagulopathy and inflammation; however, its role in the pathogenesis of acute liver failure, as suggested by its higher expression levels in such patients, remains unknown. In this study, vWF-knockout (KO) mice showed more severe carbon tetrachloride (CCl4)-induced liver injury than wild-type mice. Patients with acute liver injury also showed elevated vWF protein activity and expression in liver tissues, as compared to healthy individuals. Using the mouse model and cultured human umbilical vein endothelial cells (HUVECs), CCl4 was found to directly increase vWF protein expression through interaction with the highly expressed vWF receptor, GPIbα. Microarray analysis revealed that the genes showing the most differential expression in response to CCl4-induced liver injury and vWF deficiency were related to the MAPK signaling pathway. Subsequent inhibition of vWF protein activity in HUVECs led to activation of the MAPK signal pathway and elevated production of FGL2, and treatment with a phospho-p38 inhibitor suppressed the CCl4-induced production of FGL2. Exposure of liver sinusoidal endothelial cells isolated from the vWF-KO acute liver injury model mice to phospho-p38 inhibitor also decreased FGL2 expression. The vWF/GPIbα axis plays a protective role against development of acute liver injury by attenuating FGL2 production through the MAPK signaling pathway. Collectively, these data provide insight into the pathogenesis of acute liver injury and a potential novel strategy for its treatment.
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33
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Mashreghi M, Azarpara H, Bazaz MR, Jafari A, Masoudifar A, Mirzaei H, Jaafari MR. Angiogenesis biomarkers and their targeting ligands as potential targets for tumor angiogenesis. J Cell Physiol 2017; 233:2949-2965. [DOI: 10.1002/jcp.26049] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 06/12/2017] [Indexed: 12/20/2022]
Affiliation(s)
- Mohammad Mashreghi
- NanotechnologyResearch Center; Mashhad University of Medical Sciences; Mashhad Iran
- School of Pharmacy; Mashhad University of Medical Sciences; Mashhad Iran
| | - Hassan Azarpara
- School of Medicine; Iran University of Medical Sciences; Tehran Iran
| | - Mahere R. Bazaz
- Division of Biotechnology, Faculty of Veterinary Medicine; Ferdowsi University of Mashhad; Mashhad Iran
| | - Arash Jafari
- School of Medicine; Birjand University of Medical Sciences; Birjand Iran
| | - Aria Masoudifar
- Department of Molecular Biotechnology, Cell Science Research Center; Royan Institute for Biotechnology; ACECR Isfahan Iran
| | - Hamed Mirzaei
- Department of Medical Biotechnology, School of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | - Mahmoud R. Jaafari
- NanotechnologyResearch Center; Mashhad University of Medical Sciences; Mashhad Iran
- School of Pharmacy; Mashhad University of Medical Sciences; Mashhad Iran
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34
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Husseinzadeh H, Carrier M. Occult cancer detection in patients with hemostatic disorder and venous thromboembolism. Thromb Res 2017; 163:242-245. [PMID: 28587726 DOI: 10.1016/j.thromres.2017.05.034] [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: 03/21/2017] [Revised: 05/21/2017] [Accepted: 05/31/2017] [Indexed: 11/28/2022]
Abstract
There are physiologic ties between Von Willebrand Factor (VWF) and circulating tumor cells. VWF appears to play a role in tumor biology, but it is unclear whether cancer behavior differs in Von Willebrand Disease. In patients presenting with venous thromboembolism (VTE), occult cancer is frequently considered as an underlying cause. The prevalence of occult cancer after provoked VTE is low (3%); therefore, cancer screening in these patients is not routinely recommended. In those with unprovoked VTE, occult cancer is more prevalent, estimated between 4 and 10%. Due to this elevated risk, occult cancer screening is recommended in this population. Multiple studies have investigated whether a "limited" approach (including history and physical exam, basic labs, and chest X-ray) versus "extensive" approach (addition of advanced imaging, such as computer tomography) is more effective. Current data fails to demonstrate extensive screening strategies diagnose more occult cancer, miss fewer cancers during follow up, or improve cancer-related mortality. Furthermore, many patients may be needlessly exposed to unnecessary diagnostic procedures with their associated complications and costs, as well as significant anxiety. Therefore, the decision to perform additional testing should be made on a case-by-case basis. Additional studies are needed to identify subgroups of patients with unprovoked VTE at highest risk for occult cancer.
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Affiliation(s)
- Holleh Husseinzadeh
- Department of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA.
| | - Marc Carrier
- Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada.
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35
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High relative density of lymphatic vessels predicts poor survival in tongue squamous cell carcinoma. Eur Arch Otorhinolaryngol 2016; 273:4515-4524. [DOI: 10.1007/s00405-016-4150-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 06/14/2016] [Indexed: 01/28/2023]
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36
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Marfia G, Navone SE, Fanizzi C, Tabano S, Pesenti C, Abdel Hadi L, Franzini A, Caroli M, Miozzo M, Riboni L, Rampini P, Campanella R. Prognostic value of preoperative von Willebrand factor plasma levels in patients with Glioblastoma. Cancer Med 2016; 5:1783-90. [PMID: 27236861 PMCID: PMC4887291 DOI: 10.1002/cam4.747] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 03/24/2016] [Accepted: 04/02/2016] [Indexed: 11/26/2022] Open
Abstract
Circulating biomarker for malignant gliomas could improve both differential diagnosis and clinical management of brain tumor patients. Among all gliomas, glioblastoma (GBM) is considered the most hypervascularized tumor with activation of multiple proangiogenic signaling pathways that enhance tumor growth. To investigate whether preoperative antigen plasma level of von Willebrand Factor (VWF:Ag) might be possible marker for GBM onset, progression, and prognosis, we retrospectively examined 57 patients with histological diagnosis for GBM and 23 meningiomas (MNGs), benign intracranial expansive lesions, enrolled as controls. Blood samples were collected from all the patients before tumor resection. Plasma von Willebrand Factor (VWF):Ag levels were determined by using a latex particle‐enhanced immunoturbidimetric assay. The median levels of vWF:Ag were significantly higher in GBMs than in meningiomas (MNGs) (183 vs. 133 IU/dL, P = 0.01). The cumulative 1‐year survival was significantly shorter in patients with VWF:Ag levels >200 IU/dL than in those with levels <200 IU/dL and increased VWF levels were associated with a threefold higher risk of death in GBM patients. Our data suggest that VWF:Ag could be a circulating biomarker of disease malignancy, that could be considered, in association with other genetic and epigenetic factors, currently available in the GBM management. Future studies should investigate whether plasma VWF:Ag levels could also be used to monitor therapeutic effects and whether it may have a prognostic value.
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Affiliation(s)
- Giovanni Marfia
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, via F. Sforza, 35, Milan, 20122, Italy
| | - Stefania Elena Navone
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, via F. Sforza, 35, Milan, 20122, Italy
| | - Claudia Fanizzi
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, via F. Sforza, 35, Milan, 20122, Italy
| | - Silvia Tabano
- Division of Pathology, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, via F. Sforza, 35, Milan, 20122, Italy
| | - Chiara Pesenti
- Division of Pathology, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, via F. Sforza, 35, Milan, 20122, Italy
| | - Loubna Abdel Hadi
- Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, via Fratelli Cervi, 93, MI Milan, Segrate, 20090, Italy
| | - Andrea Franzini
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, via F. Sforza, 35, Milan, 20122, Italy
| | - Manuela Caroli
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, via F. Sforza, 35, Milan, 20122, Italy
| | - Monica Miozzo
- Division of Pathology, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, via F. Sforza, 35, Milan, 20122, Italy
| | - Laura Riboni
- Department of Medical Biotechnology and Translational Medicine, LITA-Segrate, University of Milan, via Fratelli Cervi, 93, MI Milan, Segrate, 20090, Italy
| | - Paolo Rampini
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, via F. Sforza, 35, Milan, 20122, Italy
| | - Rolando Campanella
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, via F. Sforza, 35, Milan, 20122, Italy
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GT198 Expression Defines Mutant Tumor Stroma in Human Breast Cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 186:1340-50. [PMID: 27001628 DOI: 10.1016/j.ajpath.2016.01.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 12/02/2015] [Accepted: 01/14/2016] [Indexed: 12/19/2022]
Abstract
Human breast cancer precursor cells remain to be elucidated. Using breast cancer gene product GT198 (PSMC3IP; alias TBPIP or Hop2) as a unique marker, we revealed the cellular identities of GT198 mutant cells in human breast tumor stroma. GT198 is a steroid hormone receptor coactivator and a crucial factor in DNA repair. Germline mutations in GT198 are present in breast and ovarian cancer families. Somatic mutations in GT198 are present in ovarian tumor stromal cells. Herein, we show that human breast tumor stromal cells carry GT198 somatic mutations and express cytoplasmic GT198 protein. GT198(+) stromal cells share vascular smooth muscle cell origin, including myoepithelial cells, adipocytes, capillary pericytes, and stromal fibroblasts. Frequent GT198 mutations are associated with GT198(+) tumor stroma but not with GT198(-) tumor cells. GT198(+) progenitor cells are mostly capillary pericytes. When tested in cultured cells, mutant GT198 induces vascular endothelial growth factor promoter, and potentially promotes angiogenesis and adipogenesis. Our results suggest that multiple lineages of breast tumor stromal cells are mutated in GT198. These findings imply the presence of mutant progenitors, whereas their descendants, carrying the same GT198 mutations, are collectively responsible for forming breast tumor microenvironment. GT198 expression is, therefore, a specific marker of mutant breast tumor stroma and has the potential to facilitate diagnosis and targeted treatment of human breast cancer.
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Meulendijks D, Beerepoot LV, Boot H, de Groot JWB, Los M, Boers JE, Vanhoutvin SALW, Polee MB, Beeker A, Portielje JEA, de Jong RS, Goey SH, Kuiper M, Sikorska K, Beijnen JH, Tesselaar ME, Schellens JHM, Cats A. Trastuzumab and bevacizumab combined with docetaxel, oxaliplatin and capecitabine as first-line treatment of advanced HER2-positive gastric cancer: a multicenter phase II study. Invest New Drugs 2015; 34:119-28. [PMID: 26643663 DOI: 10.1007/s10637-015-0309-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 11/11/2015] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To investigate the efficacy of bevacizumab and trastuzumab combined with docetaxel, oxaliplatin, and capecitabine (B-DOCT) as first-line treatment of advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). METHODS In this multicentre, single-arm, phase II study, tumor HER2 status was determined centrally prior to treatment. Patients with advanced HER2-positive adenocarcinoma of the stomach or gastroesophageal junction (immunohistochemistry 3+ or immunohistochemistry 2+/silver in-situ hybridization positive) were treated with six cycles of bevacizumab 7.5 mg/kg (day 1), docetaxel 50 mg/m(2) (day 1), oxaliplatin 100 mg/m(2) (day 1), capecitabine 850 mg/m(2) b.i.d. (days 1-14), and trastuzumab 6 mg/kg (day 1) every three weeks, followed by maintenance with bevacizumab, capecitabine, and trastuzumab until disease progression. The primary objective was to demonstrate an improvement of progression-free survival (PFS) to >7.6 months (observed in the ToGA trial) determined according to the lower limit of the 95 % confidence interval (CI). Secondary endpoints were safety, objective response rate (ORR), and overall survival (OS). RESULTS Twenty-five patients with HER2-positive tumors were treated with B-DOCT between March 2011 and September 2014. At a median follow-up of 17 months, median PFS was 10.8 months (95%CI: 9.0-NA), OS was 17.9 months (95%CI: 12.4-NA). One-year PFS and OS were 52 % and 79 %, respectively. The ORR was 74 % (95%CI: 52-90 %). Two patients became resectable during treatment with B-DOCT and achieved a pathological complete response. The most common treatment-related grade ≥ 3 adverse events were: neutropenia (16 %), diarrhoea (16 %), and hypertension (16 %). CONCLUSIONS B-DOCT is a safe and active combination in HER2-positive GC, supporting further investigations of DOC with HER2/vascular endothelial growth factor (VEGF) inhibition in HER2-positive GC.
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Affiliation(s)
- Didier Meulendijks
- Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | | | - Henk Boot
- Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | | | - Maartje Los
- Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands
| | - James E Boers
- Department of Pathology, Isala, Zwolle, The Netherlands
| | - Steven A L W Vanhoutvin
- Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Marco B Polee
- Department of Internal Medicine, Medical Center Leeuwarden, Leeuwarden, The Netherlands
| | - Aart Beeker
- Department of Internal Medicine, Spaarne Hospital Hoofddorp, Hoofddorp, The Netherlands
| | | | - Robert S de Jong
- Department of Internal Medicine, Martini Hospital, Groningen, The Netherlands
| | - Swan H Goey
- Department of Internal Medicine, Tweesteden Hospital, Tilburg, The Netherlands
| | - Maria Kuiper
- Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Karolina Sikorska
- Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jos H Beijnen
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands
| | - Margot E Tesselaar
- Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jan H M Schellens
- Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands
| | - Annemieke Cats
- Department of Gastroenterology and Hepatology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
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