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Tian Y, Zong Y, Pang Y, Zheng Z, Ma Y, Zhang C, Gao J. Platelets and diseases: signal transduction and advances in targeted therapy. Signal Transduct Target Ther 2025; 10:159. [PMID: 40374650 DOI: 10.1038/s41392-025-02198-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 12/18/2024] [Accepted: 02/24/2025] [Indexed: 05/17/2025] Open
Abstract
Platelets are essential anucleate blood cells that play pivotal roles in hemostasis, tissue repair, and immune modulation. Originating from megakaryocytes in the bone marrow, platelets are small in size but possess a highly specialized structure that enables them to execute a wide range of physiological functions. The platelet cytoplasm is enriched with functional proteins, organelles, and granules that facilitate their activation and participation in tissue repair processes. Platelet membranes are densely populated with a variety of receptors, which, upon activation, initiate complex intracellular signaling cascades. These signaling pathways govern platelet activation, aggregation, and the release of bioactive molecules, including growth factors, cytokines, and chemokines. Through these mechanisms, platelets are integral to critical physiological processes such as thrombosis, wound healing, and immune surveillance. However, dysregulated platelet function can contribute to pathological conditions, including cancer metastasis, atherosclerosis, and chronic inflammation. Due to their central involvement in both normal physiology and disease, platelets have become prominent targets for therapeutic intervention. Current treatments primarily aim to modulate platelet signaling to prevent thrombosis in cardiovascular diseases or to reduce excessive platelet aggregation in other pathological conditions. Antiplatelet therapies are widely employed in clinical practice to mitigate clot formation in high-risk patients. As platelet biology continues to evolve, emerging therapeutic strategies focus on refining platelet modulation to enhance clinical outcomes and prevent complications associated with platelet dysfunction. This review explores the structure, signaling pathways, biological functions, and therapeutic potential of platelets, highlighting their roles in both physiological and pathological contexts.
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Affiliation(s)
- Yuchen Tian
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yao Zong
- Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, Western Australia, Australia
| | - Yidan Pang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhikai Zheng
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiyang Ma
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Changqing Zhang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Ayana S, Aynalem M, Adane T, Shiferaw E. Coagulation profiles of breast cancer patients attending at cancer treatment centres in Northwest Ethiopia 2023: a comparative cross-sectional study. Sci Rep 2025; 15:16979. [PMID: 40374713 DOI: 10.1038/s41598-025-02104-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 05/12/2025] [Indexed: 05/17/2025] Open
Abstract
Breast cancer is the primary cause of cancer-related deaths in women, especially in developing nations where early detection and comorbidity management are challenging. Coagulopathy significantly enhance the disease severity, but its impact on Ethiopian patients is unclear. Therefore, this study aims to investigate and compare coagulation profiles in chemotherapy-experienced, chemotherapy-naive breast cancer patients, and healthy controls. An Institutional-based comparative cross-sectional study was conducted at the University of Gondar and Felege Hiwot Comprehensive Specialized Hospitals from 15 May 2023 to 30 August 2023 on a total of 180 participants. Participants socio-demographic and clinical data were collected using structured questionnaires in face-to-face interviews and medical record reviews. Blood sample for laboratory tests were taken, with 3 ml in ethylenediaminetetraacetic acid, 3 ml in trisodium citrate, and 2 ml in serum separator tubes. Coagulation parameters were measured using Genrui coagulation analyser (CA51) and Sysmex KX-21 hematology analyser. Data entry was done using Epi Data version 4.6 and transform to SPSS version 25 for analysis then descriptive statistics was presenting with tables. One-way ANOVA and Kruskal-Wallis tests were used to compare coagulation parameters among the three study groups, considering normal and skewed data, respectively. The activated partial thromboplastin time in chemotherapy-experienced, chemotherapy-naïve patients, and healthy controls showed median ± IQR values of 34.3 ± 15.8, 35 ± 13.3, and 29.2 ± 5.9 s, respectively, indicating a significant difference (p: 0.016). Similarly, the prothrombin time in the same groups had median ± IQR values of 15 ± 3.9, 15.3 ± 2.9, and 13.2 ± 1.9 s, respectively, with a significant difference (p < 0.001). Platelet count mean ± SD in chemotherapy-experienced, chemotherapy-naïve patients, and healthy controls were 351.3 ± 99.6, 345.6 ± 117.5, and 284.3 ± 79.3, respectively, showing a significant difference (p < 0.001). The mean ± SD of mean platelet volume in the same groups were 10.4 ± 2.7, 9.5 ± 2.4, and 9 ± 1.2, respectively, with a significant difference (p: 0.003). Coagulation parameters of both chemotherapy-experienced and chemotherapy-naïve patients were abnormally prolonged compared to healthy controls. This event indicates in vivo coagulation and it may increase bleeding tendency in patients. Therefore, early laboratory investigation of the coagulation profiles of breast cancer patients is critical for early detection and intervention of the coagulopathy.
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Affiliation(s)
- Sisay Ayana
- Department of Medical Laboratory Science, College of Health Science, Woldia University, Woldia, Ethiopia.
| | - Melak Aynalem
- Department of Hematology and Immunohematology, School of Biomedical and Laboratory Science, College of Medicine and Health Science, University of Gondar, Gondar, Ethiopia
| | - Tiruneh Adane
- Department of Hematology and Immunohematology, School of Biomedical and Laboratory Science, College of Medicine and Health Science, University of Gondar, Gondar, Ethiopia
| | - Elias Shiferaw
- Department of Hematology and Immunohematology, School of Biomedical and Laboratory Science, College of Medicine and Health Science, University of Gondar, Gondar, Ethiopia
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Chen Z, Xu L, Yuan Y, Zhang S, Xue R. Metabolic crosstalk between platelets and cancer: Mechanisms, functions, and therapeutic potential. Semin Cancer Biol 2025; 110:65-82. [PMID: 39954752 DOI: 10.1016/j.semcancer.2025.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 02/17/2025]
Abstract
Platelets, traditionally regarded as passive mediators of hemostasis, are now recognized as pivotal regulators in the tumor microenvironment, establishing metabolic feedback loops with tumor and immune cells. Tumor-derived signals trigger platelet activation, which induces rapid metabolic reprogramming, particularly glycolysis, to support activation-dependent functions such as granule secretion, morphological changes, and aggregation. Beyond self-regulation, platelets influence the metabolic processes of adjacent cells. Through direct mitochondrial transfer, platelets reprogram tumor and immune cells, promoting oxidative phosphorylation. Additionally, platelet-derived cytokines, granules, and extracellular vesicles drive metabolic alterations in immune cells, fostering suppressive phenotypes that facilitate tumor progression. This review examines three critical aspects: (1) the distinctive metabolic features of platelets, particularly under tumor-induced activation; (2) the metabolic crosstalk between activated platelets and other cellular components; and (3) the therapeutic potential of targeting platelet metabolism to disrupt tumor-promoting networks. By elucidating platelet metabolism, this review highlights its essential role in tumor biology and its therapeutic implications.
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Affiliation(s)
- Zhixue Chen
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Lin Xu
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yejv Yuan
- The First Affiliated Hospital of Anhui University of Science and Technology, Huainan 232001, China
| | - Si Zhang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Ruyi Xue
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
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Chou SC, Chang SL, Yu CY, Lin CI, Chang YT, Chen LF, Li JY, Pai CH, Lin SR, Cheng WC, Yuan CT, Lin SW. Tissue factor, factor VIII and IX in microvesicle-induced thrombosis and tumor growth of pancreatic cancer. Thromb J 2025; 23:32. [PMID: 40217494 PMCID: PMC11987238 DOI: 10.1186/s12959-025-00715-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 03/26/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Tissue factor (TF)-rich cancer microvesicles are correlated with thrombosis risk. Intrinsic coagulation factors are also associated with the risk of thrombosis in cancer patients. This study explored the roles of pancreatic cancer-derived microvesicles and intrinsic factors in thrombogenesis. METHODS Human pancreatic cancer cell lines rich in TF (AsPC-1-TFhigh, MIAPaCa-2-TFhigh) or poor in TF [AsPC-1-TFKO(knockout) and MIAPaCa-2-TFlow] were generated for microvesicle preparation and injected into coagulation-defective mice. Inferior vena cava (IVC) clots and lung thrombosis were evaluated. Immunodeficient hemophilia A (NSG-HA) mice were orthotopically injected with the cells mentioned above, and the tumor and IVC clot weights were analyzed. RESULTS With the injection of TFhigh microvesicles, IVC clots were rarely found in hemophilic mice. The TFlow and TFKO microvesicles resulted in few IVC clots in any mouse. Lung thrombosis was substantially reduced in the hemophilic mice infused with any microvesicle type. In orthotopic tumor models, TFhigh cells grew faster than did TFlow cells. TFhigh tumor-bearing NSG-WT mice had the most enormous IVC clots, whereas NSG-HA mice had no IVC clots. CONCLUSION Pancreatic cancer thrombosis induced by TF-expressing microvesicles strongly depended on FVIII and FIX, while VWF played a minor role. Moreover, TF, but not FVIII, was significantly related to tumor growth.
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Affiliation(s)
- Sheng-Chieh Chou
- Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shu-Lun Chang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Cheng-Yeh Yu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Chao-I Lin
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Yen-Ting Chang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Li-Fu Chen
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Jia-Yi Li
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Chen-Hsueh Pai
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Shu-Rung Lin
- Department of Bioscience Technology, College of Science, Chung-Yuan Christian University, Taoyuan, Taiwan
- Center for Nanotechnology, Chung-Yuan Christian University, Taoyuan, Taiwan
| | - Wern-Cherng Cheng
- Department of Laboratory Medicine, College of Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
- Department of Laboratory Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - Chang-Tsu Yuan
- Department of Pathology, National Taiwan University Cancer Center, Taipei, Taiwan
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Shu-Wha Lin
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.
- Department of Laboratory Medicine, College of Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.
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Reghukumar SK, Inkielewicz-Stepniak I. Tumour cell-induced platelet aggregation in breast cancer: Scope of metal nanoparticles. Biochim Biophys Acta Rev Cancer 2025; 1880:189276. [PMID: 39921012 DOI: 10.1016/j.bbcan.2025.189276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 01/30/2025] [Accepted: 02/01/2025] [Indexed: 02/10/2025]
Abstract
Breast cancer is a major cause of cancer-related mortality among the female population worldwide. Among the various factors promoting breast cancer metastasis, the role of cancer-cell platelet interactions leading to tumour cell-induced platelet aggregation (TCIPA) has garnered significant attention recently. Our state-of-the-art literature review verifies the implications of metal nanoparticles in breast cancer research and TCIPA-specific breast cancer metastasis. We have evaluated in vitro and in vivo research data as well as clinical investigations within the scope of this topic presented in the last ten years. Nanoparticle-based drug delivery platforms in cancer therapy can combat the growing concerns of multi-drug resistance, the alarming rates of chemotherapy-induced toxicities and cancer progression. Metal nanoparticles conjugated with chemotherapeutics can outperform their free drug counterparts in achieving targeted drug delivery and desired drug concentration inside the tumour tissue with minimal toxic effects. Existing data highlights the potential of metal nanoparticles as a promising tool for targeting the platelet-specific interactions associated with breast cancer metastasis including TCIPA.
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Miao L, Yang Y, Cheng M, Chen L, Han C. Ginsenoside Rb prevents the metastasis of hepatocarcinoma by blocking the platelet-tumor cell interaction. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:1721-1733. [PMID: 39172150 DOI: 10.1007/s00210-024-03387-y] [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: 04/10/2024] [Accepted: 08/15/2024] [Indexed: 08/23/2024]
Abstract
BACKGROUND The interaction between platelets and tumor cells is a crucial step in the progression of tumor metastasis. Blocking platelet-tumor cell interaction is a potential target against metastasis. Ginsenoside Rb (G-Rb) exhibits potential anti-tumor pharmacological properties and may offer a therapeutic option for cancer. PURPOSE This study aimed to investigate anti-metastatic effects of G-Rb through regulating the crosstalk of platelets with tumor cells. METHODS In order to explore anti-metastatic effects of G-Rb in vitro, HepG2 cell and platelets were co-cultured to mimic the interaction of platelets with tumor cells. Wound healing and Transwell assays were used to assess the effect of G-Rb on cell migration and invasion. The expression of epithelial-mesenchymal transition (EMT)-related markers was determined by RT-qPCR and western blot assays. The aggregation and activation of platelets were detected by flow cytometry. Moreover, a lung metastasis model of mice was established to evaluate inhibitory effects of G-Rb in vivo. Metastatic nodules on the lung surface were counted and sections of lung tissues were stained by H&E. RESULTS G-Rb effectively suppressed tumor metastasis in the co-culture of platelets with HepG2 cell. First, G-Rb treatment significantly inhibited the migration and invasion of HepG2 cells induced by platelets. Second, the expressions of EMT-related markers, including N-cadherin, Snail, and MMP9, were decreased by the treatment of G-Rb in the presence of platelets. Meanwhile, G-Rb also suppressed platelet hyperactivity by regulating the adhesion to tumor cells, activation, TCIPA, and TGF-β1 secretion of platelets in vitro. In addition, the results of in vivo experiments proved G-Rb administration not only significantly decreased lung metastasis but also attenuated platelets aberrant aggregation and activation in vivo. CONCLUSION Our findings showed that G-Rb inhibited tumor metastasis and platelet activation through mediating platelet-tumor cell interaction, indicating the potential values of G-Rb in tumor metastasis therapy.
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Affiliation(s)
- Longxing Miao
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, People's Republic of China
- The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, People's Republic of China
| | - Yijun Yang
- Department of Pharmacy, Shandong Medical College, Jinan, 250002, People's Republic of China
| | - Mengtao Cheng
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, People's Republic of China
| | - Lijing Chen
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, People's Republic of China
- The Second Affiliated Hospital of Shandong, University of Traditional Chinese Medicine, Jinan, 250000, People's Republic of China
| | - Chunchao Han
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, People's Republic of China.
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Bonifay A, Mackman N, Hisada Y, Sachetto ATA, Hau C, Gray E, Hogwood J, Aharon A, Badimon L, Barile L, Baudar J, Beckmann L, Benedikter B, Bolis S, Bouriche T, Brambilla M, Burrello J, Camera M, Campello E, Ettelaie C, Faille D, Featherby S, Franco C, Guldenpfennig M, Hansen JB, Judicone C, Kim Y, Kristensen SR, Laakmann K, Langer F, Latysheva N, Lucien F, de Menezes EM, Mullier F, Norris P, Nybo J, Orbe J, Osterud B, Paramo JA, Radu CM, Roncal C, Samadi N, Snir O, Suades R, Wahlund C, Chareyre C, Abdili E, Martinod K, Thaler J, Dignat-George F, Nieuwland R, Lacroix R. Comparison of assays measuring extracellular vesicle tissue factor in plasma samples: communication from the ISTH SSC Subcommittee on Vascular Biology. J Thromb Haemost 2024; 22:2910-2921. [PMID: 38925490 DOI: 10.1016/j.jtha.2024.05.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 04/23/2024] [Accepted: 05/23/2024] [Indexed: 06/28/2024]
Abstract
BACKGROUND Scientific and clinical interest in extracellular vesicles (EVs) is growing. EVs that expose tissue factor (TF) bind factor VII/VIIa and can trigger coagulation. Highly procoagulant TF-exposing EVs are detectable in the circulation in various diseases, such as sepsis, COVID-19, or cancer. Many in-house and commercially available assays have been developed to measure EV-TF activity and antigen, but only a few studies have compared some of these assays. OBJECTIVES The International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Subcommittee on Vascular Biology initiated a multicenter study to compare the sensitivity, specificity, and reproducibility of these assays. METHODS Platelet-depleted plasma samples were prepared from blood of healthy donors. The plasma samples were spiked either with EVs from human milk or EVs from TF-positive and TF-negative cell lines. Plasma was also prepared from whole human blood with or without lipopolysaccharide stimulation. Twenty-one laboratories measured EV-TF activity and antigen in the prepared samples using their own assays representing 18 functional and 9 antigenic assays. RESULTS There was a large variability in the absolute values for the different EV-TF activity and antigen assays. Activity assays had higher specificity and sensitivity compared with antigen assays. In addition, there was a large intra-assay and interassay variability. Functional assays that used a blocking anti-TF antibody or immunocapture were the most specific and sensitive. Activity assays that used immunocapture had a lower coefficient of variation compared with assays that isolated EVs by high-speed centrifugation. CONCLUSION Based on this multicenter study, we recommend measuring EV-TF using a functional assay in the presence of an anti-TF antibody.
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Affiliation(s)
- Amandine Bonifay
- Aix-Marseille University, C2VN, INSERM 1263, INRAE1260, Marseille, France; Department of Hematology and Vascular Biology, CHU La Conception, APHM, Marseille, France
| | - Nigel Mackman
- UNC Blood Research Center, Division of Hematology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Yohei Hisada
- UNC Blood Research Center, Division of Hematology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Ana Teresa Azevedo Sachetto
- UNC Blood Research Center, Division of Hematology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Chi Hau
- Laboratory of Experimental Clinical Chemistry, and Amsterdam Vesicle Center, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Elaine Gray
- National Institute for Biological Standards and Control, Potter's Bar, Hertfordshire, United Kingdom
| | - John Hogwood
- National Institute for Biological Standards and Control, Potter's Bar, Hertfordshire, United Kingdom
| | - Anat Aharon
- Hematology Research Laboratory, Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Lina Badimon
- Cardiovascular ICCC Program, Research Institute Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain; Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain
| | - Lucio Barile
- Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
| | - Justine Baudar
- Université Catholique de Louvain, CHU UCL NAMUR, Namur Thrombosis and Hemostasis Center (NTHC), Yvoir, Belgium
| | - Lennart Beckmann
- Department of Hematology and Oncology, University Cancer Center Hamburg (UCCH), University Medical Center Eppendorf, Hamburg, Germany
| | - Birke Benedikter
- Institute for Lung Research, Universities of Giessen and Marburg Lung Centre, Philipps-University Marburg, German Center for Lung Research (DZL), Marburg, Germany; University Eye Clinic Maastricht, MHeNs School for Mental Health and Neuroscience, Maastricht University Medical Center + (MUMC+), Maastricht, the Netherlands
| | - Sara Bolis
- Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Tarik Bouriche
- Research and Technology Department, BioCytex, Marseille, France
| | | | - Jacopo Burrello
- Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Marina Camera
- Centro Cardiologico Monzino IRCCS, Milan, Italy; Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy
| | - Elena Campello
- Department of Medicine, University of Padova, Padua, Italy
| | - Camille Ettelaie
- Biomedical Science, University of Hull/HYMS, Cottingham Road, Hull, United Kingdom
| | - Dorothée Faille
- Université Paris Cité and Université Sorbonne Paris Nord, INSERM, LVTS, Paris, France; Laboratoire d'Hématologie, AP-HP, Hôpital Bichat, Paris, France
| | - Sophie Featherby
- Biomedical Science, University of Hull/HYMS, Cottingham Road, Hull, United Kingdom
| | - Corentin Franco
- Research and Technology Department, BioCytex, Marseille, France
| | - Maite Guldenpfennig
- Université Catholique de Louvain, CHU UCL NAMUR, Namur Thrombosis and Hemostasis Center (NTHC), Yvoir, Belgium
| | - John-Bjarne Hansen
- Thrombosis Research Group (TREC), Institute of Clinical Medicine, UiT - The Arctic University of Norway, Tromsø, Norway; Thrombosis Research Center (TREC), Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
| | | | - Yohan Kim
- epartment of Urology, Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA
| | - Soren Risom Kristensen
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Katrin Laakmann
- Institute for Lung Research, Universities of Giessen and Marburg Lung Centre, Philipps-University Marburg, German Center for Lung Research (DZL), Marburg, Germany
| | - Florian Langer
- Department of Hematology and Oncology, University Cancer Center Hamburg (UCCH), University Medical Center Eppendorf, Hamburg, Germany
| | - Nadezhda Latysheva
- Thrombosis Research Group (TREC), Institute of Clinical Medicine, UiT - The Arctic University of Norway, Tromsø, Norway
| | - Fabrice Lucien
- epartment of Urology, Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA
| | - Erika Marques de Menezes
- Vitalant Research Institute, San Francisco, California, USA; Department of Laboratory Medicine, University of California, San Francisco, California, USA
| | - François Mullier
- Université Catholique de Louvain, CHU UCL NAMUR, Namur Thrombosis and Hemostasis Center (NTHC), Yvoir, Belgium
| | - Philip Norris
- Vitalant Research Institute, San Francisco, California, USA; Department of Laboratory Medicine, University of California, San Francisco, California, USA; Department of Medicine, UCSF, San Francisco, California, USA
| | - Jette Nybo
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Josune Orbe
- Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, Cima Universidad de Navarra, Pamplona, Spain; IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain; RICORS-Cerebrovascular Diseases, Instituto de Salud Carlos III, Madrid, Spain
| | - Bjarne Osterud
- Thrombosis Research Group (TREC), Institute of Clinical Medicine, UiT - The Arctic University of Norway, Tromsø, Norway
| | - Jose A Paramo
- Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain; Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, Cima Universidad de Navarra, Pamplona, Spain; IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - Claudia M Radu
- Department of Medicine, University of Padova, Padua, Italy
| | - Carmen Roncal
- Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain; Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, Cima Universidad de Navarra, Pamplona, Spain; IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain; RICORS-Cerebrovascular Diseases, Instituto de Salud Carlos III, Madrid, Spain
| | - Nazanin Samadi
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Omri Snir
- Thrombosis Research Group (TREC), Institute of Clinical Medicine, UiT - The Arctic University of Norway, Tromsø, Norway
| | - Rosa Suades
- Cardiovascular ICCC Program, Research Institute Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain; Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain
| | - Casper Wahlund
- Thrombosis Research Group (TREC), Institute of Clinical Medicine, UiT - The Arctic University of Norway, Tromsø, Norway
| | - Corinne Chareyre
- Aix-Marseille University, C2VN, INSERM 1263, INRAE1260, Marseille, France
| | - Evelyne Abdili
- Department of Hematology and Vascular Biology, CHU La Conception, APHM, Marseille, France
| | - Kimberly Martinod
- Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
| | - Johannes Thaler
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Françoise Dignat-George
- Aix-Marseille University, C2VN, INSERM 1263, INRAE1260, Marseille, France; Department of Hematology and Vascular Biology, CHU La Conception, APHM, Marseille, France.
| | - Rienk Nieuwland
- Laboratory of Experimental Clinical Chemistry, and Amsterdam Vesicle Center, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Romaric Lacroix
- Aix-Marseille University, C2VN, INSERM 1263, INRAE1260, Marseille, France; Department of Hematology and Vascular Biology, CHU La Conception, APHM, Marseille, France
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8
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Chen J, Liu S, Ruan Z, Wang K, Xi X, Mao J. Thrombotic events associated with immune checkpoint inhibitors and novel antithrombotic strategies to mitigate bleeding risk. Blood Rev 2024; 67:101220. [PMID: 38876840 DOI: 10.1016/j.blre.2024.101220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/23/2024] [Accepted: 06/05/2024] [Indexed: 06/16/2024]
Abstract
Although immunotherapy is expanding treatment options for cancer patients, the prognosis of advanced cancer remains poor, and these patients must contend with both cancers and cancer-related thrombotic events. In particular, immune checkpoint inhibitors are associated with an increased risk of atherosclerotic thrombotic events. Given the fundamental role of platelets in atherothrombosis, co-administration of antiplatelet agents is always indicated. Platelets are also involved in all steps of cancer progression. Classical antithrombotic drugs can cause inevitable hemorrhagic side effects due to blocking integrin β3 bidirectional signaling, which regulates simultaneously thrombosis and hemostasis. Meanwhile, many promising new targets are emerging with minimal bleeding risk and desirable anti-tumor effects. This review will focus on the issue of thrombosis during immune checkpoint inhibitor treatment and the role of platelet activation in cancer progression as well as explore the mechanisms by which novel antiplatelet therapies may exert both antithrombotic and antitumor effects without excessive bleeding risk.
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Affiliation(s)
- Jiayi Chen
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Shuang Liu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zheng Ruan
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Kankan Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Xiaodong Xi
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Jianhua Mao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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9
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Zhang Y, Zeng J, Bao S, Zhang B, Li X, Wang H, Cheng Y, Zhang H, Zu L, Xu X, Xu S, Song Z. Cancer progression and tumor hypercoagulability: a platelet perspective. J Thromb Thrombolysis 2024; 57:959-972. [PMID: 38760535 DOI: 10.1007/s11239-024-02993-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/26/2024] [Indexed: 05/19/2024]
Abstract
Venous thromboembolism, which is common in cancer patients and accompanies or even precedes malignant tumors, is known as cancer-related thrombosis and is an important cause of cancer- associated death. At present, the exact etiology of the elevated incidence of venous thrombosis in cancer patients remains elusive. Platelets play a crucial role in blood coagulation, which is intimately linked to the development of arterial thrombosis. Additionally, platelets contribute to tumor progression and facilitate immune evasion by tumors. Tumor cells can interact with the coagulation system through various mechanisms, such as producing hemostatic proteins, activating platelets, and directly adhering to normal cells. The relationship between platelets and malignant tumors is also significant. In this review article, we will explore these connections.
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Affiliation(s)
- Yifan Zhang
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Jingtong Zeng
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Shihao Bao
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Bo Zhang
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Xianjie Li
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Hanqing Wang
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yuan Cheng
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Hao Zhang
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Lingling Zu
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiaohong Xu
- Colleges of Nursing, Tianjin Medical University, Tianjin, China
| | - Song Xu
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China.
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Zuoqing Song
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, China.
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.
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10
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Pantazi D, Alivertis D, Tselepis AD. Underlying Mechanisms of Thrombosis Associated with Cancer and Anticancer Therapies. Curr Treat Options Oncol 2024; 25:897-913. [PMID: 38862694 DOI: 10.1007/s11864-024-01210-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/24/2024] [Indexed: 06/13/2024]
Abstract
Cancer-associated thrombosis (CAT) has been identified as the second most prevalent cause of death after cancer itself. Moreover, the risk of thrombotic events in cancer patients increases due to anticancer drugs, such as tyrosine kinase inhibitors (TKIs). Venous thromboembolism (VTE) as well as arterial thromboembolic (ATE) events are present in CAT. Although VTE occurs more frequently, ATE events are very significant and in some cases are more dangerous than VTE. Guidelines for preventing thrombosis refer mainly VTE as well as the contribution of ATE events. Several factors are involved in thrombosis related to cancer, but the whole pathomechanism of thrombosis is not clear and may differ between patients. The activation of the coagulation system and the interaction of cancer cells with other cells including platelets, endothelial cells, monocytes, and neutrophils are promoted by a hypercoagulable state caused by cancer. We present an update on the pathomechanisms of CAT and the effect of anticancer drugs, mainly targeted therapies with a focus on TKIs. Considering the risk of bleeding associated with anticoagulation in each cancer patient, the anticoagulation strategy may involve the use of FXIa inhibitors, direct oral anticoagulants, and low-molecular-weight heparin. Further research would be valuable in developing strategies for reducing CAT.
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Affiliation(s)
- Despoina Pantazi
- Laboratory of Biochemistry, Department of Chemistry/Atherothrombosis Research Centre, University of Ioannina, 451 10, Ioannina, Epirus, Greece.
| | - Dimitrios Alivertis
- Department of Biological Applications and Technology, University of Ioannina, 451 10, Ioannina, Epirus, Greece
| | - Alexandros D Tselepis
- Laboratory of Biochemistry, Department of Chemistry/Atherothrombosis Research Centre, University of Ioannina, 451 10, Ioannina, Epirus, Greece
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11
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Shi Q, Xu J, Chen C, Hu X, Wang B, Zeng F, Ren T, Huang Y, Guo W, Tang X, Ji T. Direct contact between tumor cells and platelets initiates a FAK-dependent F3/TGF-β positive feedback loop that promotes tumor progression and EMT in osteosarcoma. Cancer Lett 2024; 591:216902. [PMID: 38641310 DOI: 10.1016/j.canlet.2024.216902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 03/31/2024] [Accepted: 04/15/2024] [Indexed: 04/21/2024]
Abstract
Platelets have received growing attention for their roles in hematogenous tumor metastasis. However, the tumor-platelet interaction in osteosarcoma (OS) remains poorly understood. Here, using platelet-specific focal adhesion kinase (FAK)-deficient mice, we uncover a FAK-dependent F3/TGF-β positive feedback loop in OS. Disruption of the feedback loop by inhibition of F3, TGF-β, or FAK significantly suppresses OS progression. We demonstrate that OS F3 initiated the feedback loop by increasing platelet TGF-β secretion, and platelet-derived TGF-β promoted OS F3 expression in turn and modulated OS EMT process. Immunofluorescence results indicate platelet infiltration in OS niche and we verified it was mediated by platelet FAK. In addition, platelet FAK was proved to mediate platelet adhesion to OS cells, which was vital for the initiation of F3/TGF-β feedback loop. Collectively, these findings provide a rationale for novel therapeutic strategies targeting tumor-platelet interplay in metastatic OS.
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Affiliation(s)
- Qianyu Shi
- Department of Musculoskeletal Tumor, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Jiuhui Xu
- Department of Musculoskeletal Tumor, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Chenglong Chen
- Department of Orthopedics, Beijing Jishuitan Hospital, Beijing, China
| | - Xueyu Hu
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing, China
| | - Boyang Wang
- Department of Musculoskeletal Tumor, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Fanwei Zeng
- Department of Musculoskeletal Tumor, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Tingting Ren
- Department of Musculoskeletal Tumor, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Yi Huang
- Department of Musculoskeletal Tumor, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Wei Guo
- Department of Musculoskeletal Tumor, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Xiaodong Tang
- Department of Musculoskeletal Tumor, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
| | - Tao Ji
- Department of Musculoskeletal Tumor, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, China
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12
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Kawano T, Englisch C, Hisada Y, Paul D, Archibald S, Grover S, Pabinger I, Ay C, Mackman N. Mucin 1 and venous thrombosis in tumor-bearing mice and patients with cancer. Thromb Res 2024; 237:23-30. [PMID: 38547690 PMCID: PMC11058007 DOI: 10.1016/j.thromres.2024.03.022] [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: 01/23/2024] [Revised: 03/18/2024] [Accepted: 03/20/2024] [Indexed: 04/29/2024]
Abstract
INTRODUCTION Mucins released from epithelial tumors have been proposed to play a role in cancer-associated thrombosis. Mucin1 (MUC1) is a transmembrane mucin that is overexpressed in a variety of human malignancies, including breast and pancreatic cancer. We analyzed the association of MUC1 and venous thrombosis in a mouse tumor model and in patients with cancer. MATERIALS AND METHODS We used a human pancreatic cancer cell line HPAF-II that expresses a high level of MUC1. We grew HPAF-II tumors in the pancreas of Crl:NU-Foxn1nu male mice. MUC1 in plasma and extracellular vesicles (EVs) isolated from plasma was measured using an enzyme-linked immunosorbent assay. MUC1 in EVs and venous thrombi from tumor-bearing mice was assessed by western blotting. We measured MUC1 in plasma from healthy controls and patients with stomach, colorectal or pancreatic cancer with or without venous thromboembolism. RESULTS AND DISCUSSION MUC1 was detected in the plasma of mice bearing HPAF-II tumors and was associated with EVs. MUC1 was present in venous thrombi from mice bearing HFAP-II tumors. Recombinant MUC1 did not induce platelet aggregation. Levels of MUC1 were higher in patients with pancreatic cancer compared with healthy controls. In contrast to the mouse model, MUC1 was present in EV-free plasma in samples from healthy controls and patients with cancer. There was no significant difference in the levels of MUC1 in cancer patients with or without VTE. Our data did not find any evidence that MUC1 contributed to VTE in patients with cancer.
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Affiliation(s)
- Tomohiro Kawano
- UNC Blood Research Center, Division of Hematology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Cornelia Englisch
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Yohei Hisada
- UNC Blood Research Center, Division of Hematology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - David Paul
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Sierra Archibald
- UNC Blood Research Center, Division of Hematology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Steven Grover
- UNC Blood Research Center, Division of Hematology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Ingrid Pabinger
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Cihan Ay
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
| | - Nigel Mackman
- UNC Blood Research Center, Division of Hematology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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13
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Tatsumi K. The pathogenesis of cancer-associated thrombosis. Int J Hematol 2024; 119:495-504. [PMID: 38421488 DOI: 10.1007/s12185-024-03735-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/13/2024] [Accepted: 02/18/2024] [Indexed: 03/02/2024]
Abstract
Patients with cancer have a higher risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), compared to the general population. Cancer-associated thrombosis (CAT) is a thrombotic event that occurs as a complication of cancer or cancer therapy. Major factors determining VTE risk in cancer patients include not only treatment history and patient characteristics, but also cancer type and site. Cancer types can be broadly divided into three groups based on VTE risk: high risk (pancreatic, ovarian, brain, stomach, gynecologic, and hematologic), intermediate risk (colon and lung), and low risk (breast and prostate). This implies that the mechanism of VTE differs between cancer types and that specific VTE pathways may exist for different cancer types. This review summarizes the specific pathways that contribute to VTE in cancer patients, with a particular focus on leukocytosis, neutrophil extracellular traps (NETs), tissue factor (TF), thrombocytosis, podoplanin (PDPN), plasminogen activator inhibitor-1 (PAI-1), the intrinsic coagulation pathway, and von Willebrand factor (VWF).
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Affiliation(s)
- Kohei Tatsumi
- Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, 840 Shijo-Cho, Kashihara, Nara, 634-8521, Japan.
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14
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Willems RAL, Biesmans C, Campello E, Simioni P, de Laat B, de Vos-Geelen J, Roest M, Ten Cate H. Cellular Components Contributing to the Development of Venous Thrombosis in Patients with Pancreatic Cancer. Semin Thromb Hemost 2024; 50:429-442. [PMID: 38049115 DOI: 10.1055/s-0043-1777304] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of cancer and has a poor prognosis. Patients with PDAC are at high risk of developing thromboembolic events, which is a leading cause of morbidity and mortality following cancer progression. Plasma-derived coagulation is the most studied process in cancer-associated thrombosis. Other blood components, such as platelets, red blood cells, and white blood cells, have been gaining less attention. This narrative review addresses the literature on the role of cellular components in the development of venous thromboembolism (VTE) in patients with PDAC. Blood cells seem to play an important role in the development of VTE. Altered blood cell counts, i.e., leukocytosis, thrombocytosis, and anemia, have been found to associate with VTE risk. Tumor-related activation of leukocytes leads to the release of tissue factor-expressing microvesicles and the formation of neutrophil extracellular traps, initiating coagulation and forming a scaffold for thrombi. Tissue factor-expressing microvesicles are also thought to be released by PDAC cells. PDAC cells have been shown to stimulate platelet activation and aggregation, proposedly via the secretion of podoplanin and mucins. Hypofibrinolysis, partially explained by increased plasminogen activator inhibitor-1 activity, is observed in PDAC. In short, PDAC-associated hypercoagulability is a complex and multifactorial process. A better understanding of cellular contributions to hypercoagulability might lead to the improvement of diagnostic tests to identify PDAC patients at highest risk of VTE.
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Affiliation(s)
- Ruth Anne Laura Willems
- Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands
- Thrombosis Expert Center Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
- Division of Vascular Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- Division of Medical Oncology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- CARIM, School for Cardiovascular Diseases, Maastricht, The Netherlands
| | - Charlotte Biesmans
- Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands
- Thrombosis Expert Center Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
- Division of Vascular Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- Division of Medical Oncology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Elena Campello
- General Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Paolo Simioni
- General Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Bas de Laat
- Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands
- CARIM, School for Cardiovascular Diseases, Maastricht, The Netherlands
- Department of Platelet Pathophysiology, Synapse Research Institute, Maastricht, The Netherlands
| | - Judith de Vos-Geelen
- Division of Medical Oncology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- GROW, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Mark Roest
- Department of Platelet Pathophysiology, Synapse Research Institute, Maastricht, The Netherlands
| | - Hugo Ten Cate
- Thrombosis Expert Center Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
- Division of Vascular Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- CARIM, School for Cardiovascular Diseases, Maastricht, The Netherlands
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15
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Najafi S, Asemani Y, Majidpoor J, Mahmoudi R, Aghaei-Zarch SM, Mortezaee K. Tumor-educated platelets. Clin Chim Acta 2024; 552:117690. [PMID: 38056548 DOI: 10.1016/j.cca.2023.117690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 11/29/2023] [Accepted: 12/02/2023] [Indexed: 12/08/2023]
Abstract
Beyond traditional roles in homeostasis and coagulation, growing evidence suggests that platelets also reflect malignant transformation in cancer. Platelets are present in the tumor microenvironment where they interact with cancer cells. This interaction results in direct and indirect "education" as evident by platelet alterations in adhesion molecules, glycoproteins, nucleic acids, proteins and various receptors. Subsequently, these tumor-educated platelets (TEPs) circulate throughout the body and play pivotal roles in promotion of tumor growth and dissemination. Accordingly, platelet status can be considered a unique blood-based biomarker that can potentially predict prognosis and therapeutic success. Recently, liquid biopsies including TEPs have received much attention as safe, minimally invasive and sensitive alternatives for patient management. Herein, we provide an overview of TEPs and explore their benefits and limitations in cancer.
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Affiliation(s)
- Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yahya Asemani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Jamal Majidpoor
- Department of Anatomy, School of Medicine, Infectious Diseases Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Reza Mahmoudi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohsen Aghaei-Zarch
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Keywan Mortezaee
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
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16
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Li S, Lu Z, Wu S, Chu T, Li B, Qi F, Zhao Y, Nie G. The dynamic role of platelets in cancer progression and their therapeutic implications. Nat Rev Cancer 2024; 24:72-87. [PMID: 38040850 DOI: 10.1038/s41568-023-00639-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/13/2023] [Indexed: 12/03/2023]
Abstract
Systemic antiplatelet treatment represents a promising option to improve the therapeutic outcomes and therapeutic efficacy of chemotherapy and immunotherapy due to the critical contribution of platelets to tumour progression. However, until recently, targeting platelets as a cancer therapeutic has been hampered by the elevated risk of haemorrhagic and thrombocytopenic (low platelet count) complications owing to the lack of specificity for tumour-associated platelets. Recent work has advanced our understanding of the molecular mechanisms responsible for the contribution of platelets to tumour progression and metastasis. This has led to the identification of the biological changes in platelets in the presence of tumours, the complex interactions between platelets and tumour cells during tumour progression, and the effects of platelets on antitumour therapeutic response. In this Review, we present a detailed picture of the dynamic roles of platelets in tumour development and progression as well as their use in diagnosis, prognosis and monitoring response to therapy. We also provide our view on how to overcome challenges faced by the development of precise antiplatelet strategies for safe and efficient clinical cancer therapy.
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Affiliation(s)
- Suping Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China.
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, China.
| | - Zefang Lu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Suying Wu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Tianjiao Chu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- College of Pharmaceutical Science, Jilin University, Changchun, China
| | - Bozhao Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | - Feilong Qi
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, China
- Department of Chemistry, Tsinghua University, Beijing, China
| | - Yuliang Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Guangjun Nie
- CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China.
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, China.
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17
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Zhang T, Gu Z, Ni R, Wang X, Jiang Q, Tao R. An Update on Gemcitabine-Based Chemosensitization Strategies in Pancreatic Ductal Adenocarcinoma. FRONT BIOSCI-LANDMRK 2023; 28:361. [PMID: 38179740 DOI: 10.31083/j.fbl2812361] [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: 06/01/2023] [Revised: 07/22/2023] [Accepted: 08/10/2023] [Indexed: 01/06/2024]
Abstract
Pancreatic cancer is the seventh leading cause of cancer-related deaths, and chemotherapy is one of the most important treatments for pancreatic cancer. Unfortunately, pancreatic cancer cells can block chemotherapy drugs from entering the tumor. This is owing to interactions between the tumor's environment and the cancer cells. Here, we review the latest research on the mechanisms by which pancreatic cancer cells block the chemotherapy drug, gemcitabine. The results of our review can help identify potential therapeutic targets for the blocking of gemcitabine by pancreatic cancer cells and may provide new strategies to help chemotherapy drugs penetrate tumors.
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Affiliation(s)
- Tianpeng Zhang
- Department of Surgery, Bengbu Medical College, 233030 Bengbu, AnHui, China
| | - Zongting Gu
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, 310000 Hangzhou, Zhejiang, China
| | - Ran Ni
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, 310000 Hangzhou, Zhejiang, China
| | - Xiao Wang
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, 310000 Hangzhou, Zhejiang, China
| | - Qitao Jiang
- Department of Surgery, Bengbu Medical College, 233030 Bengbu, AnHui, China
| | - Ran Tao
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, 310000 Hangzhou, Zhejiang, China
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18
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Pavlovic D, Niciforovic D, Markovic M, Papic D. Cancer-Associated Thrombosis: Epidemiology, Pathophysiological Mechanisms, Treatment, and Risk Assessment. Clin Med Insights Oncol 2023; 17:11795549231220297. [PMID: 38152726 PMCID: PMC10752082 DOI: 10.1177/11795549231220297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 11/28/2023] [Indexed: 12/29/2023] Open
Abstract
Cancer patients represent a growing population with drastically difficult care and a lowered quality of life, especially due to the heightened risk of vast complications. Thus, it is well established so far that one of the most prominent complications in individuals with cancer is venous thromboembolism. Since there are various improved methods for screening and diagnosing cancer and its complications, the incidence of cancer-associated thrombosis has been on the rise in recent years. Therefore, the high mortality and morbidity rates among these patients are not a surprise. Consequently, there is an excruciating need for understanding the mechanisms behind this complex process, as well as the imperative for adequate analysis and application of the most suitable steps for cancer-associated thrombosis prevention. There are various and numerous mechanisms offering potential answers to cancer-associated thrombosis, some of which have already been elucidated in various preclinical and clinical scenarios, yet further and more elaborate studies are crucial to understanding and preventing this complex and harsh clinical entity. This article elaborates on the growing incidence, mortality, morbidity, and risk factors of cancer-associated thrombosis while emphasizing the pathophysiological mechanisms in the light of various types of cancer in patients and summarizes the most novel therapy and prevention guidelines recommendations.
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Affiliation(s)
- Dragica Pavlovic
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Danijela Niciforovic
- Center for Internal Oncology, University Clinical Center Kragujevac, Kragujevac, Serbia
| | - Marina Markovic
- Center for Internal Oncology, University Clinical Center Kragujevac, Kragujevac, Serbia
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Dragana Papic
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
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19
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Huang SL, Xin HY, Wang XY, Feng GG, Wu FQ, Feng ZP, Xing Z, Zhang XH, Xin HW, Luo WY. Recent Advances on the Molecular Mechanism and Clinical Trials of Venous Thromboembolism. J Inflamm Res 2023; 16:6167-6178. [PMID: 38111686 PMCID: PMC10726951 DOI: 10.2147/jir.s439205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 11/28/2023] [Indexed: 12/20/2023] Open
Abstract
Venous thromboembolism is a condition that includes deep vein thrombosis and pulmonary embolism. It is the third most common cardiovascular disease behind acute coronary heart disease and stroke. Over the past few years, growing research suggests that venous thrombosis is also related to the immune system and inflammatory factors have been confirmed to be involved in venous thrombosis. The role of inflammation and inflammation-related biomarkers in cerebrovascular thrombotic disease is the subject of ongoing debate. P-selectin leads to platelet-monocyte aggregation and stimulates vascular inflammation and thrombosis. The dysregulation of miRNAs has also been reported in venous thrombosis, suggesting the involvement of miRNAs in the progression of venous thrombosis. Plasminogen activator inhibitor-1 (PAI-1) is a crucial component of the plasminogen-plasmin system, and elevated levels of PAI-1 in conjunction with advanced age are significant risk factors for thrombosis. In addition, it has been showed that one of the ways that neutrophils promote venous thrombosis is the formation of neutrophil extracellular traps (NETs). In recent years, the role of extracellular vesicles (EVs) in the occurrence and development of VTE has been continuously revealed. With the advancement of research technology, the complex regulatory role of EVs on the coagulation process has been gradually discovered. However, our understanding of the causes and consequences of these changes in venous thrombosis is still limited. Therefore, we review our current understanding the molecular mechanisms of venous thrombosis and the related clinical trials, which is crucial for the future treatment of venous thrombosis.
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Affiliation(s)
- Shao-Li Huang
- Medical Laboratory Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524400, People’s Republic of China
- First Clinical College, Guangdong Medical University, Guangdong, 524400, People’s Republic of China
- Clinical laboratory, Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China
| | - Hong-Yi Xin
- Doctoral Scientific Research Center, Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China
- Guangdong Medical University Affiliated Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China
| | - Xiao-Yan Wang
- Doctoral Scientific Research Center, Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China
- Guangdong Medical University Affiliated Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China
| | - Guang-Gui Feng
- Clinical laboratory, Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China
| | - Fu-Qing Wu
- Clinical laboratory, Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China
| | - Zhi-Peng Feng
- Department of Gastroenterology, Yueyang Hospital Affiliated to Hunan Normal University, Yueyang, Hunan, 414000, People’s Republic of China
| | - Zhou Xing
- First Clinical College, Guangdong Medical University, Guangdong, 524400, People’s Republic of China
| | - Xi-He Zhang
- Doctoral Scientific Research Center, Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China
- Guangdong Medical University Affiliated Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China
| | - Hong-Wu Xin
- Doctoral Scientific Research Center, Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Faculty of Medicine, Yangtze University, Jingzhou, Hubei, 434023, People’s Republic of China
- Research Centre of Molecular Medicine, Medical College of Chifeng University, Chifeng, Inner Mongolian Autonomous Region, 024000, People’s Republic of China
| | - Wen-Ying Luo
- Medical Laboratory Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524400, People’s Republic of China
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20
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Ghosh LD, Jain A. The prospects of microphysiological systems in modeling platelet pathophysiology in cancer. Platelets 2023; 34:2247489. [PMID: 37610007 PMCID: PMC10578702 DOI: 10.1080/09537104.2023.2247489] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 07/10/2023] [Accepted: 08/02/2023] [Indexed: 08/24/2023]
Abstract
The contribution of platelets is well recognized in thrombosis and hemostasis. However, platelets also promote tumor progression and metastasis through their crosstalk with various cells of the tumor microenvironment (TME). For example, several cancer models continue to show that platelet functions are readily altered by cancer cells upon activation leading to the formation of platelet-tumor aggregates, triggering release of soluble factors from platelet granules and altering platelet turnover. Further, activated platelets protect tumor cells from shear forces in circulation and assault of cytotoxic natural killer (NK) cells. Platelet-secreted factors promote proliferation of malignant cells, metastasis, and chemoresistance. Much of our knowledge of platelet biology in cancer has been achieved with animal models, particularly murine. However, this preclinical understanding of the complex pathophysiology is yet to be fully realized and translated to clinical trials in terms of new approaches to treat cancer via controlling the platelet function. In this review, we summarize the current state of knowledge of platelet physiology obtained through existing in vivo and in vitro cancer models, the complex interactions of platelets with cancer cells in TME and the pathways by which platelets may confer chemoresistance. Since the FDA Modernization Act recently passed by the US government has made animal models optional in drug approvals, we critically examine the existing and futuristic value of employing bioengineered microphysiological systems and organ-chips to understand the mechanistic role of platelets in cancer metastasis and exploring novel therapeutic targets for cancer prevention and treatment.
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Affiliation(s)
- Lopamudra D. Ghosh
- Department of Biomedical Engineering, College of Engineering, Texas A&M University, College Station, Texas, USA
| | - Abhishek Jain
- Department of Biomedical Engineering, College of Engineering, Texas A&M University, College Station, Texas, USA
- Department of Medical Physiology, School of Medicine, Texas A&M Health Science Center, Bryan, Texas, USA
- Department of Cardiovascular Sciences, Houston Methodist Academic Institute, Houston, Texas, USA
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21
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Guo S, Huang J, Li G, Chen W, Li Z, Lei J. The role of extracellular vesicles in circulating tumor cell-mediated distant metastasis. Mol Cancer 2023; 22:193. [PMID: 38037077 PMCID: PMC10688140 DOI: 10.1186/s12943-023-01909-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 11/23/2023] [Indexed: 12/02/2023] Open
Abstract
Current research has demonstrated that extracellular vesicles (EVs) and circulating tumor cells (CTCs) are very closely related in the process of distant tumor metastasis. Primary tumors are shed and released into the bloodstream to form CTCs that are referred to as seeds to colonize and grow in soil-like distant target organs, while EVs of tumor and nontumor origin act as fertilizers in the process of tumor metastasis. There is no previous text that provides a comprehensive review of the role of EVs on CTCs during tumor metastasis. In this paper, we reviewed the mechanisms of EVs on CTCs during tumor metastasis, including the ability of EVs to enhance the shedding of CTCs, protect CTCs in circulation and determine the direction of CTC metastasis, thus affecting the distant metastasis of tumors.
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Affiliation(s)
- Siyin Guo
- Division of Thyroid Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Jing Huang
- Division of Thyroid Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Genpeng Li
- Division of Thyroid Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Wenjie Chen
- Division of Thyroid Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Zhihui Li
- Division of Thyroid Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Jianyong Lei
- Division of Thyroid Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
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22
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Wahab R, Hasan MM, Azam Z, Grippo PJ, Al-Hilal TA. The role of coagulome in the tumor immune microenvironment. Adv Drug Deliv Rev 2023; 200:115027. [PMID: 37517779 PMCID: PMC11099942 DOI: 10.1016/j.addr.2023.115027] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 07/25/2023] [Accepted: 07/27/2023] [Indexed: 08/01/2023]
Abstract
The rising incidence and persistent thrombosis in multiple cancers including those that are immunosuppressive highlight the need for understanding the tumor coagulome system and its role beyond hemostatic complications. Immunotherapy has shown significant benefits in solid organ tumors but has been disappointing in the treatment of hypercoagulable cancers, such as glioblastoma and pancreatic ductal adenocarcinomas. Thus, targeting thrombosis to prevent immunosuppression seems a clinically viable approach in cancer treatment. Hypercoagulable tumors often develop fibrin clots within the tumor microenvironment (TME) that dictates the biophysical characteristics of the tumor tissue. The application of systems biology and single-cell approaches highlight the potential role of coagulome or thrombocytosis in shaping the tumor immune microenvironment (TIME). In-depth knowledge of the tumor coagulome would provide unprecedented opportunities to better predict the hemostatic complications, explore how thrombotic stroma modulates tumor immunity, reexamine the significance of clinical biomarkers, and enable steering the stromal versus systemic immune response for boosting the effectiveness of immune checkpoint inhibitors in cancer treatment. We focus on the role of coagulation factors in priming a suppressive TIME and the huge potential of existing anticoagulant drugs in the clinical settings of cancer immunotherapy.
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Affiliation(s)
- Riajul Wahab
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Md Mahedi Hasan
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, TX 79968, USA; Department of Environmental Science & Engineering, College of Science, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Zulfikar Azam
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Paul J Grippo
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Taslim A Al-Hilal
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, TX 79968, USA; Department of Environmental Science & Engineering, College of Science, University of Texas at El Paso, El Paso, TX 79968, USA.
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23
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Singh M, Anvekar P, Baraskar B, Pallipamu N, Gadam S, Cherukuri ASS, Damani DN, Kulkarni K, Arunachalam SP. Prospective of Pancreatic Cancer Diagnosis Using Cardiac Sensing. J Imaging 2023; 9:149. [PMID: 37623681 PMCID: PMC10455647 DOI: 10.3390/jimaging9080149] [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: 06/14/2023] [Revised: 07/14/2023] [Accepted: 07/17/2023] [Indexed: 08/26/2023] Open
Abstract
Pancreatic carcinoma (Ca Pancreas) is the third leading cause of cancer-related deaths in the world. The malignancies of the pancreas can be diagnosed with the help of various imaging modalities. An endoscopic ultrasound with a tissue biopsy is so far considered to be the gold standard in terms of the detection of Ca Pancreas, especially for lesions <2 mm. However, other methods, like computed tomography (CT), ultrasound, and magnetic resonance imaging (MRI), are also conventionally used. Moreover, newer techniques, like proteomics, radiomics, metabolomics, and artificial intelligence (AI), are slowly being introduced for diagnosing pancreatic cancer. Regardless, it is still a challenge to diagnose pancreatic carcinoma non-invasively at an early stage due to its delayed presentation. Similarly, this also makes it difficult to demonstrate an association between Ca Pancreas and other vital organs of the body, such as the heart. A number of studies have proven a correlation between the heart and pancreatic cancer. The tumor of the pancreas affects the heart at the physiological, as well as the molecular, level. An overexpression of the SMAD4 gene; a disruption in biomolecules, such as IGF, MAPK, and ApoE; and increased CA19-9 markers are a few of the many factors that are noted to affect cardiovascular systems with pancreatic malignancies. A comprehensive review of this correlation will aid researchers in conducting studies to help establish a definite relation between the two organs and discover ways to use it for the early detection of Ca Pancreas.
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Affiliation(s)
- Mansunderbir Singh
- Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA; (M.S.); (B.B.); (N.P.)
| | - Priyanka Anvekar
- Department of Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, MN 55905, USA;
| | - Bhavana Baraskar
- Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA; (M.S.); (B.B.); (N.P.)
| | - Namratha Pallipamu
- Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA; (M.S.); (B.B.); (N.P.)
| | - Srikanth Gadam
- Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA; (M.S.); (B.B.); (N.P.)
| | - Akhila Sai Sree Cherukuri
- GIH Artificial Intelligence Laboratory (GAIL), Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Microwave Engineering and Imaging Laboratory (MEIL), Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Devanshi N. Damani
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA;
- Department of Internal Medicine, Texas Tech University Health Science Center, El Paso, TX 79995, USA
| | - Kanchan Kulkarni
- Centre de Recherche Cardio-Thoracique de Bordeaux, University of Bordeaux, INSERM, U1045, 33000 Bordeaux, France;
- IHU Liryc, Heart Rhythm Disease Institute, Fondation Bordeaux Université, 33600 Bordeaux, France
| | - Shivaram P. Arunachalam
- Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA; (M.S.); (B.B.); (N.P.)
- GIH Artificial Intelligence Laboratory (GAIL), Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Microwave Engineering and Imaging Laboratory (MEIL), Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
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24
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Shafqat A, Omer MH, Ahmed EN, Mushtaq A, Ijaz E, Ahmed Z, Alkattan K, Yaqinuddin A. Reprogramming the immunosuppressive tumor microenvironment: exploiting angiogenesis and thrombosis to enhance immunotherapy. Front Immunol 2023; 14:1200941. [PMID: 37520562 PMCID: PMC10374407 DOI: 10.3389/fimmu.2023.1200941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/15/2023] [Indexed: 08/01/2023] Open
Abstract
This review focuses on the immunosuppressive effects of tumor angiogenesis and coagulation on the tumor microenvironment (TME). We summarize previous research efforts leveraging these observations and targeting these processes to enhance immunotherapy outcomes. Clinical trials have documented improved outcomes when combining anti-angiogenic agents and immunotherapy. However, their overall survival benefit over conventional therapy remains limited and certain tumors exhibit poor response to anti-angiogenic therapy. Additionally, whilst preclinical studies have shown several components of the tumor coagulome to curb effective anti-tumor immune responses, the clinical studies reporting combinations of anticoagulants with immunotherapies have demonstrated variable treatment outcomes. By reviewing the current state of the literature on this topic, we address the key questions and future directions in the field, the answers of which are crucial for developing effective strategies to reprogram the TME in order to further the field of cancer immunotherapy.
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Affiliation(s)
- Areez Shafqat
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Mohamed H. Omer
- School of Medicine, Cardiff University, Cardiff, United Kingdom
| | | | - Ali Mushtaq
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Eman Ijaz
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Zara Ahmed
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Khaled Alkattan
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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25
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Kawano T, Hisada Y, Grover SP, Schug WJ, Paul DS, Bergmeier W, Mackman N. Decreased Platelet Reactivity and Function in a Mouse Model of Human Pancreatic Cancer. Thromb Haemost 2023; 123:501-509. [PMID: 36716775 PMCID: PMC10820933 DOI: 10.1055/s-0043-1761419] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Cancer patients have increased thrombosis and bleeding compared with the general population. Cancer is associated with activation of both platelets and coagulation. Mouse models have been used to study the dysregulation of platelets and coagulation in cancer. We established a mouse model of pancreatic cancer in which tissue factor-expressing human pancreatic tumors (BxPC-3) are grown in nude mice. Tumor-bearing mice have an activated coagulation system and increased venous thrombosis compared to control mice. We also showed that tumor-derived, tissue factor-positive extracellular vesicles activated platelets ex vivo and in vivo. In this study, we determined the effect of tumors on a platelet-dependent arterial thrombosis model. Unexpectedly, we observed significantly reduced carotid artery thrombosis in tumor-bearing mice compared to controls. In addition, we observed significantly increased tail bleeding in tumor-bearing mice compared to controls. These results suggested that the presence of the tumor affected platelets. Indeed, tumor-bearing mice exhibited a significant decrease in platelet count and an increase in mean platelet volume and percentage of reticulated platelets, findings that are consistent with increased platelet turnover. Levels of the platelet activation marker platelet factor 4 were also increased in tumor-bearing mice. We also observed decreased platelet receptor expression in tumor-bearing mice and reduced levels of active αIIb/β3 integrin in response to PAR4 agonist peptide and convulxin in platelets from tumor-bearing mice compared with platelets from control mice. In summary, our study suggests that in tumor-bearing mice there is chronic platelet activation, leading to thrombocytopenia, decreased receptor expression, and impaired platelet adhesive function.
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Affiliation(s)
- Tomohiro Kawano
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
| | - Yohei Hisada
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
| | - Steven P. Grover
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
| | - Wyatt J. Schug
- Department of Biochemistry and Biophysics, UNC Blood Research Center, University of North Carolina at Chapel Hill, North Carolina, United States
| | - David S. Paul
- Department of Biochemistry and Biophysics, UNC Blood Research Center, University of North Carolina at Chapel Hill, North Carolina, United States
| | - Wolfgang Bergmeier
- Department of Biochemistry and Biophysics, UNC Blood Research Center, University of North Carolina at Chapel Hill, North Carolina, United States
| | - Nigel Mackman
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
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26
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Marcos-Jubilar M, Lecumberri R, Páramo JA. Immunothrombosis: Molecular Aspects and New Therapeutic Perspectives. J Clin Med 2023; 12:1399. [PMID: 36835934 PMCID: PMC9958829 DOI: 10.3390/jcm12041399] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/12/2023] Open
Abstract
Thromboinflammation or immunothrombosis is a concept that explains the existing link between coagulation and inflammatory response present in many situations, such as sepsis, venous thromboembolism, or COVID-19 associated coagulopathy. The purpose of this review is to provide an overview of the current data regarding the mechanisms involved in immunothrombosis in order to understand the new therapeutic strategies focused in reducing thrombotic risk by controlling the inflammation.
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Affiliation(s)
- María Marcos-Jubilar
- Hematology and Hemotherapy Service, Clínica Universidad de Navarra, 31008 Pamplona, Spain
| | - Ramón Lecumberri
- Hematology and Hemotherapy Service, Clínica Universidad de Navarra, 31008 Pamplona, Spain
- CIBER-CV, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - José A. Páramo
- Hematology and Hemotherapy Service, Clínica Universidad de Navarra, 31008 Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain
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27
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Gheorghe G, Ionescu VA, Moldovan H, Diaconu CC. Clinical and Biological Data in Patients with Pancreatic Cancer vs. Chronic Pancreatitis-A Single Center Comparative Analysis. Diagnostics (Basel) 2023; 13:369. [PMID: 36766475 PMCID: PMC9914010 DOI: 10.3390/diagnostics13030369] [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: 12/19/2022] [Revised: 01/15/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
INTRODUCTION In some patients with chronic pancreatitis, the diagnosis of pancreatic cancer can be missed. The objective of the study was to identify clinical and paraclinical data with statistical significance in the differential diagnosis between chronic pancreatitis and pancreatic cancer. MATERIALS AND METHODS We conducted a retrospective, observational study on a cohort of 120 patients hospitalized over 3 years. The patients were equally distributed in two groups: group A, with 60 patients with pancreatic cancer, and group B, with 60 patients with chronic pancreatitis. The statistical analysis was carried out by using the R program. RESULTS The comparative analysis of pancreatic cancer vs. chronic pancreatitis revealed a stronger link between pancreatic cancer, female gender (p = 0.001) and age over 60 years (p < 0.001). Patients with pancreatic cancer had higher serum values of aspartate aminotransferase (p 0.005), alanine aminotransferase (p 0.006), total bilirubin (p < 0.001), direct bilirubin (p < 0.001), alkaline phosphatase (p 0.030), C-reactive protein (p = 0.049) and uric acid (p 0.001), while patients with chronic pancreatitis presented slightly higher values of amylase (p 0.020) and lipase (p 0.029). CONCLUSIONS Female gender, advanced age, elevated aminotransferases, cholestasis markers and uric acid were associated with a higher probability of pancreatic cancer.
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Affiliation(s)
- Gina Gheorghe
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Gastroenterology Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Vlad Alexandru Ionescu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Gastroenterology Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Horatiu Moldovan
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Department of Cardiovascular Surgery, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
- Medical Sciences Section, Academy of Romanian Scientists, 050085 Bucharest, Romania
| | - Camelia Cristina Diaconu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Medical Sciences Section, Academy of Romanian Scientists, 050085 Bucharest, Romania
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
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28
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Li H, Li H, Tang L, Niu H, He L, Luo Q. Associations Between Immune-Related Venous Thromboembolism and Efficacy of Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis. Clin Appl Thromb Hemost 2023; 29:10760296231206799. [PMID: 37844585 PMCID: PMC10586005 DOI: 10.1177/10760296231206799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/10/2023] [Accepted: 09/25/2023] [Indexed: 10/18/2023] Open
Abstract
This study aims to summarize the available data and determine if the presence of venous thromboembolism (VTE) immune-related adverse event (irAE) in patients with immune checkpoint inhibitor (ICI) therapy is associated with improved treatment efficacy and clinical outcomes, which in turn was used to help optimize patient selection for anticoagulation therapy and inform rational treatment strategies for overcoming the mechanisms of ICI resistance. PubMed, Embase, Web of Science, and Cochrane Library were searched up to March 18, 2023, for studies assessing the relationship between VTE irAE development during ICI therapy and cancer outcomes. Seven primary articles with a total of 4437 patients were included in the overall survival (OS) meta-analysis. Patients with VTE had a significant increase in overall mortality compared to patients without VTE in adjusted hazard ratios (HRs 1.36, 95% confidence interval [CI] 1.06-1.75, P = .02). In the studies where immortal time bias (ITB) was accounted for, patients with VTE irAE also had poor OS than those without. HR and the corresponding 95% CI values in the non-ITB group were 2.53 (1.75-3.66, P < .00001) with low heterogeneity (P = .17, I2 = 48%) and 1.21 (1.06-1.37, P = .004) in the ITB group with no heterogeneity (P = .95, I2 = 0%), respectively. Despite the heterogeneity identified, the evidence does suggest that VTE irAE occurrence could be served as a prognostic indicator, with higher frequencies of occurrence associated with poorer OS. However, the fundamental role of this association with clinical consequences should be further investigated in large cohorts and clinical trials.
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Affiliation(s)
- Huimin Li
- Department of Respiratory and Neurology, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China
| | - Hong Li
- Department of Respiratory and Neurology, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China
| | - Le Tang
- Department of Respiratory and Neurology, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China
| | - Haiwen Niu
- Department of Respiratory and Neurology, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China
| | - Lili He
- Department of Respiratory and Neurology, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China
| | - Qin Luo
- Department of Respiratory and Neurology, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China
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Tissue factor in cancer-associated thromboembolism: possible mechanisms and clinical applications. Br J Cancer 2022; 127:2099-2107. [PMID: 36097177 PMCID: PMC9467428 DOI: 10.1038/s41416-022-01968-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 01/29/2023] Open
Abstract
Venous and arterial thromboses, called as cancer-associated thromboembolism (CAT), are common complications in cancer patients that are associated with high mortality. The cell-surface glycoprotein tissue factor (TF) initiates the extrinsic blood coagulation cascade. TF is overexpressed in cancer cells and is a component of extracellular vesicles (EVs). Shedding of TF+EVs from cancer cells followed by association with coagulation factor VII (fVII) can trigger the blood coagulation cascade, followed by cancer-associated venous thromboembolism in some cancer types. Secretion of TF is controlled by multiple mechanisms of TF+EV biogenesis. The procoagulant function of TF is regulated via its conformational change. Thus, multiple steps participate in the elevation of plasma procoagulant activity. Whether cancer cell-derived TF is maximally active in the blood is unclear. Numerous mechanisms other than TF+EVs have been proposed as possible causes of CAT. In this review, we focused on a wide variety of regulatory and shedding mechanisms for TF, including the effect of SARS-CoV-2, to provide a broad overview for its role in CAT. Furthermore, we present the current technical issues in studying the relationship between CAT and TF.
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Adnani L, Spinelli C, Tawil N, Rak J. Role of extracellular vesicles in cancer-specific interactions between tumour cells and the vasculature. Semin Cancer Biol 2022; 87:196-213. [PMID: 36371024 DOI: 10.1016/j.semcancer.2022.11.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 09/25/2022] [Accepted: 11/08/2022] [Indexed: 11/11/2022]
Abstract
Cancer progression impacts and exploits the vascular system in several highly consequential ways. Among different types of vascular cells, blood cells and mediators that are engaged in these processes, endothelial cells are at the centre of the underlying circuitry, as crucial constituents of angiogenesis, angiocrine stimulation, non-angiogenic vascular growth, interactions with the coagulation system and other responses. Tumour-vascular interactions involve soluble factors, extracellular matrix molecules, cell-cell contacts, as well as extracellular vesicles (EVs) carrying assemblies of molecular effectors. Oncogenic mutations and transforming changes in the cancer cell genome, epigenome and signalling circuitry exert important and often cancer-specific influences upon pathways of tumour-vascular interactions, including the biogenesis, content, and biological activity of EVs and responses of cancer cells to them. Notably, EVs may carry and transfer bioactive, oncogenic macromolecules (oncoproteins, RNA, DNA) between tumour and vascular cells and thereby elicit unique functional changes and forms of vascular growth and remodeling. Cancer EVs influence the state of the vasculature both locally and systemically, as exemplified by cancer-associated thrombosis. EV-mediated communication pathways represent attractive targets for therapies aiming at modulation of the tumour-vascular interface (beyond angiogenesis) and could also be exploited for diagnostic purposes in cancer.
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Affiliation(s)
- Lata Adnani
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Cristiana Spinelli
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Nadim Tawil
- McGill University and Research Institute of the McGill University Health Centre, Canada
| | - Janusz Rak
- McGill University and Research Institute of the McGill University Health Centre, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
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31
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Tumour-associated Mucin1 correlates with the procoagulant properties of cancer cells of epithelial origin. THROMBOSIS UPDATE 2022. [DOI: 10.1016/j.tru.2022.100123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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32
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He Y, Wu Q. The Effect of Extracellular Vesicles on Thrombosis. J Cardiovasc Transl Res 2022:10.1007/s12265-022-10342-w. [DOI: 10.1007/s12265-022-10342-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 11/17/2022] [Indexed: 11/29/2022]
Abstract
Abstract
The risk of cardiovascular events caused by acute thrombosis is high, including acute myocardial infarction, acute stroke, acute pulmonary embolism, and deep vein thrombosis. In this review, we summarize the roles of extracellular vesicles of different cellular origins in various cardiovascular events associated with acute thrombosis, as described in the current literature, to facilitate the future development of a precise therapy for thrombosis caused by such vesicles. We hope that our review will indicate a new horizon in the field of cardiovascular research with regard to the treatment of acute thrombosis, especially targeting thrombosis caused by extracellular vesicles secreted by individual cells. As more emerging technologies are being developed, new diagnostic and therapeutic strategies related to EVs are expected to be identified for related diseases in the future.
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Badimon L, Padro T, Arderiu G, Vilahur G, Borrell-Pages M, Suades R. Extracellular vesicles in atherothrombosis: From biomarkers and precision medicine to therapeutic targets. Immunol Rev 2022; 312:6-19. [PMID: 35996799 DOI: 10.1111/imr.13127] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of global mortality. Extracellular vesicles (EVs) are small phospholipid vesicles that convey molecular bioactive cargoes and play essential roles in intercellular communication and, hence, a multifaceted role in health and disease. The present review offers a glimpse into the current state and up-to-date concepts on EV field. It also covers their association with several cardiovascular risk factors and ischemic conditions, being subclinical atherosclerosis of utmost relevance for prevention. Interestingly, we show that EVs hold promise as prognostic and diagnostic as well as predictive markers of ASCVD in the precision medicine era. We then report on the role of EVs in atherothrombosis, disentangling the mechanisms involved in the initiation, progression, and complication of atherosclerosis and showing their direct effect in the context of arterial thrombosis. Finally, their potential use for therapeutic intervention is highlighted.
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Affiliation(s)
- Lina Badimon
- Cardiovascular Program ICCC, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.,CIBERCV Instituto de Salud Carlos III, Madrid, Spain.,Cardiovascular Research Chair, UAB, Barcelona, Spain
| | - Teresa Padro
- Cardiovascular Program ICCC, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.,CIBERCV Instituto de Salud Carlos III, Madrid, Spain
| | - Gemma Arderiu
- Cardiovascular Program ICCC, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.,CIBERCV Instituto de Salud Carlos III, Madrid, Spain
| | - Gemma Vilahur
- Cardiovascular Program ICCC, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.,CIBERCV Instituto de Salud Carlos III, Madrid, Spain
| | - Maria Borrell-Pages
- Cardiovascular Program ICCC, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.,CIBERCV Instituto de Salud Carlos III, Madrid, Spain
| | - Rosa Suades
- Cardiovascular Program ICCC, Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain.,CIBERCV Instituto de Salud Carlos III, Madrid, Spain
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Lamtai H, Boutayeb S, Mrabti H, El Ghissassi I, Errihani H. Cancer patients and COVID-19 vaccination, from safety to protocol adherence: A real-life setting report. Front Oncol 2022; 12:1014786. [PMID: 36263207 PMCID: PMC9573984 DOI: 10.3389/fonc.2022.1014786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/12/2022] [Indexed: 12/03/2022] Open
Abstract
Background The SARS-CoV-2 pandemic has slowed down cancer prevention and treatment strategies; consequently, cancer patients are prioritized to get the COVID-19 vaccines. Being constantly threatened by a new outbreak, the dive within the immunogenicity response is of great value; nonetheless, evaluating the side effects of these vaccines on fragile patients will assure their adherence to the vaccination protocol. Objectives This study sets out to investigate the adverse events reported about the vaccine according to its doses and types, and to compare the prevalence and severity of toxicities across two subgroups of cancer patients, those who received the injection during active therapy cycles, and those who have not started the therapy yet at vaccination time, moreover, this paper examines the will and commitment of this population to the vaccination schemes. Methods This is an observational, retrospective, cohort study, in which we conducted a semi-constructed interview with 415 random solid cancer patients treated at the National Institute of Oncology in Morocco. The assessment of adverse events was carried out with a standardized scale. Results Eleven months after the launch of the campaign, 75.2% of patients received at least one dose of the vaccine. Altogether, the analysis demonstrates a significant difference between the adverse effects reported post the second dose compared to the first one (p=0.004; odds ratio=2 [95% CI: 1.23 - 3.31]). Besides, the results indicate an increase in the rank of the severity of systemic events (p<0.001, r=0.28) after the second dose, but not for the local events (p=0.92, r=0.005). In the adjusted subgroup analysis, no effect was detected linking active therapy with the occurrence of toxicity (p=0.51, v=0.04) as well as with the level of severity reported after both; the first and second dose. Due to the fear of interactions with the therapy, we noticed a significant trend to delay the booster dose among the participants who completed the initial vaccine protocol. Conclusion A considerable body of evidence exists to persuade cancer patients to take the Coronavirus vaccines, and to also follow their vaccination schemes under the supervision of their treating physicians.
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Chen Y, Liu J, Su Y, Zhao H, Zhao Y, Wen M, Lu S, Cao X, Zhang W, Liu L, Wu J. Annexin V - and tissue factor + microparticles as biomarkers for predicting deep vein thrombosis in patients after joint arthroplasty. Clin Chim Acta 2022; 536:169-179. [PMID: 36191610 DOI: 10.1016/j.cca.2022.09.011] [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: 02/21/2021] [Revised: 08/29/2022] [Accepted: 09/08/2022] [Indexed: 11/03/2022]
Abstract
OBJECTIVE Venous thromboembolism (VTE) is a common and severe complication of joint arthroplasty. Microparticles (MPs) containing phosphatidylserine (PS) and tissue factor (TF) can trigger coagulation in VTE. This study aims to measure and compare MP levels in joint arthroplasty patients with and without VTE. METHODS This prospective cohort study enrolled 181 patients who underwent joint arthroplasty. Ultrasound examination was used to diagnose VTE on preoperative day 0 and postoperative day 6. MPs were analysed using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and flow cytometry. The levels of platelet-derived microparticles (PMPs), endothelial cell-derived microparticles (EMPs), granulocyte-derived microparticles (GMPs), red cell-derived microparticles (RMPs), monocyte-derived microparticles (MMPs), Annexin V+ MPs (AV+ MPs), and tissue factor+ MPs (TF+ MPs) derived from five kinds of MPs were measured on day 0 (before surgery), 1, 2, 3, 4, 5, and 6 after surgery. RESULTS The levels of AV-TF+ EMPs and AV-TF+ MMPs were significantly increased in patients with VTE on postoperative day 5 compared to those without VTE (P=0.031 and P=0.031, respectively). CONCLUSION AV-TF+ MPs may indicate the development of VTE and serve as predictive markers in joint arthroplasty patients.
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Affiliation(s)
- Yuying Chen
- Department of Clinical Laboratory, Peking University Fourth School of Clinical Medicine, Beijing, P.R.China
| | - Jian Liu
- Adult reconstruction department, Beijing Jishuitan Hospital, Beijing, P.R.China
| | - Yu Su
- Department of Clinical Laboratory, Beijing Jishuitan Hospital, Beijing, P.R.China
| | - Huiru Zhao
- Department of Clinical Laboratory, Beijing Jishuitan Hospital, Beijing, P.R.China
| | - Yujing Zhao
- Department of Clinical Laboratory, Beijing Jishuitan Hospital, Beijing, P.R.China
| | - Meng Wen
- Department of Clinical Laboratory, Beijing Jishuitan Hospital, Beijing, P.R.China
| | - Shan Lu
- Department of Clinical Laboratory, Beijing Jishuitan Hospital, Beijing, P.R.China
| | - Xiangyu Cao
- Department of Clinical Laboratory, Peking University Fourth School of Clinical Medicine, Beijing, P.R.China
| | - Wenjie Zhang
- Department of Clinical Laboratory, Peking University Fourth School of Clinical Medicine, Beijing, P.R.China
| | - Lei Liu
- Department of Clinical Laboratory, Liyuan Hospital of Tongji Medical College of Huazhong University of Science and Technology, Hubei, P.R.China
| | - Jun Wu
- Department of Clinical Laboratory, Peking University Fourth School of Clinical Medicine, Beijing, P.R.China; Department of Clinical Laboratory, Beijing Jishuitan Hospital, Beijing, P.R.China.
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Kim J, Sunkara V, Kim J, Ro J, Kim CJ, Clarissa EM, Jung SW, Lee HJ, Cho YK. Prediction of tumor metastasis via extracellular vesicles-treated platelet adhesion on a blood vessel chip. LAB ON A CHIP 2022; 22:2726-2740. [PMID: 35763032 DOI: 10.1039/d2lc00364c] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
In preclinical and clinical studies, it has been demonstrated that tumor-educated platelets play a critical role in tumorigenesis, cancer development, and metastasis. Unlike the role of cancer-derived chemokines in platelet activation, the role of cancer-derived extracellular vesicles (EVs) has remained elusive. Here, we found that interleukin-8 (IL-8) in cancer-derived EVs contributed to platelet activation by increasing P-selectin expression and ligand affinity, resulting in increased platelet adhesion on the human vessel-mimicking microfluidic system. Furthermore, platelet adhesion levels on vessels treated with human plasma-derived EVs demonstrated good discrimination between breast cancer patients with metastasis and those without, with the area under the curve (AUC) value of 0.88. While EpCAM expression on EVs could detect the existence of a tumor (AUC = 0.89), it performed poorly in predicting metastasis (AUC = 0.42). We believe that these findings shed light on the role of the interaction between cancer-derived EVs and platelets in pre-metastatic niche formation and tumor metastasis, potentially leading to the development of platelet-tumor interaction-based novel diagnostic and therapeutic strategies.
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Affiliation(s)
- Junyoung Kim
- Center for Soft and Living Matter, Institute for Basic Science (IBS), Ulsan 44919, Republic of Korea
- Department of Biomedical Engineering, School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
| | - Vijaya Sunkara
- Center for Soft and Living Matter, Institute for Basic Science (IBS), Ulsan 44919, Republic of Korea
| | - Jungmin Kim
- Center for Soft and Living Matter, Institute for Basic Science (IBS), Ulsan 44919, Republic of Korea
- Department of Biomedical Engineering, School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
| | - Jooyoung Ro
- Center for Soft and Living Matter, Institute for Basic Science (IBS), Ulsan 44919, Republic of Korea
- Department of Biomedical Engineering, School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
| | - Chi-Ju Kim
- Center for Soft and Living Matter, Institute for Basic Science (IBS), Ulsan 44919, Republic of Korea
| | - Elizabeth Maria Clarissa
- Department of Biomedical Engineering, School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
| | - Sung Wook Jung
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
| | - Hee Jin Lee
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
| | - Yoon-Kyoung Cho
- Center for Soft and Living Matter, Institute for Basic Science (IBS), Ulsan 44919, Republic of Korea
- Department of Biomedical Engineering, School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
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Abstract
Tissue factor (TF), an initiator of extrinsic coagulation pathway, is positively correlated with venous thromboembolism (VTE) of tumor patients. Beyond thrombosis, TF plays a vital role in tumor progression. TF is highly expressed in cancer tissues and circulating tumor cell (CTC), and activates factor VIIa (FVIIa), which increases tumor cells proliferation, angiogenesis, epithelial-mesenchymal transition (EMT) and cancer stem cells(CSCs) activity. Furthermore, TF and TF-positive microvesicles (TF+MVs) activate the coagulation system to promote the clots formation with non-tumor cell components (e.g., platelets, leukocytes, fibrin), which makes tumor cells adhere to clots to form CTC clusters. Then, tumor cells utilize clots to cause its reducing fluid shear stress (FSS), anoikis resistance, immune escape, adhesion, extravasation and colonization. Herein, we review in detail that how TF signaling promotes tumor metastasis, and how TF-targeted therapeutic strategies are being in the preclinical and clinical trials.
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Ryan TAJ, O'Neill LAJ. Innate immune signaling and immunothrombosis: New insights and therapeutic opportunities. Eur J Immunol 2022; 52:1024-1034. [PMID: 35569038 PMCID: PMC9543829 DOI: 10.1002/eji.202149410] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/11/2022] [Accepted: 05/11/2022] [Indexed: 01/10/2023]
Abstract
Activation of the coagulation cascade is a critical, evolutionarily conserved mechanism that maintains hemostasis by rapidly forming blood clots in response to blood-borne infections and damaged blood vessels. Coagulation is a key component of innate immunity since it prevents bacterial dissemination and can provoke inflammation. The term immunothrombosis describes the process by which the innate immune response drives aberrant coagulation, which can result in a lethal condition termed disseminated intravascular coagulation, often seen in sepsis. In this review, we describe the recently uncovered molecular mechanisms underlying inflammasome- and STING-driven immunothrombosis induced by bacterial and viral infections, culminating in tissue factor (TF) activation and release. Current anticoagulant therapeutics, while effective, are associated with a life-threatening bleeding risk, requiring the urgent development of new treatments. Targeting immunothrombosis may provide a safer option. Thus, we highlight preclinical tools which target TF and/or block canonical (NLRP3) or noncanonical (caspase-11) inflammasome activation as well as STING-driven TF release and discuss clinically approved drugs which block key immunothrombotic processes and, therefore, may be redeployed as safer anticoagulants.
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Affiliation(s)
- Tristram A. J. Ryan
- School of Biochemistry and ImmunologyTrinity Biomedical Sciences InstituteTrinity College DublinDublin 2Ireland
| | - Luke A. J. O'Neill
- School of Biochemistry and ImmunologyTrinity Biomedical Sciences InstituteTrinity College DublinDublin 2Ireland
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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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Hisada Y, Sachetto ATA, Mackman N. Circulating tissue factor-positive extracellular vesicles and their association with thrombosis in different diseases. Immunol Rev 2022; 312:61-75. [PMID: 35708588 DOI: 10.1111/imr.13106] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 05/27/2022] [Indexed: 12/23/2022]
Abstract
Tissue factor (TF) is a procoagulant protein released from activated host cells, such as monocytes, and tumor cells on extracellular vesicles (EVs). TF + EVs are observed in the circulation of patients with various types of diseases. In this review, we will summarize the association between TF + EVs and activation of coagulation and survival in different types of diseases, including cancer, sepsis, and infections with different viruses, such as human immunodeficiency virus (HIV), influenza A virus (IAV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We will also discuss the source of TF + EVs in various diseases. EVTF activity is associated with thrombosis in pancreatic cancer patients and coronavirus disease 2019 patients (COVID-19) and with disseminated intravascular coagulation in cancer patients. EVTF activity is also associated with worse survival in patients with cancer and COVID-19. Monocytes are the major sources of TF + EVs in sepsis, and viral infections, such as HIV, Ebola virus, and SARS-CoV-2. In contrast, alveolar epithelial cells are the major source of TF + EVs in bronchoalveolar lavage fluid in COVID-19 and influenza A patients. These studies indicate that EVTF activity could be used as a biomarker to identify patients that have an increased risk of coagulopathy and mortality.
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Affiliation(s)
- Yohei Hisada
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Ana Teresa Azevedo Sachetto
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Nigel Mackman
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Extracellular Vesicles as Drivers of Immunoinflammation in Atherothrombosis. Cells 2022; 11:cells11111845. [PMID: 35681540 PMCID: PMC9180657 DOI: 10.3390/cells11111845] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 05/30/2022] [Accepted: 06/01/2022] [Indexed: 02/07/2023] Open
Abstract
Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality all over the world. Extracellular vesicles (EVs), small lipid-bilayer membrane vesicles released by most cellular types, exert pivotal and multifaceted roles in physiology and disease. Emerging evidence emphasizes the importance of EVs in intercellular communication processes with key effects on cell survival, endothelial homeostasis, inflammation, neoangiogenesis, and thrombosis. This review focuses on EVs as effective signaling molecules able to both derail vascular homeostasis and induce vascular dysfunction, inflammation, plaque progression, and thrombus formation as well as drive anti-inflammation, vascular repair, and atheroprotection. We provide a comprehensive and updated summary of the role of EVs in the development or regression of atherosclerotic lesions, highlighting the link between thrombosis and inflammation. Importantly, we also critically describe their potential clinical use as disease biomarkers or therapeutic agents in atherothrombosis.
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Ng TL, Tsui DCC, Wang S, Usari T, Patil T, Wilner K, Camidge DR. Association of anticoagulant use with clinical outcomes from crizotinib in ALK- and ROS1-rearranged advanced non-small cell lung cancers: A retrospective analysis of PROFILE 1001. Cancer Med 2022; 11:4422-4429. [PMID: 35510711 PMCID: PMC9741966 DOI: 10.1002/cam4.4789] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 04/11/2022] [Accepted: 04/17/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND ROS1- and ALK-rearranged advanced NSCLCs are associated with increased thromboembolic risk. We hypothesized that a prothrombotic phenotype offers an evolutionary advantage to subsets of these cancers. The impact of this phenotype could alter outcomes from targeted therapy. METHODS In a retrospective analysis of ROS1- and ALK-rearranged NSCLCs treated with crizotinib in a phase 1 trial, we compared progression-free survival (PFS) and objective response rate (ORR) based on the history of anticoagulation use (a possible surrogate of thromboembolism) at baseline (within 90 days before study enrollment) or within 90 days of study treatment. RESULTS Twelve out of 53 (22.6%) ROS1- and 39 out of 153 (25.5%) ALK-rearranged NSCLCs received anticoagulation before or during the trial. Most ROS1 and ALK patients on anticoagulation received low-molecular-weight heparin (75% and 64.1%, respectively). In the ROS1-rearranged group, the median PFS (95% CI) values were 5.1 (4.4-14.4) and 29.0 (16.5-48.8) months, and the ORR values were 41.7% (95% CI: 15.2 to 72.3) and 80.5% (95% CI: 65.1 to 91.2) among those with and without anticoagulation treatment, respectively. In the ALK-rearranged group, the median PFS (95% CI) was 7.1 (5.4-7.7) and 12.0 (9.4-18.3) months, and the ORR was 41% (95% CI: 25.6 to 57.9) and 74.3% (95% CI: 65.3 to 82.1) among those with and without anticoagulation, respectively. CONCLUSIONS Anticoagulation (as a potential surrogate of a prothrombotic subset) in ROS1- and ALK-rearranged NSCLCs may be associated with a lower PFS and ORR to crizotinib. CLINICALTRIAL gov: NCT00585195.
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Affiliation(s)
- Terry L. Ng
- Division of Medical Oncology, Department of MedicineUniversity of OttawaOttawaCanada
| | - David C. C. Tsui
- Division of Medical Oncology, Department of MedicineUniversity of Colorado School of MedicineAuroraColoradoUSA
| | | | | | - Tejas Patil
- Division of Medical Oncology, Department of MedicineUniversity of Colorado School of MedicineAuroraColoradoUSA
| | | | - David R. Camidge
- Division of Medical Oncology, Department of MedicineUniversity of Colorado School of MedicineAuroraColoradoUSA
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Poenou G, Dumitru Dumitru T, Lafaie L, Mismetti V, Heestermans M, Bertoletti L. Factor XI Inhibition for the Prevention of Venous Thromboembolism: An Update on Current Evidence and Future perspectives. Vasc Health Risk Manag 2022; 18:359-373. [PMID: 35707632 PMCID: PMC9191224 DOI: 10.2147/vhrm.s331614] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 04/30/2022] [Indexed: 12/18/2022] Open
Abstract
During the past decade, emergence of direct oral anticoagulants (DOACs) has drastically improved the prevention of thrombosis. However, several unmet needs prevail in the field of thrombosis prevention, even in the DOACs’ era. The use of DOACs is still constrained and the drugs cannot be administered in every clinical scenario, such as an increased anticoagulant-associated bleeding risk, particularly in some specific populations (cancer – notably those with gastrointestinal or genitourinary cancer – and frail patients), the impossibility to be used in certain patients (eg, end-stage kidney failure during hemodialysis, pregnancy and breastfeeding), and their lack of efficacy in certain clinical scenarios (eg, mechanical heart valves, triple-positive antiphospholipid syndrome). Efforts to find a factor that upon antagonization prevents thrombosis but spares haemostasis have resulted in the identification of coagulation factor XI (FXI) as a therapeutic target. After briefly recapitulating the role of factor XI in the balance of haemostasis, we propose a narrative review of the key data published to date with compounds targeting factor XI to prevent thrombosis as well as the main ongoing clinical studies, opening up prospects for improving the care of patients requiring thrombosis prevention.
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Affiliation(s)
- Geraldine Poenou
- Therapeutic and Vascular Medicine Department, University Hospital of Saint Etienne, Saint Etienne, France
| | - Teona Dumitru Dumitru
- Therapeutic and Vascular Medicine Department, University Hospital of Saint Etienne, Saint Etienne, France
- Internal Medicine Department, University Hospital Santa Lucía, Cartagena, Murcia, Spain
- Catholic University San Antonio, Murcia, Spain
| | - Ludovic Lafaie
- Geriatric Department, University Hospital of Saint Etienne, Saint Etienne, France
- INSERM, UMR1059, Haemostasis and Vascular Dysfunction Team, Jean Monnet University, Saint-Etienne, F-42055, France
| | - Valentine Mismetti
- INSERM, UMR1059, Haemostasis and Vascular Dysfunction Team, Jean Monnet University, Saint-Etienne, F-42055, France
- Pneumology Department, University Hospital of Saint Etienne, Saint Etienne, France
| | - Marco Heestermans
- INSERM, UMR1059, Haemostasis and Vascular Dysfunction Team, Jean Monnet University, Saint-Etienne, F-42055, France
- Auvergne-Rhône-Alpes French Blood Donation Agency, Saint-Etienne, F-42100, France
| | - Laurent Bertoletti
- Therapeutic and Vascular Medicine Department, University Hospital of Saint Etienne, Saint Etienne, France
- INSERM, UMR1059, Haemostasis and Vascular Dysfunction Team, Jean Monnet University, Saint-Etienne, F-42055, France
- INSERM, CIC-1408, University Hospital of Saint Etienne, Saint Etienne, France
- Correspondence: Laurent Bertoletti, Therapeutic and Vascular Medicine Department, University Hospital of Saint Etienne, Saint Etienne, France, Tel +33477827771, Fax +33477820482, Email
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Campello E, Bosh F, Simion C, Spiezia L, Simioni P. Mechanisms of thrombosis in pancreatic ductal adenocarcinoma. Best Pract Res Clin Haematol 2022; 35:101346. [DOI: 10.1016/j.beha.2022.101346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/19/2022] [Indexed: 11/29/2022]
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Chen Z, Wei X, Dong S, Han F, He R, Zhou W. Challenges and Opportunities Associated With Platelets in Pancreatic Cancer. Front Oncol 2022; 12:850485. [PMID: 35494001 PMCID: PMC9039220 DOI: 10.3389/fonc.2022.850485] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/15/2022] [Indexed: 01/02/2023] Open
Abstract
Pancreatic cancer is one of the most common malignant tumors in the digestive system with a poor prognosis. Accordingly, better understanding of the molecular mechanisms and innovative therapies are warranted to improve the prognosis of this patient population. In addition to playing a crucial role in coagulation, platelets reportedly contribute to the growth, invasion and metastasis of various tumors, including pancreatic cancer. This narrative review brings together currently available evidence on the impact of platelets on pancreatic cancer, including the platelet-related molecular mechanisms of cancer promotion, pancreatic cancer fibrosis, immune evasion, drug resistance mechanisms, thrombosis, targeted platelet therapy, combined radiotherapy and chemotherapy treatment, platelet combined with nanotechnology treatment and potential applications of pancreatic cancer organoids. A refined understanding of the role of platelets in pancreatic cancer provides the foothold for identifying new therapeutic targets.
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Affiliation(s)
- Zhou Chen
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xiaodong Wei
- Emergency Department, Gansu Provincial Hospital, Lanzhou, China
| | - Shi Dong
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Fangfang Han
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Ru He
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Wence Zhou
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
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Immunothrombosis and the molecular control of tissue factor by pyroptosis: prospects for new anticoagulants. Biochem J 2022; 479:731-750. [PMID: 35344028 DOI: 10.1042/bcj20210522] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 02/06/2023]
Abstract
The interplay between innate immunity and coagulation after infection or injury, termed immunothrombosis, is the primary cause of disseminated intravascular coagulation (DIC), a condition that occurs in sepsis. Thrombosis associated with DIC is the leading cause of death worldwide. Interest in immunothrombosis has grown because of COVID-19, the respiratory disease caused by SARS-CoV-2, which has been termed a syndrome of dysregulated immunothrombosis. As the relatively new field of immunothrombosis expands at a rapid pace, the focus of academic and pharmacological research has shifted from generating treatments targeted at the traditional 'waterfall' model of coagulation to therapies better directed towards immune components that drive coagulopathies. Immunothrombosis can be initiated in macrophages by cleavage of the non-canonical inflammasome which contains caspase-11. This leads to release of tissue factor (TF), a membrane glycoprotein receptor that forms a high-affinity complex with coagulation factor VII/VIIa to proteolytically activate factors IX to IXa and X to Xa, generating thrombin and leading to fibrin formation and platelet activation. The mechanism involves the post-translational activation of TF, termed decryption, and release of decrypted TF via caspase-11-mediated pyroptosis. During aberrant immunothrombosis, decryption of TF leads to thromboinflammation, sepsis, and DIC. Therefore, developing therapies to target pyroptosis have emerged as an attractive concept to counteract dysregulated immunothrombosis. In this review, we detail the three mechanisms of TF control: concurrent induction of TF, caspase-11, and NLRP3 (signal 1); TF decryption, which increases its procoagulant activity (signal 2); and accelerated release of TF into the intravascular space via pyroptosis (signal 3). In this way, decryption of TF is analogous to the two signals of NLRP3 inflammasome activation, whereby induction of pro-IL-1β and NLRP3 (signal 1) is followed by activation of NLRP3 (signal 2). We describe in detail TF decryption, which involves pathogen-induced alterations in the composition of the plasma membrane and modification of key cysteines on TF, particularly at the location of the critical, allosterically regulated disulfide bond of TF in its 219-residue extracellular domain. In addition, we speculate towards the importance of identifying new therapeutics to block immunothrombotic triggering of TF, which can involve inhibition of pyroptosis to limit TF release, or the direct targeting of TF decryption using cysteine-modifying therapeutics.
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Beck S, Hochreiter B, Schmid JA. Extracellular Vesicles Linking Inflammation, Cancer and Thrombotic Risks. Front Cell Dev Biol 2022; 10:859863. [PMID: 35372327 PMCID: PMC8970602 DOI: 10.3389/fcell.2022.859863] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 02/21/2022] [Indexed: 12/13/2022] Open
Abstract
Extracellular vesicles (EVs) being defined as lipid-bilayer encircled particles are released by almost all known mammalian cell types and represent a heterogenous set of cell fragments that are found in the blood circulation and all other known body fluids. The current nomenclature distinguishes mainly three forms: microvesicles, which are formed by budding from the plasma membrane; exosomes, which are released, when endosomes with intraluminal vesicles fuse with the plasma membrane; and apoptotic bodies representing fragments of apoptotic cells. Their importance for a great variety of biological processes became increasingly evident in the last decade when it was discovered that they contribute to intercellular communication by transferring nucleotides and proteins to recipient cells. In this review, we delineate several aspects of their isolation, purification, and analysis; and discuss some pitfalls that have to be considered therein. Further on, we describe various cellular sources of EVs and explain with different examples, how they link cancer and inflammatory conditions with thrombotic processes. In particular, we elaborate on the roles of EVs in cancer-associated thrombosis and COVID-19, representing two important paradigms, where local pathological processes have systemic effects in the whole organism at least in part via EVs. Finally, we also discuss possible developments of the field in the future and how EVs might be used as biomarkers for diagnosis, and as vehicles for therapeutics.
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Affiliation(s)
- Sarah Beck
- Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
- Institute of Experimental Biomedicine, University Hospital Würzburg and Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany
- *Correspondence: Sarah Beck, ; Johannes A. Schmid,
| | - Bernhard Hochreiter
- Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Johannes A. Schmid
- Institute of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
- *Correspondence: Sarah Beck, ; Johannes A. Schmid,
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Abstract
Cancer-associated thrombosis (including venous thromboembolism (VTE) and arterial events) is highly consequential for patients with cancer and is associated with worsened survival. Despite substantial improvements in cancer treatment, the risk of VTE has increased in recent years; VTE rates additionally depend on the type of cancer (with pancreas, stomach and primary brain tumours having the highest risk) as well as on individual patient's and cancer treatment factors. Multiple cancer-specific mechanisms of VTE have been identified and can be classified as mechanisms in which the tumour expresses proteins that alter host systems, such as levels of platelets and leukocytes, and in which the tumour expresses procoagulant proteins released into the circulation that directly activate the coagulation cascade or platelets, such as tissue factor and podoplanin, respectively. As signs and symptoms of VTE may be non-specific, diagnosis requires clinical assessment, evaluation of pre-test probability, and objective diagnostic testing with ultrasonography or CT. Risk assessment tools have been validated to identify patients at risk of VTE. Primary prevention of VTE (thromboprophylaxis) has long been recommended in the inpatient and post-surgical settings, and is now an option in the outpatient setting for individuals with high-risk cancer. Anticoagulant therapy is the cornerstone of therapy, with low molecular weight heparin or newer options such as direct oral anticoagulants. Personalized treatment incorporating risk of bleeding and patient preferences is essential, especially as a diagnosis of VTE is often considered by patients even more distressing than their cancer diagnosis, and can severely affect the quality of life. Future research should focus on current knowledge gaps including optimizing risk assessment tools, biomarker discovery, next-generation anticoagulant development and implementation science.
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Castle J, Blower E, Kirwan CC. Update on the role of circulating tumour cells in cancer-associated thrombosis. THROMBOSIS UPDATE 2021. [DOI: 10.1016/j.tru.2021.100066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Mackman N, Grover SP, Antoniak S. Tissue factor expression, extracellular vesicles, and thrombosis after infection with the respiratory viruses influenza A virus and coronavirus. J Thromb Haemost 2021; 19:2652-2658. [PMID: 34418279 PMCID: PMC9770926 DOI: 10.1111/jth.15509] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 02/06/2023]
Abstract
Tissue factor (TF) is induced in a variety of cell types during viral infection, which likely contributes to disseminated intravascular coagulation and thrombosis. TF-expressing cells also release TF-positive extracellular vesicles (EVs) into the circulation that can be measured using an EVTF activity assay. This review summarizes studies that analyze TF expression, TF-positive EVs, activation of coagulation, and thrombosis after infection with influenza A virus (IAV) and coronaviruses (CoVs), including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, and Middle East respiratory syndrome CoV (MERS-CoV). The current pandemic of coronavirus disease 2019 (COVID-19) is caused by infection with SARS-CoV-2. Infection of mice with IAV increased TF expression in lung epithelial cells as well as increased EVTF activity and activation of coagulation in the bronchoalveolar lavage fluid (BALF). Infection of mice with MERS-CoV, SARS-CoV, and SARS-CoV-2 also increased lung TF expression. Single-cell RNA sequencing analysis on the BALF from severe COVID-19 patients revealed increased TF mRNA expression in epithelial cells. TF expression was observed in peripheral blood mononuclear cells infected with SARS-CoV. TF was also expressed by peripheral blood mononuclear cells, monocytes in platelet-monocyte aggregates, and neutrophils isolated from COVID-19 patients. Elevated circulating EVTF activity was observed in severe IAV and COVID-19 patients. Importantly, EVTF activity was associated with mortality in severe IAV patients and with plasma D-dimer, severity, thrombosis, and mortality in COVID-19 patients. These studies strongly suggest that increased TF expression in patients infected with IAV and pathogenic CoVs contributes to thrombosis.
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Affiliation(s)
- Nigel Mackman
- Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Steven P Grover
- Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Silvio Antoniak
- Department of Pathology and Laboratory Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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