[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-384196-105":59,"doc-detail-384196-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","the-unfolded-protein-response-links-er-stress-to-cancer-associated-thrombosis","The unfolded protein response links ER stress to cancer-associated thrombosis","","A proteomic plasma evaluation in patients with gastric and non–small cell lung cancer, monitored for venous thromboembolism, identified higher levels of unfolded protein response (UPR) markers in those who developed clots. UPR induction enhanced procoagulant activity release from cancer cell supernatants, while UPR-receptor antagonists blocked this effect. UPR also increased extracellular vesicles bearing tissue factor (EVTFs) via IRE1α/XBP1 and PERK pathways, promoting TF localization to the cell surface and vesicular trafficking-dependent EVTF delivery.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/the-unfolded-protein-response-links-er-stress-to-cancer-associated-thrombosis/384196/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/the-unfolded-protein-response-links-er-stress-to-cancer-associated-thrombosis/384196.png","ImageObject",300,407,{"name":92,"@type":93},"Aran","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What study evidence links the unfolded protein response to cancer-associated thrombosis?","Question",{"text":112,"@type":113},"Plasma from gastric and non–small cell lung cancer patients showed increased UPR-related markers in individuals who developed clots compared with those who did not.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does UPR affect procoagulant activity in cancer cells?",{"text":117,"@type":113},"UPR induction enhanced release of procoagulant activity into supernatants from cancer cells, and this release was blocked by antagonists of UPR receptors IRE1α and PERK.",{"name":119,"@type":110,"acceptedAnswer":120},"Does UPR increase tissue factor synthesis or change how tissue factor is delivered?",{"text":121,"@type":113},"UPR did not increase tissue factor synthesis; instead, it stimulated tissue factor localization to the cell surface and increased UPR-dependent delivery to EVTFs through vesicular trafficking.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},384196,1790483830,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},137455076865,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","RESE AR CH  \nARTICLE  \nConflict of interest: JIZ and RF are named inventors on a provisional  \npatent titled “COMPOSITIONSAND METHODS FOR IDENTIFYING AND MODULATING THROMBOTIC CONDITIONS IN A CANCER PATIENT.”  \nCopyright: © 2023, Muse et al. This isan open access article published under the terms of the Creative Commons Attribution 4.0 International License.  \nSubmitted: March 1, 2023  \nAccepted: August 29, 2023  \nPublished: October 9, 2023  \nReference information: JCI Insight. 2023;8(19):e170148 .  \n[https://doi.org/10.1172/jci](https://doi.org/10.1172/jci).  \ninsight.170148 .  \nThe unfolded protein response links ER stress to cancer-associated thrombosis  \nOluwatoyosi Muse,1 Rushad Patell,1 Christian G. Peters,1 Moua Yang,1 Emale El-Darzi,1 Sol Schulman,1 Anna Falanga,2 Marina Marchetti,2 Laura Russo,2 Jeffrey I. Zwicker,3 and Robert Flaumenhaft1  \n1Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 2Immunohematology and Transfusion Medicine, ASST Papa Giovanni XXIII, Bergamo, Italy. 3Hematology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.  \nThrombosis is a common complication of advanced cancer, yet the cellular mechanisms linking malignancy to thrombosis are poorly understood. The unfolded protein response (UPR) is an ER stress response associated with advanced cancers. A proteomic evaluation of plasma from patients with gastric and non–small cell lung cancer who were monitored prospectively for venous thromboembolism demonstrated increased levels of UPR-related markers in plasma of patients who developed clots compared with those who did not. Release of procoagulant activity into supernatants of gastric, lung, and pancreatic cancer cells was enhanced by UPR induction and blocked by antagonists of the UPR receptors inositol-requiring enzyme 1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK). Release of extracellular vesicles bearing tissue factor (EVTFs) from pancreatic cancer cells was inhibited by siRNA-mediated knockdown of IRE1α/XBP1 or PERK pathways. Induction of UPR did not increase tissue factor (TF) synthesis, but rather stimulated localization of TF to the cell surface. UPR-induced TF delivery to EVTFs was inhibited by ADP-ribosylation factor 1 knockdown or GBF1 antagonism, verifying the role of vesicular trafficking. Our findings show that UPR activation resulted in increased vesicular trafficking leading to release of prothrombotic EVTFs, thus providing a mechanistic link between ER stress and cancer-associated thrombosis.  \nIntroduction  \nThrombosis is a deadly and common complication of cancer. Both venous and arterial thrombosis are increased in the setting of malignancy (1–3) . Nearly 10% of patients with cancer receiving outpatient chemotherapy die from thrombotic complications (4) . The incidence of thrombosis in cancer ranges 4%–20% depending on several factors, including patient characteristics (e.g. , age, sex, race, comorbidities), treatment-related factors (e.g. , surgery, hospitalization, chemotherapy), and tumor-related factors (5, 6) . One example of a tumor-related factor is the type of cancer, with brain, gastric, and pancreatic cancers posing the highest risk (6) . Another important risk factor is stage of cancer, with advanced-stage cancer posing a greater risk (7) . These observations underscore the importance of tumor-related characteristics in cancer-associated thrombosis (CAT) (8) .  \nProgression of cancer is associated with activation of the unfolded protein response (UPR) . Malignant transformation of pancreatic cancer to a more aggressive phenotype results from an anabolic switch with increased protein metabolism, enhanced accumulation of unfolded or misfolded proteins, and the activation of ER stress pathways, including the UPR (9, 10) . The UPR increases the protein-folding capacity within the lumen of the ER ","cbCaiaUNRhKkXOBX","https://ap.wps.com/l/cbCaiaUNRhKkXOBX","pdf",11378423,17,"English","# Introduction\n## Cancer-associated thrombosis and incidence\n## Unfolded protein response and ER stress mechanisms\n## UPR-mediated extracellular vesicles and tissue factor","[{\"question\":\"What study evidence links the unfolded protein response to cancer-associated thrombosis?\",\"answer\":\"Plasma from gastric and non–small cell lung cancer patients showed increased UPR-related markers in individuals who developed clots compared with those who did not.\"},{\"question\":\"How does UPR affect procoagulant activity in cancer cells?\",\"answer\":\"UPR induction enhanced release of procoagulant activity into supernatants from cancer cells, and this release was blocked by antagonists of UPR receptors IRE1α and PERK.\"},{\"question\":\"Does UPR increase tissue factor synthesis or change how tissue factor is delivered?\",\"answer\":\"UPR did not increase tissue factor synthesis; instead, it stimulated tissue factor localization to the cell surface and increased UPR-dependent delivery to EVTFs through vesicular trafficking.\"}]","The unfolded protein response links ER stress to cancer-associated thrombosis | PDF",1790261652,43]