{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T14:15:29Z","timestamp":1789654529710,"version":"4.0.1"},"reference-count":49,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008730","name":"Kreftforeningen","doi-asserted-by":"publisher","award":["215613"],"award-info":[{"award-number":["215613"]}],"id":[{"id":"10.13039\/100008730","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008730","name":"Kreftforeningen","doi-asserted-by":"publisher","award":["245151"],"award-info":[{"award-number":["245151"]}],"id":[{"id":"10.13039\/100008730","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["isevjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Extracellular Bio"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The tumour microenvironment (TME) constitution is decisive for cancer outcome and is manifested in diffusion\u2010weighted (DW) magnetic resonance imaging (MRI). We hypothesized that the TME metabolic state is reflected by mitochondrial DNA (mtDNA) secreted in extracellular vesicles (EVs) and examined whether plasma EV\u2010mtDNA variants may divulge MRI\u2010assessed TME attributes of rectal cancer aggressiveness. On the diagnostic MRI scans from 60 rectal cancer patients, the apparent diffusion coefficient (ADC) was calculated on DW images (\n                    <jats:italic>n<\/jats:italic>\n                    = 29), and tumour volume (\n                    <jats:italic>n<\/jats:italic>\n                    = 57) and extramural vascular invasion (EMVI; all patients) were determined on anatomical images. Plasma EVs (all patients) were isolated by size exclusion chromatography and verified for EV features. The EV\u2010mtDNA was sequenced along with mtDNA in whole blood (WB; normal tissue) to calculate the EV\/WB\u2010mtDNA total variant number (TVN) and heteroplasmic variant number (HVN)\u2014as a proxy for TME intracellular mtDNA variants expelled in EVs. Low EV\/WB\u2010mtDNA TVN and HVN, indicative of hampered clearance of mutated mtDNA via EVs, were associated with low ADC (high TME cell density;\n                    <jats:italic>p<\/jats:italic>\n                    = 0.018,\n                    <jats:italic>p<\/jats:italic>\n                    = 0.005) and a large tumour volume (\n                    <jats:italic>p<\/jats:italic>\n                    = 0.002,\n                    <jats:italic>p<\/jats:italic>\n                    = 0.003). Likewise, low EV\/WB\u2010mtDNA TVN and HVN were associated with positive EMVI (tumour infiltration in blood vessels;\n                    <jats:italic>p<\/jats:italic>\n                    = 0.002,\n                    <jats:italic>p<\/jats:italic>\n                    = 0.003) and histologic ypN stage 1\u20132 (lymph nodes with tumour cells surviving radiotherapy;\n                    <jats:italic>p<\/jats:italic>\n                    = 0.002,\n                    <jats:italic>p<\/jats:italic>\n                    = 0.005), both indicators of high tumour aggressiveness. High cellular density may hamper the clearance of pathogenic tumour mtDNA variants by EVs and thus promote rectal cancer aggressiveness.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration<\/jats:bold>\n                    : ClinicalTrials.gov: NCT01816607. Registered 22 March 2013,\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01816607\">https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01816607<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1002\/jex2.70097","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T07:02:06Z","timestamp":1761894126000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dissemination of Mitochondrial DNA Variants: Looking at the \u2018Bigger\u2019 Picture of the Tumour Microenvironment in Rectal Cancer Patients"],"prefix":"10.1002","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2127-752X","authenticated-orcid":false,"given":"Kine Mari","family":"Bakke","sequence":"first","affiliation":[{"name":"Department of Oncology Akershus University Hospital  L\u00f8renskog Norway"},{"name":"Department of Physics and Computational Radiology, Clinic for Radiology and Nuclear Medicine Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonje","family":"Bj\u00f8rnetr\u00f8","sequence":"additional","affiliation":[{"name":"Department of Oncology Akershus University Hospital  L\u00f8renskog Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula A.","family":"Bousquet","sequence":"additional","affiliation":[{"name":"Department of Oncology Akershus University Hospital  L\u00f8renskog Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana M.","family":"Sanabria","sequence":"additional","affiliation":[{"name":"Department of Oncology Akershus University Hospital  L\u00f8renskog Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Meltzer","sequence":"additional","affiliation":[{"name":"Department of Oncology Akershus University Hospital  L\u00f8renskog 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Radiology Akershus University Hospital  L\u00f8renskog Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elin Agathe","family":"Fr\u00f8yen","sequence":"additional","affiliation":[{"name":"Department of Radiology Akershus University Hospital  L\u00f8renskog Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aida Kapic","family":"Lunder","sequence":"additional","affiliation":[{"name":"Department of Radiology Akershus University Hospital  L\u00f8renskog Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars Gustav","family":"Lyckander","sequence":"additional","affiliation":[{"name":"Department of Pathology Akershus University Hospital  L\u00f8renskog Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans Christian D.","family":"Aass","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry Oslo University Hospital  Oslo 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