{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T06:41:31Z","timestamp":1781246491687,"version":"3.54.1"},"reference-count":32,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T00:00:00Z","timestamp":1709683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Utrecht Province","award":["13.036222"],"award-info":[{"award-number":["13.036222"]}]},{"name":"Utrecht Centre Food &amp; Health","award":["13.036222"],"award-info":[{"award-number":["13.036222"]}]},{"name":"private anonymous","award":["13.036222"],"award-info":[{"award-number":["13.036222"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Colorectal cancer metastasizes predominantly to the liver but also to the lungs and the peritoneum. The presence of extra-hepatic metastases limits curative (surgical) treatment options and is associated with very poor survival. The mechanisms governing multi-organ metastasis formation are incompletely understood. Here, we tested the hypothesis that the site of tumor growth influences extra-hepatic metastasis formation. To this end, we implanted murine colon cancer organoids into the primary tumor site (i.e., the caecum) and into the primary metastasis site (i.e., the liver) in immunocompetent mice. The organoid-initiated liver tumors were significantly more efficient in seeding distant metastases compared to tumors of the same origin growing in the caecum (intra-hepatic: 51 vs. 40%, p = 0.001; peritoneal cavity: 51% vs. 33%, p = 0.001; lungs: 30% vs. 7%, p = 0.017). The enhanced metastatic capacity of the liver tumors was associated with the formation of \u2018hotspots\u2019 of vitronectin-positive blood vessels surrounded by macrophages. RNA sequencing analysis of clinical samples showed a high expression of vitronectin in liver metastases, along with signatures reflecting hypoxia, angiogenesis, coagulation, and macrophages. We conclude that \u2018onward spread\u2019 from liver metastases is facilitated by liver-specific microenvironmental signals that cause the formation of macrophage-associated vascular hotspots. The therapeutic targeting of these signals may help to contain the disease within the liver and prevent onward spread.<\/jats:p>","DOI":"10.3390\/cancers16051073","type":"journal-article","created":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T08:43:14Z","timestamp":1709714594000},"page":"1073","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Onward Spread from Liver Metastases Is a Major Cause of Multi-Organ Metastasis in a Mouse Model of Metastatic Colon Cancer"],"prefix":"10.3390","volume":"16","author":[{"given":"Liza A.","family":"Wijler","sequence":"first","affiliation":[{"name":"Laboratory of Translational Oncology, Division of Imaging and Cancer, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7281-5872","authenticated-orcid":false,"given":"Bastiaan J.","family":"Viergever","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Oncology, Division of Imaging and Cancer, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Strating","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Oncology, Division of Imaging and Cancer, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne J.","family":"van Schelven","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Oncology, Division of Imaging and Cancer, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Poghosyan","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Oncology, Division of Imaging and Cancer, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola C.","family":"Frenkel","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Oncology, Division of Imaging and Cancer, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hedy","family":"te Rietmole","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Oncology, Division of Imaging and Cancer, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"Verheem","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Oncology, Division of Imaging and Cancer, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle A. E.","family":"Raats","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Oncology, Division of Imaging and Cancer, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inne H. M.","family":"Borel Rinkes","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Oncology, Division of Imaging and Cancer, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"},{"name":"Department of Surgical Oncology, Division of Imaging and Cancer, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen","family":"Hagendoorn","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Oncology, Division of Imaging and Cancer, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"},{"name":"Department of Surgical Oncology, Division of Imaging and Cancer, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2112-4390","authenticated-orcid":false,"given":"Onno","family":"Kranenburg","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Oncology, Division of Imaging and Cancer, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"},{"name":"Department of Surgical Oncology, Division of Imaging and Cancer, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"},{"name":"Utrecht Platform for Organoid Technology, Utrecht University, Heidelberglaan 8, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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