{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T17:10:24Z","timestamp":1773335424012,"version":"3.50.1"},"reference-count":206,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT","doi-asserted-by":"crossref","award":["RS-2024-00359396"],"award-info":[{"award-number":["RS-2024-00359396"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"crossref","award":["RS-2024-00407869"],"award-info":[{"award-number":["RS-2024-00407869"]}],"id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["RS-2024-00411137"],"award-info":[{"award-number":["RS-2024-00411137"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"Phase III Postdoctoral Fellowship grant of the SNU\u2013SNUH Physician Scientist Training Program","doi-asserted-by":"publisher","award":["R03HL177119"],"award-info":[{"award-number":["R03HL177119"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R01HL159514"],"award-info":[{"award-number":["R01HL159514"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["R01HL162928"],"award-info":[{"award-number":["R01HL162928"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001674","name":"Leducq Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["25TPA1474605"],"award-info":[{"award-number":["25TPA1474605"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Wild Family Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Bone metastasis is a devastating complication of advanced osteotropic malignancies, notably breast, prostate, lung carcinomas, and malignant melanoma, and remains a primary driver of mortality. Historical paradigms have conceptualized skeletal dissemination almost exclusively as a hematogenous process wherein circulating tumor cells colonize receptive bone marrow niches. However, this model fails to reconcile why lymph node metastasis consistently serves as a potent predictor of bone involvement even though therapeutic lymphadenectomy rarely prevents distant spread. This discordance suggests that lymph nodes function not merely as passive reservoirs but as active \u2018evolutionary gateways\u2019 that sculpt bone-tropic metastatic clones. In this review, we introduce the Lymphatic\u2013Bone Axis, a framework integrating lymphatic biology into models of bone metastasis. We synthesize emerging evidence elucidating how the lymph node microenvironment primes tumor cells through CCR7-CXCR4 switching, induction of osteomimicry programs, and metabolic reprogramming that favors survival within the bone marrow. We also discuss preclinical data demonstrating direct intranodal intravasation via high endothelial venules (HEVs), providing a rapid route into the systemic circulation that bypasses the thoracic duct. Beyond consolidating current knowledge, we outline a research agenda for dissecting this axis, including longitudinal single-cell transcriptomic mapping and functional assessments of lymph node-derived tumor cells. Finally, we consider translational implications, highlighting why bone-targeted agents alone may prove insufficient once cells are conditioned within lymphatic niches. By mechanistically linking lymphatic priming to skeletal colonization, this review informs the rational design of multimodal therapeutic approaches that jointly target lymphatic transit and the bone microenvironment.<\/jats:p>","DOI":"10.3390\/cancers18060892","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T09:55:38Z","timestamp":1773136538000},"page":"892","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Lymphatic\u2013Bone Axis in Cancer Metastasis"],"prefix":"10.3390","volume":"18","author":[{"given":"Ahlim","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"},{"name":"Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2181-4957","authenticated-orcid":false,"given":"James","family":"Rhee","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0120-4630","authenticated-orcid":false,"given":"Rajeev","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jang Hee","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8067-7772","authenticated-orcid":false,"given":"Kangsan","family":"Roh","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1152\/physrev.00012.2019","article-title":"Bone metastasis: Mechanisms, therapies, and biomarkers","volume":"101","author":"Clezardin","year":"2021","journal-title":"Physiol. 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