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While tumor angiogenesis involves the formation of new blood vessels from pre-existing ones, vessel co-option represents a non-angiogenic vascularization strategy whereby tumor cells utilize pre-existing host vessels. Co-opted vessels have been considered refractory to anti-angiogenic therapies, and pharmacological modulation of co-opted vessels remains limited. In this study, we investigate the effects of low-dose cilengitide on tumor vascular remodeling in vessel co-option and angiogenic metastatic models. Our results reveal that cilengitide exerts distinct vascular effects depending on the mode of tumor vascularization. In vessel co-option-driven tumors, cilengitide treatment is associated with the remodeling of the co-opted vasculature into a more organized normalized vascular network, characterized by an increased number of functional blood vessels and enhanced vascular barrier integrity. In contrast, in angiogenic-driven tumors, cilengitide treatment promotes an expansion of the vascular network consistent with augmented, but structurally immature angiogenesis. Importantly, vascular remodeling in vessel co-option metastases is accompanied by enhanced blood vessel perfusion and reduced hypoxia, which correlates with enhanced responsiveness to chemotherapy. Conversely, in angiogenic metastases, the vascular network induced by low-dose cilengitide fails to support immunocompetent microenvironmental features and is associated with increased chemotherapy resistance. This study provides the first evidence that co-opted vasculature can be therapeutically targeted via integrin inhibition, suggesting vascular normalization remodeling as a potential strategy to overcome resistance in tumors undergoing vessel co-option.<\/jats:p>","DOI":"10.1007\/s10456-026-10085-1","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:57:54Z","timestamp":1787245074000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrin inhibition differentially remodels vascular networks in lung metastases driven by vessel co-option or angiogenesis"],"prefix":"10.1007","volume":"29","author":[{"given":"Laura","family":"Marcos-Zazo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iv\u00e1n","family":"Carrera-Aguado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"G\u00f3mez-Escudero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Berlana-Gal\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Torre-Cea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Guerra-Paes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Redondo-Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"S\u00e1nchez-Mateos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"C\u00e1ceres-Calle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d3scar","family":"Maiques","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Pericacho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Fraile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Telmo","family":"Rodrigues-Teixeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Garc\u00eda-Mac\u00edas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Garc\u00eda-S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Benito-Garz\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"S\u00e1nchez-Juanes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 M.","family":"Mu\u00f1oz-F\u00e9lix","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"10085_CR1","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1038\/nm.2537","volume":"17","author":"SM Weis","year":"2011","unstructured":"Weis SM, Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. 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