Integrin inhibition differentially remodels vascular networks in lung metastases driven by vessel co-option or angiogenesis.

Authors

Laura Marcos-Zazo, Iván Carrera-Aguado, Jesús Gómez-Escudero, Patricia Berlana-Galán, Irene Torre-Cea, Elena Guerra-Paes, Celia Redondo-Gonzalez, Juan Sánchez-Mateos, Daniel Cáceres-Calle, Óscar Maiques, Miguel Pericacho, Susana Fraile, Telmo Rodrigues-Teixeira, Carmen García-Macías, Omar García-Sánchez, Lorena Benito-Garzón, Fernando Sánchez-Juanes, José M Muñoz-Félix

Published in

Angiogenesis. Volume 29. Issue 4. Aug 20, 2026. Epub Aug 20, 2026.

Abstract

Tumor progression depends on an adequate blood supply to sustain oxygen and nutrients delivery. 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.

PMID:
42624948
Bibliographic data and abstract were imported from PubMed on 21 Aug 2026.

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