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Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

Lookup NU author(s): Dr Jason Zhai, Ross Cordiner, Professor Helen ArthurORCiD

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Abstract

Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer.


Publication metadata

Author(s): Anderberg C, Cunha S, Zhai Z, Cortez E, Pardali E, Johnson J, Franco M, Paez-Ribes M, Cordiner R, Fuxe J, Johansson BR, Goumans MJ, Casanovas O, ten Dijke P, Arthur HM, Pietras K

Publication type: Article

Publication status: Published

Journal: Journal of Experimental Medicine

Year: 2013

Volume: 210

Issue: 3

Pages: 563-579

Print publication date: 11/02/2013

ISSN (print): 0022-1007

ISSN (electronic): 1540-9538

Publisher: Rockefeller University Press

URL: http://dx.doi.org/10.1084/jem.20120662

DOI: 10.1084/jem.20120662


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