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

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 DOI: https://doi.org/10.1084/jem.20120662
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences
Additional Information: © 2013 Anderberg et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
Uncontrolled Keywords: Immunology and Allergy,Immunology
Publication ISSN: 1540-9538
Full Text Link:
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2013-02-11
Authors: Anderberg, Charlotte
Cunha, Sara I.
Zhai, Zhenhua
Cortez, Eliane
Pardali, Evangelia
Johnson, Jill R. (ORCID Profile 0000-0002-5149-0084)
Franco, Marcela
Páez-Ribes, Marta
Cordiner, Ross
Fuxe, Jonas
Johansson, Bengt R.
Goumans, Marie José
Casanovas, Oriol
Dijke, Peter ten
Arthur, Helen M.
Pietras, Kristian

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