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

Anderberg, Charlotte; Cunha, Sara I.; Zhai, Zhenhua; Cortez, Eliane LU ; Pardali, Evangelia; Johnson, Jill R.; Franco, Marcela; Paez-Ribes, Marta; Cordiner, Ross and Fuxe, Jonas, et al. (2013) In Journal of Experimental Medicine 210(3). p.563-579
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-beta 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... (More)
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-beta 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. (Less)
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Contribution to journal
publication status
published
subject
in
Journal of Experimental Medicine
volume
210
issue
3
pages
563 - 579
publisher
Rockefeller University Press
external identifiers
  • wos:000315997000011
  • scopus:84877629719
ISSN
1540-9538
DOI
10.1084/jem.20120662
language
English
LU publication?
yes
id
77f3f3ba-bb91-41c5-a05e-134cae5ce63e (old id 3651257)
date added to LUP
2013-05-02 08:55:02
date last changed
2019-04-21 04:13:43
@article{77f3f3ba-bb91-41c5-a05e-134cae5ce63e,
  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-beta 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.},
  author       = {Anderberg, Charlotte and Cunha, Sara I. and Zhai, Zhenhua and Cortez, Eliane and Pardali, Evangelia and Johnson, Jill R. and Franco, Marcela and Paez-Ribes, Marta and Cordiner, Ross and Fuxe, Jonas and Johansson, Bengt R. and Goumans, Marie-Jose and Casanovas, Oriol and ten Dijke, Peter and Arthur, Helen M. and Pietras, Kristian},
  issn         = {1540-9538},
  language     = {eng},
  number       = {3},
  pages        = {563--579},
  publisher    = {Rockefeller University Press},
  series       = {Journal of Experimental Medicine},
  title        = {Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination},
  url          = {http://dx.doi.org/10.1084/jem.20120662},
  volume       = {210},
  year         = {2013},
}