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

Author:
  • Charlotte Anderberg
  • Sara I. Cunha
  • Zhenhua Zhai
  • Eliane Cortez
  • Evangelia Pardali
  • Jill R. Johnson
  • Marcela Franco
  • Marta Paez-Ribes
  • Ross Cordiner
  • Jonas Fuxe
  • Bengt R. Johansson
  • Marie-Jose Goumans
  • Oriol Casanovas
  • Peter ten Dijke
  • Helen M. Arthur
  • Kristian Pietras
Publishing year: 2013
Language: English
Pages: 563-579
Publication/Series: Journal of Experimental Medicine
Volume: 210
Issue: 3
Document type: Journal article
Publisher: Rockefeller University Press

Abstract english

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.

Keywords

  • Cancer and Oncology

Other

Published
  • Experimental oncology
  • ISSN: 1540-9538
Kristian Pietras
E-mail: kristian [dot] pietras [at] med [dot] lu [dot] se

Professor

Division of Translational Cancer Research

+46 46 222 64 29

MV404 A31B1

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Project manager

Experimental oncology