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Compound genetically engineered mouse models of cancer reveal dual targeting of ALK1 and endoglin as a synergistic opportunity to impinge on angiogenic TGF-β signaling

Author:
  • Nikolas M. Eleftheriou
  • Jonas Sjölund
  • Matteo Bocci
  • Eliane Cortez
  • Se Jin Lee
  • Sara I. Cunha
  • Kristian Pietras
Publishing year: 2016
Language: English
Pages: 84314-84325
Publication/Series: Oncotarget
Volume: 7
Issue: 51
Document type: Journal article
Publisher: Impact Journals, LLC

Abstract english

Angiogenesis occurs early in tumor development, sustains primary tumor growth and provides a route for metastatic escape. The TGF-β family receptors modulate angiogenesis via endothelial-cell specific pathways. Here we investigate the interaction of two such receptors, ALK1 and endoglin, in pancreatic neuroendocrine tumors (PanNET). Independently, ALK1 and endoglin deficiencies exhibited genetically divergent phenotypes, while both highly correlate to an endothelial metagene in human and mouse PanNETs. A concurrent deficiency of both receptors synergistically decreased tumor burden to a greater extent than either individual knockdown. Furthermore, the knockout of Gdf2 (BMP9), the primary ligand for ALK1 and endoglin, exhibited a mixed phenotype from each of ALK1 and endoglin deficiencies; overall primary tumor burden decreased, but hepatic metastases increased. Tumors lacking BMP9 display a hyperbranching vasculature, and an increase in vascular mesenchymal-marker expression, which may be implicit in the increase in metastases. Taken together, our work cautions against singular blockade of BMP9 and instead demonstrates the utility of dual blockade of ALK1 and endoglin as a strategy for antiangiogenic therapy in PanNET.

Keywords

  • Cell and Molecular Biology
  • Medical Genetics
  • Immunology in the medical area
  • ALK1
  • Angiogenesis
  • BMP9
  • Endoglin
  • Targeted therapy

Other

Published
  • ISSN: 1949-2553
Kristian Pietras
E-mail: kristian.pietras [at] med.lu.se

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Division of Translational Cancer Research

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Experimental oncology