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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

Eleftheriou, Nikolas M. LU ; Sjölund, Jonas LU ; Bocci, Matteo LU ; Cortez, Eliane LU ; Lee, Se Jin; Cunha, Sara I. and Pietras, Kristian LU (2016) In Oncotarget 7(51). p.84314-84325
Abstract

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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ALK1, Angiogenesis, BMP9, Endoglin, Targeted therapy
in
Oncotarget
volume
7
issue
51
pages
12 pages
publisher
Impact Journals, LLC
external identifiers
  • scopus:85007413630
  • wos:000391353200042
ISSN
1949-2553
DOI
10.18632/oncotarget.12604
language
English
LU publication?
yes
id
9f363f89-d3a8-4dda-9cc6-2a0d633ddecd
date added to LUP
2017-01-19 12:11:59
date last changed
2017-10-22 05:25:12
@article{9f363f89-d3a8-4dda-9cc6-2a0d633ddecd,
  abstract     = {<p>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.</p>},
  author       = {Eleftheriou, Nikolas M. and Sjölund, Jonas and Bocci, Matteo and Cortez, Eliane and Lee, Se Jin and Cunha, Sara I. and Pietras, Kristian},
  issn         = {1949-2553},
  keyword      = {ALK1,Angiogenesis,BMP9,Endoglin,Targeted therapy},
  language     = {eng},
  number       = {51},
  pages        = {84314--84325},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {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},
  url          = {http://dx.doi.org/10.18632/oncotarget.12604},
  volume       = {7},
  year         = {2016},
}