Research Papers:
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
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Abstract
Nikolas M. Eleftheriou1, Jonas Sjölund1, Matteo Bocci1, Eliane Cortez1, Se-Jin Lee2, Sara I. Cunha3,*, Kristian Pietras1,*
1Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, Lund, Sweden
2Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
3Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
*These authors contributed equally to this work
Correspondence to:
Sara I. Cunha, email: [email protected]
Kristian Pietras, email: [email protected]
Keywords: angiogenesis, targeted therapy, BMP9, ALK1, endoglin
Received: June 04, 2016 Accepted: October 03, 2016 Published: October 12, 2016
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 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 anti-angiogenic therapy in PanNET.
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