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.
Highlights
Induction of neo-angiogenesis is a compulsory hallmark of cancer and an early event during tumor progression [1]
Our previous studies indicate that genetic ablation of Acvrl1 or Eng in the context of pancreatic neuroendocrine tumorigenesis in RIP1-TAg2 mice [16] gives rise to divergent phenotypes, despite the fact that the two receptors both bind the predominant ligand BMP9, and transforming growth factor (TGF)-β [9, 12, 14]
All correlations were confirmed in mouse pancreatic neuroendocrine tumors (PanNET) from RIP1-TAg2 mice, where expression of Acvrl1 and Eng was found to be highest during the angiogenic phase of tumor development, compared to premalignant lesions, primary tumors, or hepatic metastases (Figure 1E–1H)
Summary
Induction of neo-angiogenesis is a compulsory hallmark of cancer and an early event during tumor progression [1]. Substantial efforts to develop angiogenesis inhibitors to treat cancer have resulted in a set of clinically approved drugs with blockade of vascular endothelial growth factor (VEGF) signaling as a common mechanism of action [2, 3]. Evidence for a profound role for TGF-β signaling in angiogenesis comes from studies demonstrating that family ligands, such as TGF-β and bone morphogenetic protein (BMP) 9, activate receptor complexes on many cell types relevant to angiogenesis, including endothelial cells and www.impactjournals.com/oncotarget perivascular cells. Gene knock-out for endoglin, an endothelial-cell selective TGF-β type III receptor, gives rise to a phenotype with close similarities to that of ALK1 ablation, in line with their analogous expression patterns, similar upregulation during active angiogenesis both in development and pathological conditions, and causal role in the genetic vascular deficiency syndrome hereditary hemorrhagic telangiectasia [6, 7]. The precise role for these signaling partners and their ligands during the complex process of angiogenesis has proven difficult to pinpoint, as their actions appear highly concentration and context dependent [8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
