Abstract
BackgroundAngiogenesis has become an attractive target for cancer therapy. However, despite the initial success of anti-VEGF (Vascular endothelial growth factor) therapies, the overall survival appears only modestly improved and resistance to therapy often develops. Other anti-angiogenic targets are thus urgently needed. The predominant expression of the type I BMP (bone morphogenetic protein) receptor ALK1 (activin receptor-like kinase 1) in endothelial cells makes it an attractive target, and phase I/II trials are currently being conducted. ALK1 binds with strong affinity to two ligands that belong to the TGF-ß family, BMP9 and BMP10. In the present work, we addressed their specific roles in tumor angiogenesis, cancer development and metastasis in a mammary cancer model.MethodsFor this, we used knockout (KO) mice for BMP9 (constitutive Gdf2-deficient), for BMP10 (inducible Bmp10-deficient) and double KO mice (Gdf2 and Bmp10) in a syngeneic immunocompetent orthotopic mouse model of spontaneous metastatic breast cancer (E0771).ResultsOur studies demonstrate a specific role for BMP9 in the E0771 mammary carcinoma model. Gdf2 deletion increased tumor growth while inhibiting vessel maturation and tumor perfusion. Gdf2 deletion also increased the number and the mean size of lung metastases. On the other hand, Bmp10 deletion did not significantly affect the E0771 mammary model and the double deletion (Gdf2 and Bmp10) did not lead to a stronger phenotype than the single Gdf2 deletion.ConclusionsAltogether, our data show that in a tumor environment BMP9 and BMP10 play different roles and thus blocking their shared receptor ALK1 is maybe not appropriate. Indeed, BMP9, but not BMP10, acts as a quiescence factor on tumor growth, lung metastasis and vessel normalization. Our results also support that activating rather than blocking the BMP9 pathway could be a new strategy for tumor vessel normalization in order to treat breast cancer.
Highlights
Angiogenesis has become an attractive target for cancer therapy
In accordance with this receptor profile, we found that only high doses of BMP9 (5 ng/mL) induced Smad1/5/9 phosphorylation (Additional file 1: Fig. S1C), suggesting that this phosphorylation is not mediated by the high affinity receptor Activin receptor-like kinase 1 (ALK1), in accordance with the low amount of the high affinity receptor ALK1 in these cells (Additional file 1: Fig. S1A), but by either ALK2 or ALK3
Loss of BMP9 decreases vessel perfusion in the mouse E0771 mammary carcinoma model As we could not observe any effect of BMP9 on tumor cell proliferation that could explain the increase in tumor size in Gdf2−/− mice, we addressed whether the loss of BMP9 could be due to an effect on tumor angiogenesis
Summary
Angiogenesis has become an attractive target for cancer therapy. despite the initial success of anti-VEGF (Vascular endothelial growth factor) therapies, the overall survival appears only modestly improved and resistance to therapy often develops. The transforming growth factor (TGF)-β family type I receptor ALK1 (activin receptor-like kinase 1), which is mainly expressed on endothelial cells, has been identified as a potential target for anti-angiogenic cancer treatment [6, 7]. It was recently shown that BMP9 and BMP10 play redundant roles in retinal vascularization and ductus arteriosus closure [17, 20, 23] Together, these data clearly demonstrate, in vivo, the crucial roles of ALK1 and its two ligands, BMP9 and BMP10, in vascular development. These data clearly demonstrate, in vivo, the crucial roles of ALK1 and its two ligands, BMP9 and BMP10, in vascular development Their precise role during the complex process of physiological angiogenesis has proven difficult to pinpoint from in vitro studies, as their actions appear highly concentrationand context-dependent [24]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
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
