Alk1 signaling promotes the normalization of tumor blood vessels

Orateur : Claire VIALLARD (Centre de Recherche Hôpital Maisonneuve-Rosemont, Université de Montréal, Canada)

The dysregulation of angiogenic factors in tumors leads to an immature vascular network, characterized by dilated, disorganized and highly permeable blood vessels. These factors create an unfavorable microenvironment which contributes to the invasive phenotype of cancer cells. Consequently, it is of great therapeutic interest to normalize tumor blood vessels to counter the effects of this abnormal vasculature. Alk1 is a TGFβ receptor expressed on endothelial cells with a specific affinity for bone morphogenetic protein 9 (BMP9). During development Alk1 is involved in the maturation and stabilization of vascular network in part by stimulating pericyte recruitment. Consequently, we investigated whether induction of Alk1 signaling in tumor blood vessels could restore a proper vascular network, and its subsequent impact on tumor perfusion. We created tumor cell lines (Lewis Lung Carcinoma, LLC) overexpressing BMP9 (agonist) or Alk1-Fc (Ligand trap, antagonist). In mice, BMP9 overexpression induced a significant slowdown in tumor growth compared to LLC-pLenti6 or LLC-Alk1-Fc. LLC-BMP9 tumors showed increased vascular density associated with better perfusion. Tumor blood vessels in BMP9 tumors also showed increased maturation markers and perivascular cell coverage. Increased vessel functionality in BMP9-overexpressing tumors was associated with reduced hypoxia, tumor cell apoptosis and better infiltration of lymphocytes cells. Furthermore, BMP9 overexpression inhibited the expression of genes associated with endothelial cell activation and promoted those involved in pericyte recruitment and cellular junctions. In conclusion, these data show that promotion of BMP9 signaling in the tumor vasculature can lead to significant changes in maturation and perfusion of blood vessels, leading to changes in tumor oxygenation, micro-environment and immune cells infiltration.

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