Bmpr2 Loss in the Vascular Endothelium Enhances Neoangiogenesis and Growth of Lung Metastatic Lesions in a Mouse Model of Breast Cancer

Abstract

Bone morphogenetic protein-9 (BMP9) has been implicated as a regulator of metastasis and tumor angiogenesis, with contrasting studies demonstrating both pro- and antiangiogenic roles for BMP9 across different cancer cell lines and animal models. However, these works have yet to define the contribution of the type-II BMP receptor (BMPR-II) to these processes, or assess whether the effects of BMP9 are mediated via actions on the endothelium, the tumor, or its microenvironment. Here, we demonstrate that the heterozygous (Bmpr2^EC+/−) or homozygous (Bmpr2^EC−/−) deletion of BMPR-II in the pulmonary endothelium is associated with increased overall burden and vascularization of metastases in the lungs of mice subjected to the EO771 orthotopic engraftment model of metastatic breast cancer. These increases, relative to Bmpr2^EC+/+ littermates, were observed despite equivalent primary mammary tumor growth across mice of all genotypes. In vitro, secreted factors or extracellular matrix components from BMPR-II-silenced human pulmonary arterial endothelial cells (HPAECs) did not alter EO771 proliferation relative to controls. However, endothelial BMPR-II depletion did eliminate the capacity of BMP9 to suppress both HPAEC migration to VEGF₁₆₅ and EO771 transmigration across an HPAEC monolayer. In a tail vein injection model, the short-term establishment of EO771 cell metastatic lesions was equivalent in the lungs of female Bmpr2^EC+/− and Bmpr2^EC−/− mice, relative to Bmpr2^EC+/+ controls, suggesting that the enhanced lung tumor burden observed in orthotopically implanted mice with endothelial Bmpr2 deletion is likely a consequence of enhanced tumor vascularization, rather than altered lung retention and engraftment. Our findings identify an important role for endothelial BMPR-II signaling in regulating the vascularization of metastatic lesions in the lungs.