Endothelial-to-Osteoblast Conversion Generates Osteoblastic Metastasis of Prostate Cancer

Prostate cancer (PCa) bone metastasis is frequently associated with bone-forming lesions, but the source of the osteoblastic lesions remains unclear. We show that the tumor-induced bone derives partly from tumor-associated endothelial cells that have undergone endothelial-to-osteoblast (EC-to-OSB) conversion. The tumor-associated osteoblasts in PCa bone metastasis specimens and patient-derived xenografts (PDXs) were found to co-express endothelial marker Tie-2. BMP4, identified in PDX-conditioned medium, promoted EC-to-OSB conversion of 2H11 endothelial cells. BMP4 overexpression in non-osteogenic C4-2b PCa cells led to ectopic bone formation under subcutaneous implantation. Tumor-induced bone was reduced in trigenic mice (Tie2cre/Osxf/f/SCID) with endothelial-specific deletion of osteoblast cell-fate determinant OSX compared with bigenic mice (Osxf/f/SCID). Thus, tumor-induced EC-to-OSB conversion is one mechanism that leads to osteoblastic bone metastasis of PCa. [Display omitted] •Osteoblasts in human PCa bone metastasis specimens co-express osteocalcin and Tie2•Human prostate cancer bone metastases express high levels of BMP4•BMP4 induces tumor-associated endothelial cells to become osteoblasts•Deletion of Osx in endothelial cells in mice reduces PCa-induced bone formation Lin et al. show that osteoblasts in prostate cancer bone metastasis specimens co-express osteoblast and endothelial markers. Prostate cancer cell-secreted BMP4 converts tumor-associated endothelial cells into osteoblasts in the bone marrow. This endothelial-to-osteoblast conversion is one mechanism underlying the bone-forming lesions of prostate cancer bone metastasis.