Excessive bone deposition associated with
prostate cancer bone
metastases is believed to aid in metastatic progression. One mechanism of osteoblast expansion is the transdifferentiation of bone marrow endothelial cells.
Prostate cancer cells contribute several secreted factors, including
bone morphogenetic protein 4 (BMP4), to the microenvironment that support osteoblastic transdifferentiation. In this issue of
Cancer Research, Yu and colleagues share their findings of how BMP-mediated endothelial conversion can be inhibited by treatment with
retinoic acid receptor (RAR) agonists. Using agonists like the
all-trans retinoic acid or
palovarotene, the authors demonstrated the role of the interaction of BMP-activated SMAD1 with RARγ for osteoblastic differentiation. RARγ agonists potentiated the proteasomal degradation of the Smad1-RARγ complex, blocking BMP signaling. Because
palovarotene is clinically effective in the treatment of aberrant bone formation found in
fibrodysplasia ossificans progressiva, its repurposing for the treatment of osteoblastic
cancer metastasis is promising. However, patient selection and dose-finding studies will be critical for the translation of these findings to
complement standard of care for patients with bone metastatic
prostate cancer. See related article by Yu et al., p. 3158.