Anti-Placental Growth Factor Reduces Bone Metastasis by Blocking Tumor Cell Engraftment and Osteoclast Differentiation

Treatment of bone metastases is largely symptomatic and is still an unmet medical need. Current therapies mainly target the late phase of tumor-induced osteoclast activation and hereby inhibit further metastatic growth. This treatment method is, however, less effective in preventing initial tumor engraftment, a process that is supposed to depend on the bone microenvironment. We explored whether bone-derived placental growth factor (PlGF), a homologue of vascular endothelial growth factor-A, regulates osteolytic metastasis. Osteogenic cells secrete PlGF, the expression of which is enhanced by bone-metastasizing breast tumor cells. Selective neutralization of host-derived PlGF by anti-mouse PlGF (alpha PlGF) reduced the incidence, number, and size of bone metastases, and preserved bone mass. alpha PlGF did not affect metastatic tumor angiogenesis but inhibited osteoclast formation by preventing the upregulation of the osteoclastogenic cytokine receptor activator of NF-kappa B ligand in osteogenic cells, as well as by blocking the autocrine osteoclastogenic activity of PlGF. alpha PlGF also reduced the engraftment of tumor cells in the bone and inhibited their interaction with matrix components in the metastatic niche. alpha PlGF therefore inhibits not only the progression of metastasis but also the settlement of tumor in the bone. These findings identify novel properties of PlGF and suggest that alpha PlGF might offer opportunities for adjuvant therapy of bone metastasis. Cancer Res; 70(16); 6537-47. (C)2010 AACR.