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

Abstract

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 (αPlGF) reduced the incidence, number, and size of bone metastases, and preserved bone mass. αPlGF did not affect metastatic tumor angiogenesis but inhibited osteoclast formation by preventing the upregulation of the osteoclastogenic cytokine receptor activator of NF-κB ligand in osteogenic cells, as well as by blocking the autocrine osteoclastogenic activity of PlGF. αPlGF also reduced the engraftment of tumor cells in the bone and inhibited their interaction with matrix components in the metastatic niche. αPlGF 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 αPlGF might offer opportunities for adjuvant therapy of bone metastasis.

Assessment of bone vascularization and its role in bone remodeling

“…Thus, studying the roles of vascularization in bone by the means of adequate tools and reproducible techniques should provide similar benefits for the comprehension and treatment of metabolic bone diseases. [76][77][78] …”

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

“…Moreover, recent studies document a tumor cell $ stroma cross talk, in which tumor cells can "educate" stroma cells to produce PlGF. This was shown for bone marrow stromal cells in preclinical models of bone metastasis of breast cancer and of chronic myeloid leukemia (Coenegrachts et al 2010;Schmidt et al 2011). PlGF thereby creates a fertile microenvironmental soil for the seeding tumor cells to foster their survival and expansive growth.…”

“…Phenocopying the effects seen upon PlGF blockade by gene inactivation or RNA interference (Carmeliet et al 2001;Van de Veire et al 2010;Laurent et al 2011), pharmacological PlGF inhibition by neutralizing antibodies (anti-PlGF antibodies 5D11D4, 3C7A5) or by PlGF/FLT1 peptide antagonists reduced tumor growth, angiogenesis, lymphangiogenesis, inflammation, and metastasis in different ectopically and orthotopically implanted tumors in mouse models, in the absence of adverse side effects (Fischer et al 2007;Taylor and Goldenberg 2007;Coenegrachts et al 2010;Bagley et al 2011). PlGF is also diffusely expressed in medulloblastoma, the most common malignant brain tumor of childhood, and genetic and pharmacologic inhibition of PlGF leads to growth delay and regression of medulloblastoma models in mice as well (Snuderl et al 2010).…”

VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology

“…25 The addition of an anti-PIGF antibody has been shown to reduce the osteolysis in metastatic tumours. 26 PIGF is a homologue of VEGF-C; both are RANKL targets and mediate RANKL activity. 27 We found, however, that VEGF-C was not able to support human osteoclast formation independent of M-CSF.…”