PS 10. Osteomimicry in prostate stromal-epithelial interaction: from biology to therapy

Prostate cancer progression toward the development of bone and soft tissue metastases are major causes of morbidity and mortality in prostate cancer patients. Our laboratory developed and characterized a series of isogenic human prostate cancer cell lines recapitulating the lethal progression of human prostate cancer bone metastasis. We found that prostate cancer cells with bone metastatic potential often expressed bone-like proteins (osteomimicry), including osteocalcin, osteopontin, bone sialoprotein, osteonectin, receptor activator of NF-κB (RANK), RANK ligand (RANKL), and/or osteoprotegerin (OPG). β2-Microglobulin (β2-M), a light chain of MHC class 1 molecule, was identified as an important stromal factor driving osteomimicry. Further, β2-M conferred bone metastases and lethality in immune-compromised mice inoculated with human prostate, breast, lung and renal cancer cells, through a dynamic process called Epithelial to Mesenchymal Transition (EMT) in which cancer cells assumed mesenchymal phenotype and gained increased migratory, invasive and metastatic potential. We identified a novel β2-M receptor, the hereditary hemochromatosis gene HFE, which is a MHC-like protein, as being responsible for the regulation of intracellular iron through binding to transferrin and transferrin receptor. Anti-β2-M monoclonal antibody (anti-β2-M Ab) was effectively targeted EMT and the growth and survival of cancer cells in bone by interfering with the iron flux closely linked to intracellular oxidative stress and elevated hypoxia inducing factor 1-α in prostate cancer cells. Additional evidence supports the synergistic growth inhibitory action of anti-β2-M Ab against prostate cancer cells in vitro and prostate tumors in mice when applied in combination with radiation or chemotherapy, in which the iron concentration in the culture medium was shown to play a role.

RANKL, a target gene of β2-M, was shown to participate in osteoclastogenesis associated with aging and age-associated chronic inflammation and cancer bone metastases. We found that RANKL expressed by metastatic human prostate cancer cells and tissues participated directly in prostate cancer bone metastases. These data support the clinical benefits of targeting the RANKL-RANK axis with bisphosphonates (Zoledronic Acid) or Denosumab (a RANKL monoclonal antibody) to reduce bone pain and skeletal related events in castrationresistant prostate cancer patients treated with androgen deprivation therapy. The RANKL-RANK autocrine/paracrine signaling axes were shown to drive EMT and converge with downstream signaling elicited by other osteoclastogenic hormones, such as hepatocyte growth factor/scatter factor (HGF/SF). New approaches targeting osteomimicry and the converging signaling between RANKL/RANK and HGF/SF/ c-MET will be described from the perspective of developing novel therapies for the control of bone metastasis and the lethal progression of prostate cancer in patients.