Bone resorption by osteoclasts is thought to promote the proliferation of
prostate cancer cells disseminated to the skeleton (Mundy, 2002). Using a mouse model of experimental
metastasis, we found that although late-stage metastatic
tumors were indeed surrounded by osteoclasts, these cells were spatially unrelated to the small foci of
cancer cells in early-stage
metastases. This is the first evidence that survival and growth of disseminated
prostate cancer cells immediately after their extravasation may not depend on osteoclast involvement. Interestingly,
prostate cancer cells expressing the alpha-receptor for
platelet-derived growth factor (
PDGFRalpha) progress during early-stages of skeletal dissemination, whereas cells expressing lower levels or lacking this receptor fail to survive after extravasation in the bone marrow. However, non-metastatic cells acquire bone-metastatic potential upon ectopic overexpression of
PDGFRalpha. Finally, functional blockade of human
PDGFRalpha on
prostate cancer cells utilizing a novel humanized
monoclonal antibody -- soon to undergo phase-II clinical trials -- significantly impairs the establishment of early skeletal
metastases. In conclusion, our results strongly implicate
PDGFRalpha in
prostate cancer bone tropism through its promotion of survival and progression of early-metastatic foci, providing ground for therapeutic strategies aimed at preventing or containing the initial progression of skeletal
metastases in patients affected by prostate
adenocarcinoma.