The alpha-receptor for platelet-derived growth factor as a target for antibody-mediated inhibition of skeletal metastases from prostate cancer cells.
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.
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
M R
MR
Russell
W L
WL
Jamieson
N G
NG
Dolloff
A
A
Fatatis
D000293:Adolescent; D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D055815:Young Adult
D000911:Antibodies, Monoclonal; D020796:Receptor, Platelet-Derived Growth Factor alpha