Prostate
adenocarcinoma is the second leading cause of
cancer death among men, due primarily to the fact that the majority of
prostate cancers will eventually spread to the skeleton. Metastatic dissemination requires a complex series of coordinated events that result in cells that escape from the primary
tumor into the circulation and eventually colonize a distant organ. The ability of these cells to evolve into macroscopic
metastases depends strongly on their compatibility with, and ability to utilize, this new microenvironment. We previously showed that bone-metastatic
prostate cancer cells exposed to human bone marrow respond by activation of cell survival pathways, such as
phosphoinositide 3-kinase/Akt, and that these events are mediated by the alpha-receptor for
platelet-derived growth factor (
PDGFRalpha). Our studies and others have shown that
PDGFRalpha may be activated by mechanisms independent of PDGF
ligand binding. Here, we provide conclusive evidence that soluble components of human bone marrow can activate
PDGFRalpha through a mechanism that does not require the canonical binding of PDGF
ligand(s) to the receptor. In particular, we found that dimerization of
PDGFRalpha monomers is not induced by human bone marrow, but this does not prevent receptor phosphorylation and downstream signaling from occurring. To establish the relevance of this phenomenon in vivo, we used a
PDGFRalpha mutant lacking the extracellular
ligand-binding domain. Our studies show that this truncated
PDGFRalpha is able to restore bone-metastatic potential of
prostate cancer cells as effectively as the full-length form of the receptor.