Disseminated cancer cells might require nutrients to survive in foreign tissues and develop into secondary tumors. Thus, stromal factors have been proposed to contribute to the tissue tropism characteristic of several forms of tumors. For instance, prostate adenocarcinoma (PCa) metastasizes to the skeleton more frequently than any other organ. Thus, bone marrow - which is the access to the bone for migrating cancer cells - might represent an environment particularly congenial to PCa cells. Bone-produced factors might specifically select only the disseminated PCa cells which are susceptible to their trophic effects, thus conferring them with a selective advantage for the establishment of skeletal metastases. Platelet derived growth factor (PDGF) is produced by osteoblasts and osteoclasts and is integral to the regulation of the perpetual bone remodeling process. There is evidence for the expression of PDGF receptors (PDGFRs) in primitive PCa and their targeting to block the growth of PCa cells has been proposed. However, a direct correlation between PDGFR signaling and the metastatic potential of PCa cells is still missing. The aim of this study was to test the possibility that PDGF activates survival signaling pathways in human PCa cells and that a significant difference in PDGF responsiveness exists among PCa cells with different bone-metastatic potential. We employed two sub-lines derived from the human PC3 prostate cancer cell line. Both sub-lines are tumorigenic in vivo when injected subcutaneously in SCID mice. However, the PC3-N cells are unable to induce metastases in SCID mice, whereas PC3-ML cells induce skeletal metastases in more than 80% of cases. The exposure to PDGF causes a significantly stronger activation of the Akt/PKB pro-survival pathway in PC3-ML cells compared to non-metastatic PC3-N cells. In addition, normal prostate epithelial cells (PrEC) as well as DU-145 cells, originally derived from a brain PCa metastasis, are not responsive to PDGF. Interestingly, Epidermal Growth Factor - which is found in the trabecolar bone but not in the marrow - stimulates the Akt signaling pathway to the same extent in all prostate cells tested. While all cell types test negative for β-PDGFR expression, the difference in responsiveness to PDGF depends on the expression of the α-PDGFR isoform, as bone metastatic PC3-ML cells express significantly more of this receptor than non-metastatic PC3-N cells. In addition, normal PrEC and metastatic prostate cells derived from tissues other the bone such as DU-145 and LNCaP do not express α-PDGFRs. The expression of α-PDGFR by prostate cells is considered a general indication of malignant transformation. We propose that this receptor more specifically identifies those cells within the primitive tumor that respond to PDGF survival signals and therefore possess the highest propensity to metastasize to the skeleton.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]