Akt activation via the alpha platelet-derived growth factor receptor in bone-metastatic prostate cancer cells

Nathan G. Dolloff

doi:10.17918/00000661

Prostate cancer patients develop skeletal metastases with high incidence (Bubendorf et al., 2000). A critical event in the metastatic process is the survival and growth of tumor cells at secondary sites. It has been postulated that bone is a particularly "fertile" environment for prostate cancer cells thus contributing to their skeletal tropism (Poste and Fidler, 1980; Paget, 1889). Currently, there are no effective treatments for patients with advanced, metastatic prostate cancer, propagating a need for development of novel therapeutic strategies. Promising targets for such new therapies include specific bone-derived factors and their cancer cell-expressed receptors, which mediate preferential colonization of bone by prostate cancer cells. Platelet-derived growth factor (PDGF) is a potent survival and growth factor for multiple cell types, including prostate cancer cells (Lee et al., 2003). PDGF has two cognate receptors, [alpha]-PDGFR and [beta]-PDGFR. The [alpha]-PDGFR isoform is expressed in primary prostate cancer samples (Fudge et al., 1994; Fudge et al., 1996) as well as in bone metastases originating from prostate tumors (Chott et al., 1999). PDGF is a regulator of bone remodeling, as it is a differentiation factor for osteoblasts and osteoclasts. Therefore, the presence of PDGF within the bone may establish an environment that favors the initial survival and growth of prostate cancer cells. In fact, inhibition of PDGFR signaling in vivo has been shown to reduce formation of prostate cancer bone metastases (Uehara et al., 2003). This dissertation investigated the ability of bone- and non-bone-metastatic prostate cancer cells to activate the critical Akt pro-survival pathway in response to PDGF. PC3-ML cells, which are highly bone-metastatic in vivo (Wang and Stearns, 1991; Dolloff et al., 2007), most efficiently activated Akt in response to PDGF, when compared to non-bone-metastatic PC3-N cells, DU145 cells and normal prostate epithelial cells. PC3-ML cells have heightened responsiveness to PDGF due to their over-expression of the [alpha]-PDGFR, which was not observed for other receptor tyrosine kinases, such as [beta]-PDGFR and epidermal growth factor receptor (EGFR). Furthermore, PC3-ML cells activated Akt to the highest degree in response to human bone marrow aspirates and osteoblast-conditioned medium. These results suggest PC3-ML cells are most sensitive to anti-apoptotic factors normally found in the bone stromal compartment. The majority of Akt activation in response to bone marrow and osteoblast-conditioned medium was dependent on [alpha]-PDGFR signaling. It was further determined that bone marrow activated [alpha]-PDGFR by a ligand-independent mechanism, which is termed transactivation. In conclusion, PC3-ML cells over-express the [alpha]-PDGFR and possess the greatest bone-metastatic potential in an in vivo model of experimental metastasis. [alpha]-PDGFR signaling leads to activation of Akt, a critical pro-survival pathway, in response to soluble factors found in the bone marrow microenvironment. Therefore, a selective survival advantage within the bone may underscore the bone-tropic phenotype of PC3-ML cells. Finally, [alpha]-PDGFR represents a promising molecular target for the development of therapeutic strategies in the treatment of advanced prostate cancer.

Akt activation via the alpha platelet-derived growth factor receptor in bone-metastatic prostate cancer cells

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Akt activation via the alpha platelet-derived growth factor receptor in bone-metastatic prostate cancer cells

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