Human Bone Marrow Activates the Akt Pathway in Metastatic Prostate Cells through Transactivation of the α-Platelet–Derived Growth Factor Receptor

Abstract

The factors regulating the bone tropism of disseminated prostate cancer cells are still vaguely defined. We report that prostate cancer cells that metastasize to the skeleton respond to human bone marrow with a robust stimulation of the phosphatidylinositol 3-kinase/Akt pathway, whereas prostate cells that lack bone-metastatic potential respond negligibly.

The α-receptor for platelet-derived growth factor as a target for antibody-mediated inhibition of skeletal metastases from prostate cancer cells

“…When PC3-N cells were stably transduced with the cDNA for human PDGFRa, they showed a significant increase in downstream Akt phosphorylation in response to PDGF-AA as compared to their wild-type counterparts ( Figure 3d). We have previously described that human bone marrow aspirates are able to activate Akt in PC3-ML cells by recruiting PDGFRa (Dolloff et al, 2007). When PC3-N(PDGFRa) cells were tested upon similar conditions, we observed a phosphorylation of Akt comparable to that detected in PC3-ML cells (Figure 3e .…”

“…As osteoclast involvement appears to be a delayed event in metastatic progression, single cells and small foci would initially have to rely on the trophic support exerted by factors immediately available in the bone marrow stroma, through the stimulation of compatible cellular receptors. We have previously reported that PC3-ML cells express high levels of PDGFRa, a tyrosine-kinase receptor responsible for a strong in vitro activation of the PI3K/Akt survival pathway in response to human bone marrow (Dolloff et al, 2007). The PC3-N prostate cancer cellsa non-invasive counterpart of PC3-ML cells (Wang and Stearns, 1991)-express low levels of PDGFRa, whereas brain metastasis-derived DU-145 prostate cells lack this receptor (Dolloff et al, 2005).…”

“…The PC3-N prostate cancer cellsa non-invasive counterpart of PC3-ML cells (Wang and Stearns, 1991)-express low levels of PDGFRa, whereas brain metastasis-derived DU-145 prostate cells lack this receptor (Dolloff et al, 2005). When exposed in vitro to human bone marrow, these cells show a modest or negligible activation of the PI3-K/Akt pathway, respectively (Dolloff et al, 2007). Inoculation of fluorescent DU-145 or PC3-N cells in SCID mice failed to produce macroscopic skeletal metastases after 4 weeks, in agreement with other studies (Wang and Stearns, 1991;Nemeth et al, 1999).…”

Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor α

“…Olaratumab blocks ligand binding and receptor dimerization by specifically binding to PDGFRa and as such is able to suppress potential kinase domain-independent signaling (37). Furthermore, olaratumab-bound PDGFRa is internalized and degraded, which attenuates downstream pathway activation and likely further contributes to drug activity (8,37).…”

Trial Watch: Monoclonal antibodies in cancer therapy

“…92 PDGF receptors constitute promising targets for anticancer therapies as they are involved in the proliferation and survival of different tumors as well as in the regulation of the as immunostimulatory agents by taking T cells in the close proximity of tumor cells. 28,109,110 Another interesting approach that is being tested in phase I-II trials is known as pre-targeted radioimmunotherapy and is exemplified by TF2, a bispecific mAb that simultaneously targets the tumor-associated carcinoembryonic antigen (CEA) and a heterologous hapten peptide (IMP-288).…”