Platelet-derived growth factor receptors (PDGFR) α and β have been suggested as potential targets for treatment of
rhabdomyosarcoma, the most common
soft tissue sarcoma in children. This study identifies
biologic activities linked to PDGF signaling in
rhabdomyosarcoma models and human sample collections. Analysis of gene expression profiles of 101 primary human
rhabdomyosarcomas revealed elevated
PDGF-C and -D expression in all subtypes, with PDGF-D as the solely overexpressed PDGFRβ
ligand. By immunohistochemistry,
PDGF-CC, PDGF-DD, and PDGFRα were found in
tumor cells, whereas PDGFRβ was primarily detected in vascular stroma. These results are concordant with the
biologic processes and pathways identified by data mining. While
PDGF-CC/PDGFRα signaling associated with genes involved in the reactivation of developmental programs, PDGF-DD/PDGFRβ signaling related to wound healing and leukocyte differentiation. Clinicopathologic correlations further identified associations between PDGFRβ in vascular stroma and the alveolar subtype and with presence of
metastases. Functional validation of our findings was carried out in molecularly distinct model systems, where therapeutic targeting reduced
tumor burden in a PDGFR-dependent manner with effects on cell proliferation, vessel density, and macrophage infiltration. The PDGFR-selective inhibitor
CP-673,451 regulated cell proliferation through mechanisms involving reduced phosphorylation of GSK-3α and GSK-3β. Additional tissue culture studies showed a PDGFR-dependent regulation of rhabdosphere formation/
cancer cell stemness, differentiation, senescence, and apoptosis. In summary, the study shows a clinically relevant distinction in PDGF signaling in human
rhabdomyosarcoma and also suggests continued exploration of the influence of stromal PDGFRs on
sarcoma progression.