Distinct Effects of Ligand-Induced PDGFR alpha and PDGFR beta Signaling in the Human Rhabdomyosarcoma Tumor Cell and Stroma Cell Compartments
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Platelet-derived growth factor receptors (PDGFR) alpha and beta 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 PDGFR beta ligand. By immunohistochemistry, PDGF-CC, PDGF-DD, and PDGFR alpha were found in tumor cells, whereas PDGFR beta was primarily detected in vascular stroma. These results are concordant with the biologic processes and pathways identified by data mining. While PDGF-CC/PDGFR alpha signaling associated with genes involved in the reactivation of developmental programs, PDGF-DD/PDGFR beta signaling related to wound healing and leukocyte differentiation. Clinicopathologic correlations further identified associations between PDGFR beta 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-3 alpha and GSK-3 beta. 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. Cancer Res; 73(7); 2139-49. (C)2013 AACR.
|Research areas and keywords||
Subject classification (UKÄ) – MANDATORY
|Publication status||Published - 2013|
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Medicine (013031200)