Distinct effects of ligand-induced PDGFRα and PDGFRβ signaling in the human rhabdomyosarcoma tumor cell and stroma cell compartments.
Détails
Télécharger: emss-51345.pdf (1936.60 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_946C8AB8E80F
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Distinct effects of ligand-induced PDGFRα and PDGFRβ signaling in the human rhabdomyosarcoma tumor cell and stroma cell compartments.
Périodique
Cancer research
ISSN
1538-7445 (Electronic)
ISSN-L
0008-5472
Statut éditorial
Publié
Date de publication
01/04/2013
Peer-reviewed
Oui
Volume
73
Numéro
7
Pages
2139-2149
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
Mots-clé
Animals, Apoptosis, Blotting, Western, Cell Cycle, Cell Differentiation, Cell Proliferation, Child, Child, Preschool, Female, Fluorescent Antibody Technique, Humans, Immunoenzyme Techniques, Mice, Mice, SCID, Muscle, Skeletal/cytology, Muscle, Skeletal/metabolism, Phosphorylation, Receptor, Platelet-Derived Growth Factor alpha/genetics, Receptor, Platelet-Derived Growth Factor alpha/metabolism, Receptor, Platelet-Derived Growth Factor beta/genetics, Receptor, Platelet-Derived Growth Factor beta/metabolism, Rhabdomyosarcoma/genetics, Rhabdomyosarcoma/metabolism, Rhabdomyosarcoma/pathology, Signal Transduction, Stromal Cells/metabolism, Stromal Cells/pathology, Tissue Array Analysis, Tumor Cells, Cultured, Tyrosine/metabolism, Xenograft Model Antitumor Assays
Pubmed
Web of science
Open Access
Oui
Création de la notice
26/09/2023 9:53
Dernière modification de la notice
04/10/2023 14:23