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Kristian Pietras

Kristian Pietras

Research team manager

Kristian Pietras

Distinct Effects of Ligand-Induced PDGFR alpha and PDGFR beta Signaling in the Human Rhabdomyosarcoma Tumor Cell and Stroma Cell Compartments

Author

  • Monika Ehnman
  • Edoardo Missiaglia
  • Erika Folestad
  • Joanna Selfe
  • Carina Strell
  • Khin Thway
  • Bertha Brodin
  • Kristian Pietras
  • Janet Shipley
  • Arne Ostman
  • Ulf Eriksson
Show all

Summary, in English

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.

Department/s

  • Department of Translational Medicine
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation

Publishing year

2013

Language

English

Pages

2139-2149

Publication/Series

Cancer Research

Volume

73

Issue

7

Document type

Journal article

Publisher

American Association for Cancer Research Inc.

Topic

  • Cancer and Oncology

Status

Published

ISBN/ISSN/Other

  • ISSN: 1538-7445