Platelet-derived growth factor receptors differentially inform intertumoral and intratumoral heterogeneity
Year: 2012
Type: preprint
Abstract: Growth factor-mediated proliferation and self-renewal maintain tissue-specific stem cells and are frequently dysregulated in cancers. Platelet-derived growth factor (PDGF) ligands and receptors (PDGFRs) are commonly overexpressed in gliomas and initiate tumors, as proven in genetically engineered models. While PDGFRα alterations inform intertumoral heterogeneity toward a proneural glioblastoma (GBM) subtype, we interrogated the role of PDGFRs in intratumoral GBM heterogeneity. We found that PDGFRα is expressed only in a subset of GBMs, while PDGFRβ is more commonly expressed in tumors but is preferentially expressed by self-renewing tumorigenic GBM stem cells (GSCs). Genetic or pharmacological targeting of PDGFRβ (but not PDGFRα) attenuated GSC self-renewal, survival, tumor growth, and invasion. PDGFRβ inhibition decreased activation of the cancer stem cell signaling node STAT3, while constitutively active STAT3 rescued the loss of GSC self-renewal caused by PDGFRβ targeting. In silico survival analysis demonstrated that PDGFRB informed poor prognosis, while PDGFRA was a positive prognostic factor. Our results may explain mixed clinical responses of anti-PDGFR-based approaches and suggest the need for integration of models of cancer as an organ system into development of cancer therapies.
Source: Genes & Development
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
Funders: James S. McDonnell Foundation, American Brain Tumor Association, World Health Organization, Ohio Department of Development, Goldhirsh Foundation, Cleveland Clinic, Cleveland Clinic Foundation, National Science Council, National Institutes of Health, National Cancer Institute, National Institute of Neurological Disorders and Stroke
Awards: G127680468, Adult Brain Tumor Consortium (ABTC), Microenvironmental regulation of the cancer stem cell phenotype by integrin a6, G1513784061, G1525968632, G2291570324, G2407259800, G2752773248, G2798916649, G3819981206, G433562357, G4562118696, G4754476913, Homeostatic regulation of NG2 cell dynamics, G5616767386, Detecting invading glioma cells through in vivo molecular imaging of the cell sur, G6400057685, G6503978670, G6777828783, G6800522323, Stem Cell-Like Glioma Cells in Angiogenesis, G733516987, G738160294, G7611178616, G7747265227, Chemokine Secreting Dendritic Cells for Glioma Immunotherapy, G7894947954, G826790257, G827132552, Microenvironmental modulation as a result of glioma therapy, G9000002011, G9000246794, G9000335273
OpenAlex ID: W2148476801