Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD
- 16 February 2016
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 113 (7), E864-E873
- https://doi.org/10.1073/pnas.1509384113
Abstract
Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.Funding Information
- Cancerfonden (CAN 2012/713)
- Vetenskapsrådet (2013-3634)
- Vetenskapsrådet (STARGET)
- Lunds Universitet (Core funding)
- EC | European Research Council (TUMORGAN)
This publication has 56 references indexed in Scilit:
- Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion SequencingThe New England Journal of Medicine, 2012
- PDGF signalling controls age-dependent proliferation in pancreatic β-cellsNature, 2011
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Emerging roles of PDGF-D signaling pathway in tumor development and progressionBiochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2010
- Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factorsNature Reviews Cancer, 2010
- Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesisThe Journal of Experimental Medicine, 2010
- miR-200 Regulates PDGF-D-Mediated Epithelial–Mesenchymal Transition, Adhesion, and Invasion of Prostate Cancer CellsThe International Journal of Cell Cloning, 2009
- Role of platelet-derived growth factors in physiology and medicineGenes & Development, 2008
- Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesisProceedings of the National Academy of Sciences of the United States of America, 2006
- Efficacy and Safety of Imatinib Mesylate in Advanced Gastrointestinal Stromal TumorsThe New England Journal of Medicine, 2002