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Proc Natl Acad Sci U S A. 2016 Feb 16;113(7):E864-73. doi: 10.1073/pnas.1509384113. Epub 2016 Feb 1.

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD.

Author information

1
Department of Laboratory Medicine, Lund University, Medicon Village, SE-22381 Lund, Sweden;
2
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden;
3
Department of Medicine, Karolinska Institutet, SE-14186, Stockholm, Sweden;
4
Swiss Institute for Experimental Cancer Research, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
5
Department of Laboratory Medicine, Lund University, Medicon Village, SE-22381 Lund, Sweden; kristian.pietras@med.lu.se.

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.

KEYWORDS:

neuroendocrine tumor; platelet-derived growth factor-DD; tumor heterogeneity

PMID:
26831065
PMCID:
PMC4763770
DOI:
10.1073/pnas.1509384113
[Indexed for MEDLINE]
Free PMC Article

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