期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 38, 页码 E5618-E5627出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1608384113
关键词
pericyte; PDGF; fibroblast; metastasis; mesenchymal cell
资金
- Swedish Research Council
- Swedish Cancer Foundation
- Karolinska Institute Foundation
- Karolinska Institute
- Torsten Soderbergs Foundation
- Tore Nilsons Foundation
- Ruth and Richard Julin Foundation
- Ogonfonden Foundation
- Martin Rinds Foundation
- Maud and Birger Gustavssons Foundation
- Lars Hiertas Minne Foundation
- Alex and Eva Wallstroms Foundation
- Robert Lundbergs Memorial Foundation
- Swedish Diabetes Foundation
- Swedish Children Cancer Foundation
- European Research Council Advanced Grant ANGIOFAT [250021]
- Knut Alice Wallenberg Foundation
- NOVO Nordisk Foundation
- British Heart Foundation [PG/14/1/30549] Funding Source: researchfish
- Novo Nordisk Fonden [NNF14OC0012835] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [25293093] Funding Source: KAKEN
Vascular pericytes, an important cellular component in the tumor microenvironment, are often associated with tumor vasculatures, and their functions in cancer invasion and metastasis are poorly understood. Here we show that PDGF-BB induces pericyte-fibroblast transition (PFT), which significantly contributes to tumor invasion and metastasis. Gain-and loss-of-function experiments demonstrate that PDGF-BB-PDGFR beta signaling promotes PFT both in vitro and in in vivo tumors. Genome-wide expression analysis indicates that PDGF-BB-activated pericytes acquire mesenchymal progenitor features. Pharmacological inhibition and genetic deletion of PDGFR beta ablate the PDGF-BB-induced PFT. Genetic tracing of pericytes with two independent mouse strains, TN-AP-CreERT2:R26R-tdTomato and NG2-CreERT2: R26R-tdTomato, shows that PFT cells gain stromal fibroblast and myofibroblast markers in tumors. Importantly, coimplantation of PFT cells with less-invasive tumor cells in mice markedly promotes tumor dissemination and invasion, leading to an increased number of circulating tumor cells and metastasis. Our findings reveal a mechanism of vascular pericytes in PDGF-BB-promoted cancer invasion and metastasis by inducing PFT, and thus targeting PFT may offer a new treatment option of cancer metastasis.
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