Pericyte-fibroblast Transition Promotes Tumor Growth and Metastasis

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2016 Sep 9

PMID 27608497

Citations 190

Authors

Kayoko Hosaka

Yunlong Yang

Takahiro Seki

Carina Fischer

Olivier Dubey

Erik Fredlund

Johan Hartman

Piotr Religa

Hiromasa Morikawa

Yoko Ishii

Masakiyo Sasahara

Ola Larsson

Giulio Cossu

Renhai Cao

Sharon Lim

Yihai Cao

Affiliations

Soon will be listed here.

Abstract

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-PDGFRβ 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 PDGFRβ 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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References

Joyce J, Pollard J . Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009; 9(4):239-52. PMC: 3251309. DOI: 10.1038/nrc2618. View

Hosaka K, Yang Y, Seki T, Nakamura M, Andersson P, Rouhi P . Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis. Nat Commun. 2013; 4:2129. DOI: 10.1038/ncomms3129. View

Dellavalle A, Maroli G, Covarello D, Azzoni E, Innocenzi A, Perani L . Pericytes resident in postnatal skeletal muscle differentiate into muscle fibres and generate satellite cells. Nat Commun. 2011; 2:499. DOI: 10.1038/ncomms1508. View

Lindahl P, Johansson B, Leveen P, Betsholtz C . Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science. 1997; 277(5323):242-5. DOI: 10.1126/science.277.5323.242. View

Gao Z, Sasaoka T, Fujimori T, Oya T, Ishii Y, Sabit H . Deletion of the PDGFR-beta gene affects key fibroblast functions important for wound healing. J Biol Chem. 2004; 280(10):9375-89. DOI: 10.1074/jbc.M413081200. View

Kuhnert F, Tam B, Sennino B, Gray J, Yuan J, Jocson A . Soluble receptor-mediated selective inhibition of VEGFR and PDGFRbeta signaling during physiologic and tumor angiogenesis. Proc Natl Acad Sci U S A. 2008; 105(29):10185-90. PMC: 2474564. DOI: 10.1073/pnas.0803194105. View

Pillai V, Samant S, Sundaresan N, Raghuraman H, Kim G, Bonner M . Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat Commun. 2015; 6:6656. PMC: 4441304. DOI: 10.1038/ncomms7656. View

Cao R, Ji H, Feng N, Zhang Y, Yang X, Andersson P . Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis. Proc Natl Acad Sci U S A. 2012; 109(39):15894-9. PMC: 3465417. DOI: 10.1073/pnas.1208324109. View

Dong M, Yang X, Lim S, Cao Z, Honek J, Lu H . Cold exposure promotes atherosclerotic plaque growth and instability via UCP1-dependent lipolysis. Cell Metab. 2013; 18(1):118-29. PMC: 3701322. DOI: 10.1016/j.cmet.2013.06.003. View

10.

Chen Y, Chang F, Wu C, Chou Y, Hsu H, Chiang W . Platelet-derived growth factor receptor signaling activates pericyte-myofibroblast transition in obstructive and post-ischemic kidney fibrosis. Kidney Int. 2011; 80(11):1170-81. DOI: 10.1038/ki.2011.208. View

11.

Tian X, Hu T, Zhang H, He L, Huang X, Liu Q . Vessel formation. De novo formation of a distinct coronary vascular population in neonatal heart. Science. 2014; 345(6192):90-4. PMC: 4275002. DOI: 10.1126/science.1251487. View

12.

Cao Y, Arbiser J, DAmato R, DAmore P, Ingber D, Kerbel R . Forty-year journey of angiogenesis translational research. Sci Transl Med. 2011; 3(114):114rv3. PMC: 8265598. DOI: 10.1126/scitranslmed.3003149. View

13.

Wright G, Simon R . A random variance model for detection of differential gene expression in small microarray experiments. Bioinformatics. 2003; 19(18):2448-55. DOI: 10.1093/bioinformatics/btg345. View

14.

Grivennikov S, Greten F, Karin M . Immunity, inflammation, and cancer. Cell. 2010; 140(6):883-99. PMC: 2866629. DOI: 10.1016/j.cell.2010.01.025. View

15.

Folkman J . Angiogenesis: an organizing principle for drug discovery?. Nat Rev Drug Discov. 2007; 6(4):273-86. DOI: 10.1038/nrd2115. View

16.

Mueller M, Fusenig N . Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 2004; 4(11):839-49. DOI: 10.1038/nrc1477. View

17.

Thiery J, Acloque H, Huang R, Nieto M . Epithelial-mesenchymal transitions in development and disease. Cell. 2009; 139(5):871-90. DOI: 10.1016/j.cell.2009.11.007. View

18.

Vaillancourt R, Kazlauskas A, DiMaio D . Ligand-independent activation of the platelet-derived growth factor beta receptor: requirements for bovine papillomavirus E5-induced mitogenic signaling. Mol Cell Biol. 1995; 15(5):2570-81. PMC: 230487. DOI: 10.1128/MCB.15.5.2570. View

19.

Heinrich M, Corless C, Duensing A, McGreevey L, Chen C, Joseph N . PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003; 299(5607):708-10. DOI: 10.1126/science.1079666. View

20.

Shah N, Sawyers C . Recent success with the tyrosine kinase inhibitor STI-571--lessons for targeted therapy of cancer. Curr Opin Investig Drugs. 2001; 2(3):422-3. View