PDGF-BB modulates hematopoiesis and tumor angiogenesis by inducing erythropoietin production in stromal cells

Funding Agencies|Swedish Research Council||Swedish Cancer Foundation||Karolinska Institute Foundation||Karolinska Institute||ImClone||European Union of Metoxia|222741|European Research Council|250021|
The platelet-derived growth factor (PDGF) signaling system contributes to tumor angiogenesis and vascular remodeling. Here we show in mouse tumor models that PDGF-BB induces erythropoietin (EPO) mRNA and protein expression by targeting stromal and perivascular cells that express PDGF receptor-beta (PDGFR-beta). Tumor-derived PDGF-BB promoted tumor growth, angiogenesis and extramedullary hematopoiesis at least in part through modulation of EPO expression. Moreover, adenoviral delivery of PDGF-BB to tumor-free mice increased both EPO production and erythropoiesis, as well as protecting from irradiation-induced anemia. At the molecular level, we show that the PDGF-BB PDGFR-beta signaling system activates the EPO promoter, acting in part through transcriptional regulation by the transcription factor Atf3, possibly through its association with two additional transcription factors, c-Jun and Sp1. Our findings suggest that PDGF-BB-induced EPO promotes tumor growth through two mechanisms: first, paracrine stimulation of tumor angiogenesis by direct induction of endothelial cell proliferation, migration, sprouting and tube formation, and second, endocrine stimulation of extramedullary hematopoiesis leading to increased oxygen perfusion and protection against tumor-associated anemia.

Lim, SharonKarolinska Institutet (författare)
Yang, YunlongKarolinska Institutet (författare)
Wang, ZongweiKarolinska Institute (författare)
Dahl Ejby Jensen, LasseLinköpings universitet,Kardiologi,Hälsouniversitetet(Swepub:liu)larje86 (författare)
Hedlund, Eva-MariaKarolinska Institutet (författare)
Andersson, PatrikKarolinska Institutet (författare)
Sasahara, MasakiyoToyama University (författare)
Larsson, OlaKarolinska Institutet (författare)
Galter, DagmarKarolinska Institutet (författare)
Gao, RenhaiKarolinska Institute (författare)
Hosaka, KayokoKarolinska Institutet (författare)
Cao, YihaiLinköpings universitet,Avdelningen för kardiovaskulär medicin,Hälsouniversitetet(Swepub:liu)yihca64 (författare)
Karolinska InstitutetKarolinska Institute (creator_code:org_t)

Ingår i:Nature Medicine: Nature Publishing Group18:1, s. 100-1101078-89561546-170X

Av författaren/redakt...: Xue, Yuan; Lim, Sharon; Yang, Yunlong; Wang, Zongwei; Dahl Ejby Jensen ...; Hedlund, Eva-Mar ...; visa fler...; Andersson, Patri ...; Sasahara, Masaki ...; Larsson, Ola; Galter, Dagmar; Gao, Renhai; Hosaka, Kayoko; Cao, Yihai; visa färre...

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.