title: PDGF-BB modulates hematopoiesis and tumor angiogenesis by inducing erythropoietin production in stromal cells.
abstract: 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-β (PDGFR-β). 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-bβ 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.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xue
authors.forename: Sharon
authors.initials: S
authors.lastname: Lim
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Yang
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Wang
authors.forename: Lasse Dahl Ejby
authors.initials: LD
authors.lastname: Jensen
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Hedlund
authors.forename: Patrik
authors.initials: P
authors.lastname: Andersson
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sasahara
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.forename: Dagmar
authors.initials: D
authors.lastname: Galter
authors.forename: Renhai
authors.initials: R
authors.lastname: Cao
authors.forename: Kayoko
authors.initials: K
authors.lastname: Hosaka
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000740:Anemia / Q000235:genetics; D000818:Animals; D000077214:Becaplermin; D018827:Carcinoma, Lewis Lung / Q000098:blood supply; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D004921:Erythropoietin; D000077214:Becaplermin