TY - JOUR
T1 - PDGF-BB modulates hematopoiesis and tumor angiogenesis by inducing erythropoietin production in stromal cells
AU - Xue, Yuan
AU - Lim, Sharon
AU - Yang, Yunlong
AU - Wang, Zongwei
AU - Jensen, Lasse Dahl Ejby
AU - Hedlund, Eva Maria
AU - Andersson, Patrik
AU - Sasahara, Masakiyo
AU - Larsson, Ola
AU - Galter, Dagmar
AU - Cao, Renhai
AU - Hosaka, Kayoko
AU - Cao, Yihai
N1 - Funding Information:
We thank J. Nissen and Z. Peng for their technical support. We thank Z. Zhu at ImClone for providing us the antibodies specific to mouse PDGFR-α and PDGFR-β. The MS-5 and S17 cell lines were provided by A. Berardi (Ospedale Bambin Gesu, Italy) and K. Dorshkind (University of California, Los Angeles, California, USA), and the adenoviruses were provided by S. Ylä-Herttuala (University of Kuopio, Kuopio, Finland). This work was supported by the laboratory of Y.C. through research grants from the Swedish Research Council, the Swedish Cancer Foundation, the Karolinska Institute Foundation, the Karolinska Institute distinguished professor award Torsten och Ragnar Söderbergs Stiftelser, a grant from ImClone, the European Union Integrated Project of Metoxia (project number 222741) and the European Research Council advanced grant ANGIOFAT (project number 250021).
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84855545329&partnerID=8YFLogxK
U2 - 10.1038/nm.2575
DO - 10.1038/nm.2575
M3 - 学術論文
C2 - 22138754
AN - SCOPUS:84855545329
SN - 1078-8956
VL - 18
SP - 100
EP - 110
JO - Nature Medicine
JF - Nature Medicine
IS - 1
ER -