title: VEGFR2-mediated vascular dilation as a mechanism of VEGF-induced anemia and bone marrow cell mobilization.
abstract: Molecular mechanisms underlying tumor VEGF-induced host anemia and bone marrow cell (BMC) mobilization remain unknown. Here, we report that tumor VEGF markedly induced sinusoidal vasculature dilation in bone marrow (BM) and BMC mobilization to tumors and peripheral tissues in mouse and human tumor models. Unexpectedly, anti-VEGFR2, but not anti-VEGFR1, treatment completely blocked VEGF-induced anemia and BMC mobilization. Genetic deletion of Vegfr2 in endothelial cells markedly ablated VEGF-stimulated BMC mobilization. Conversely, deletion of the tyrosine kinase domain from Vegfr1 gene (Vegfr1(TK-/-)) did not affect VEGF-induced BMC mobilization. Analysis of VEGFR1(+)/VEGFR2(+) populations in peripheral blood and BM showed no significant ratio difference between VEGF- and control tumor-bearing animals. These findings demonstrate that vascular dilation through the VEGFR2 signaling is the mechanism underlying VEGF-induced BM mobilization and anemia. Thus, our data provide mechanistic insights on VEGF-induced BMC mobilization in tumors and have therapeutic implications by targeting VEGFR2 for cancer therapy.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Sharon
authors.initials: S
authors.lastname: Lim
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden; Department of Pathology, Tianjin Medical University, 22 Qi Xiang Tai Road, Heping, Tianjin 300070, China.
authors.forename: Danfang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden; The First Affiliated Hospital of Zhejiang Chinese Medicine University, 54 Youdian Road, Hangzhou, Zhejiang 310006, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Hosaka
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden; Department of Urology, The Second Hospital of Wuxi, 68 Zhongshan Road, Wuxi, Jiangsu 214002, China.
authors.forename: Ninghan
authors.initials: N
authors.lastname: Feng
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Andersson
authors.affiliation: Simcere Pharmaceutical R&D, Nanjing, 699-18 Xuan Wu Avenue, Jiangsu 210042, China.
authors.forename: Jingrong
authors.initials: J
authors.lastname: Li
authors.affiliation: Simcere Pharmaceutical R&D, Nanjing, 699-18 Xuan Wu Avenue, Jiangsu 210042, China.
authors.forename: Jingwu
authors.initials: J
authors.lastname: Zang
authors.affiliation: Department of Pathology, Tianjin Medical University, 22 Qi Xiang Tai Road, Heping, Tianjin 300070, China.
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden; Department of Medicine and Health Sciences, Linköping University, 581 83 Linköping, Sweden; Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK. Electronic address: yihai.cao@ki.se.
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000740:Anemia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000502:physiology; D016026:Bone Marrow Transplantation; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D017353:Gene Deletion; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000150:complications / Q000378:metabolism / Q000628:therapy; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D014664:Vasodilation
chemical_list: D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2