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VEGFR2-Mediated Vascular Dilation as a Mechanism of VEGF-Induced Anemia and Bone Marrow Cell Mobilization

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posted on 17.03.2015, 16:40 by S. Lim, Y. Zhang, D. Zhang, F. Chen, K. Hosaka, N. Feng, T. Seki, P. Andersson, J. Li, J. Zang, B. Sun, Yihai Cao
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 (Vegfr1TK−/−) 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.

Funding

Y.C.’s laboratory is supported by research grants from the Swedish Research Council, the Swedish Cancer Foundation, the Karolinska Institute Foundation, the Karolinska Institute distinguished professor award, the Torsten Söderbergs Foundation, the Novo Nordisk Foundation, and the European Research Council advanced grant ANGIOFAT (project no. 250021).

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Citation

Cell Reports Volume 9, Issue 2, 23 October 2014, Pages 569–580

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VoR (Version of Record)

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Cell Reports Volume 9

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Elsevier (Cell Press)

issn

2211-1247

eissn

2211-1247

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1016

Available date

17/03/2015

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http://www.sciencedirect.com/science/article/pii/S2211124714007712

Notes

Supplemental materials at: Document S1. Supplemental Experimental Procedures and Figures S1–S5. http://www.sciencedirect.com/science/MiamiMultiMediaURL/1-s2.0-S2211124714007712/1-s2.0-S2211124714007712-mmc1.pdf/280959/FULL/S2211124714007712/fc714754e08d8a44f5c473c0afb58d19/mmc1.pdf and Document S2. Article plus Supplemental Information. http://www.sciencedirect.com/science/MiamiMultiMediaURL/1-s2.0-S2211124714007712/1-s2.0-S2211124714007712-mmc2.pdf/280959/FULL/S2211124714007712/71e9db57318036cf22be437be66e29a2/mmc2.pdf?_role=article-plus

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en

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