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Sinusoidal ephrin receptor EPHB4 controls hematopoietic progenitor cell mobilization from bone marrow
Hyeongil Kwak, … , Jason M. Butler, Giovanna Tosato
Hyeongil Kwak, … , Jason M. Butler, Giovanna Tosato
Published November 7, 2016
Citation Information: J Clin Invest. 2016;126(12):4554-4568. https://doi.org/10.1172/JCI87848.
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Research Article Hematology Oncology Article has an altmetric score of 7

Sinusoidal ephrin receptor EPHB4 controls hematopoietic progenitor cell mobilization from bone marrow

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Abstract

Hematopoietic stem and progenitor cells (HSPCs) reside in the bone marrow. Stress signals from cancer and other conditions promote HSPC mobilization into circulation and subsequent homing to tissue microenvironments. HSPC infiltration into tissue microenvironments can influence disease progression; notably, in cancer, HSPCs encourage tumor growth. Here we have uncovered a mutually exclusive distribution of EPHB4 receptors in bone marrow sinusoids and ephrin B2 ligands in hematopoietic cells. We determined that signaling interactions between EPHB4 and ephrin B2 control HSPC mobilization from the bone marrow. In mice, blockade of the EPHB4/ephrin B2 signaling pathway reduced mobilization of HSPCs and other myeloid cells to the circulation. EPHB4/ephrin B2 blockade also reduced HSPC infiltration into tumors as well as tumor progression in murine models of melanoma and mammary cancer. These results identify EPHB4/ephrin B2 signaling as critical to HSPC mobilization from bone marrow and provide a potential strategy for reducing cancer progression by targeting the bone marrow.

Authors

Hyeongil Kwak, Ombretta Salvucci, Roberto Weigert, Jorge L. Martinez-Torrecuadrada, Mark Henkemeyer, Michael G. Poulos, Jason M. Butler, Giovanna Tosato

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Figure 6

Ephrin B2/EPHB4 blockade inhibits 4T1 tumor growth, hematopoietic cell mobilization, and tumor infiltration with hematopoietic cells.

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Ephrin B2/EPHB4 blockade inhibits 4T1 tumor growth, hematopoietic cell m...
(A) Schematic of experiment. On day 0, BALB/c mice were injected with pcDNA or TNYL-RAW vectors and with syngeneic, blue-Azurite+ 4T1 cells; they were euthanized on day 7 for blood and tumor evaluation. (B) 4T1 tumor weight; median (red lines; n = 8/group). (C) Plasma G-CSF levels in 4T1-bearing mice; median (red lines; n = 6/group). (D–F) wbc differential counts and colony-forming precursors in blood removed on day 7 from 4T1-bearing mice. Median (red lines; n = 6/group). (G) Azurite– methylcellulose colonies in 4T1 tumors; median (red lines; n = 6); Azurite– colonies/107 Azurite+ tumor cells. (H and I) Representative Gr-1 immunostaining of 4T1 tumor tissue from pcDNA-injected mouse. Scale bar: 20 μm (H). Gr-1+ cell quantitation in 4T1 tumors (I); median % Gr-1+ cells/total number of DAPI+ cells (red lines; n = 6/group). (J and K) Azurite–B220/CD45R+ (J) and Azurite–CD3+ (K) cells in 4T1 tumors; median % Azurite– infiltrating cells/Azurite+ tumor cells (n = 6) by flow cytometry. (L–N) The tumor vasculature was visualized by FITC-dextran (green) perfusion and CD31 (red) immunostaining. (L) Representative confocal images of 4T1 tumors (day 7 after injection) from pcDNA- or TNYL-RAW–injected mice (scale bars: 500 μm). The boxed areas are magnified on the right (scale bars: 100 μm). (M) Quantitation of FITC-dextran perfusion as a function of CD31; results expressed as % fluorescence intensities; median (red lines, n = 7). (N) Quantitation of FITC-dextran perfusion as a function of tumor weight. Ratio of μg FITC-dextran to g tumor weight; median (red lines, n = 4). P values by Student’s t test: **P < 0.01.

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