Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 126, Issue 12, Pages 4554-4568Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI87848
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Funding
- intramural research program of the CCR/NCI/NIH
- Regional Government of Madrid (Angiobodies Programme) [BIPEDD2 S2011/BMD-2312]
- European Social Fund
- Ansary Stem Cell Institute
- American Society of Hematology Scholar Award
- American Federation for Aging Research grant
- Leukemia and Lymphoma Society Quest for Cures award
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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.
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