title: VEGF-A/VEGFR Inhibition Restores Hematopoietic Homeostasis in the Bone Marrow and Attenuates Tumor Growth.
abstract: Antiangiogenesis-based cancer therapies, specifically those targeting the VEGF-A/VEGFR2 pathway, have been approved for subsets of solid tumors. However, these therapies result in an increase in hematologic adverse events. We surmised that both the bone marrow vasculature and VEGF receptor-positive hematopoietic cells could be impacted by VEGF pathway-targeted therapies. We used a mouse model of spontaneous breast cancer to decipher the mechanism by which VEGF pathway inhibition alters hematopoiesis. Tumor-bearing animals, while exhibiting increased angiogenesis at the primary tumor site, showed signs of shrinkage in the sinusoidal bone marrow vasculature accompanied by an increase in the hematopoietic stem cell-containing Lin-cKit(+)Sca1(+) (LKS) progenitor population. Therapeutic intervention by targeting VEGF-A, VEGFR2, and VEGFR3 inhibited tumor growth, consistent with observed alterations in the primary tumor vascular bed. These treatments also displayed systemic effects, including reversal of the tumor-induced shrinkage of sinusoidal vessels and altered population balance of hematopoietic stem cells in the bone marrow, manifested by the restoration of sinusoidal vessel morphology and hematopoietic homeostasis. These data indicate that tumor cells exert an aberrant systemic effect on the bone marrow microenvironment and VEGF-A/VEGFR targeting restores bone marrow function.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Rebekah K
authors.initials: RK
authors.lastname: O'Donnell
authors.affiliation: Eli Lilly & Company, Indianapolis, Indiana.
authors.forename: Beverly
authors.initials: B
authors.lastname: Falcon
authors.affiliation: Eli Lilly & Company, Indianapolis, Indiana.
authors.forename: Jeff
authors.initials: J
authors.lastname: Hanson
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Whitney E
authors.initials: WE
authors.lastname: Goldstein
authors.affiliation: Eli Lilly & Company, Indianapolis, Indiana.
authors.forename: Carole
authors.initials: C
authors.lastname: Perruzzi
authors.affiliation: Department of Genetic and Regenerative Medicine, Weill Cornell Medical College, New York City, New York.
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: William C
authors.initials: WC
authors.lastname: Aird
authors.affiliation: Eli Lilly & Company, Indianapolis, Indiana. lbenjami@mac.com.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Benjamin
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism*; D005260:Female; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006706:Homeostasis; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor