VEGF-A/VEGFR Inhibition Restores Hematopoietic Homeostasis in the Bone Marrow and Attenuates Tumor Growth
| Autor: | Laura E. Benjamin, Carole A. Perruzzi, Beverly L. Falcon, Whitney E. Goldstein, William C. Aird, Jeffrey C. Hanson, Shahin Rafii, Rebekah K. O'Donnell |
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| Rok vydání: | 2016 |
| Předmět: |
Vascular Endothelial Growth Factor A
0301 basic medicine Cancer Research Pathology medicine.medical_specialty Angiogenesis Population Biology Mice 03 medical and health sciences Bone Marrow medicine Animals Homeostasis education education.field_of_study Mammary Neoplasms Experimental Cancer Hematopoietic Stem Cells medicine.disease Antibodies Neutralizing Immunohistochemistry Primary tumor Hematopoiesis Haematopoiesis Vascular endothelial growth factor A Receptors Vascular Endothelial Growth Factor 030104 developmental biology medicine.anatomical_structure Oncology Female Bone marrow Stem cell |
| Zdroj: | Cancer Research. 76:517-524 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-14-3023 |
| Popis: | 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. Cancer Res; 76(3); 517–24. ©2015 AACR. |
| Databáze: | OpenAIRE |
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