VEGF-A/VEGFR Inhibition Restores Hematopoietic Homeostasis in the Bone Marrow and Attenuates Tumor Growth.
VEGF-A/VEGFR Inhibition Restores Hematopoietic Homeostasis in the Bone Marrow and Attenuates Tumor Growth.
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DOI：
10.1158/0008-5472.can-14-3023
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发表时间：
2016-02
期刊：
影响因子：
11.2
通讯作者：
Rebekah K. O’Donnell;Beverly L. Falcón;J. Hanson;Whitney E. Goldstein;C. Perruzzi;S. Rafii;W. Aird
中科院分区：
文献类型：
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作者：
Rebekah K. O’Donnell;Beverly L. Falcón;J. Hanson;Whitney E. Goldstein;C. Perruzzi;S. Rafii;W. Aird
基于抗血管生成的癌症疗法，特别是靶向VEGF-A/VEGFR 2通路的那些，已被批准用于实体瘤的子集。然而，这些治疗导致血液学不良事件增加。我们推测，骨髓血管和VEGF受体阳性造血细胞都可能受到VEGF通路靶向治疗的影响。我们使用自发性乳腺癌小鼠模型来解释VEGF通路抑制改变造血的机制。荷瘤动物在原发肿瘤部位表现出血管生成增加的同时，也表现出骨髓窦状隙血管收缩的迹象，伴随着含造血干细胞的Lin-cKit（+）Sca 1（+）（LKS）祖细胞群的增加。通过靶向VEGF-A、VEGFR 2和VEGFR 3的治疗性干预抑制了肿瘤生长，这与观察到的原发性肿瘤血管床的改变一致。这些治疗还显示出全身效应，包括逆转肿瘤诱导的窦状血管收缩和改变骨髓中造血干细胞的群体平衡，表现为窦状血管形态和造血稳态的恢复。这些数据表明，肿瘤细胞对骨髓微环境产生异常的全身效应，并且VEGF-A/VEGFR靶向恢复骨髓功能。
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.