Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, North Carolina, USA.
Duke Cancer Institute, Duke University, Durham, North Carolina, USA.
Stem Cells. 2018 Feb;36(2):252-264. doi: 10.1002/stem.2731. Epub 2017 Nov 10.
Hematopoietic regeneration following chemotherapy may be distinct from regeneration following radiation. While we have shown that epidermal growth factor (EGF) accelerates regeneration following radiation, its role following chemotherapy is currently unknown. We sought to identify EGF as a hematopoietic growth factor for chemotherapy-induced myelosuppression. Following 5-fluorouracil (5-FU), EGF accelerated hematopoietic stem cell regeneration and prolonged survival compared with saline-treated mice. To mitigate chemotherapy-induced injury to endothelial cells in vivo, we deleted Bax in VEcadherin cells (VEcadherinCre;Bax mice). Following 5-FU, VEcadherinCre;Bax mice displayed preserved hematopoietic stem/progenitor content compared with littermate controls. 5-FU and EGF treatment resulted in increased cellular proliferation, decreased apoptosis, and increased DNA double-strand break repair by non-homologous end-joining recombination compared with saline-treated control mice. When granulocyte colony stimulating factor (G-CSF) is given with EGF, this combination was synergistic for regeneration compared with either G-CSF or EGF alone. EGF increased G-CSF receptor (G-CSFR) expression following 5-FU. Conversely, G-CSF treatment increased both EGF receptor (EGFR) and phosphorylation of EGFR in hematopoietic stem/progenitor cells. In humans, the expression of EGFR is increased in patients with colorectal cancer treated with 5-FU compared with cancer patients not on 5-FU. Similarly, EGFR signaling is responsive to G-CSF in humans in vivo with both increased EGFR and phospho-EGFR in healthy human donors following G-CSF treatment compared with donors who did not receive G-CSF. These data identify EGF as a hematopoietic growth factor following myelosuppressive chemotherapy and that dual therapy with EGF and G-CSF may be an effective method to accelerate hematopoietic regeneration. Stem Cells 2018;36:252-264.
化疗后的造血再生可能与放疗后的再生不同。虽然我们已经表明表皮生长因子（EGF）可加速放疗后的再生，但它在化疗后的作用目前尚不清楚。我们试图确定 EGF 是化疗引起的骨髓抑制的造血生长因子。在 5-氟尿嘧啶（5-FU）之后，EGF 加速了造血干细胞的再生并延长了与生理盐水处理的小鼠相比的存活时间。为了减轻体内内皮细胞的化疗损伤，我们在 VEcadherin 细胞中删除了 Bax（VEcadherinCre；Bax 小鼠）。在 5-FU 之后，与同窝对照相比，VEcadherinCre；Bax 小鼠显示出保留的造血干细胞/祖细胞含量。与生理盐水处理的对照小鼠相比，5-FU 和 EGF 处理导致细胞增殖增加、凋亡减少和非同源末端连接重组的 DNA 双链断裂修复增加。当粒细胞集落刺激因子（G-CSF）与 EGF 一起给予时，与单独给予 G-CSF 或 EGF 相比，这种组合对再生具有协同作用。5-FU 后 EGF 增加 G-CSF 受体（G-CSFR）的表达。相反，G-CSF 处理增加了造血干细胞/祖细胞中的 EGF 受体（EGFR）和 EGFR 的磷酸化。在人类中，与未接受 5-FU 的癌症患者相比，接受 5-FU 治疗的结直肠癌患者的 EGFR 表达增加。同样，在体内，G-CSF 对人类的 EGFR 信号具有反应性，与未接受 G-CSF 治疗的供体相比，接受 G-CSF 治疗的健康人类供体中的 EGFR 和磷酸化 EGFR 均增加。这些数据表明 EGF 是骨髓抑制化疗后的造血生长因子，EGF 和 G-CSF 的双重治疗可能是加速造血再生的有效方法。干细胞 2018；36:252-264.
