| Autor: |
Piryani, Sadhna O., Kam, Angel Y.F., Kliassov, Evelyna G., Chen, Benny J., Spector, Neil L., Chute, John P., Hsu, David S., Chao, Nelson J., Doan, Phuong L. |
| Jazyk: |
angličtina |
| Rok vydání: |
2017 |
| Předmět: |
|
| Popis: |
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 to saline-treated mice. To mitigate chemotherapy-induced injury to endothelial cells in vivo, we deleted Bax in VEcadherin+ cells (VEcadherinCre;BaxFL/FL mice). Following 5-FU, VEcadherinCre;BaxFL/FL mice displayed preserved hematopoietic stem/progenitor content compared to 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 to saline-treated control mice. When granulocyte colony stimulating factor (G-CSF) is given with EGF, this combination was synergistic for regeneration compared to either G-CSF or EGF alone. EGF increased granulocyte colony stimulating factor receptor (G-CSFR) expression following 5-FU. Conversely, G-CSF treatment increased both 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 to cancer patients not on 5-FU. Likewise, 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 to 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
