Epidermal Growth Factor and Granulocyte Colony Stimulating Factor Signaling Are Synergistic for Hematopoietic Regeneration

Sadhna O Piryani; Angel Y F Kam; Evelyna G Kliassov; Benny J Chen; Neil L Spector; John P Chute; David S Hsu; Nelson J Chao; Phuong L Doan

doi:10.1002/stem.2731

Epidermal Growth Factor and Granulocyte Colony Stimulating Factor Signaling Are Synergistic for Hematopoietic Regeneration

Stem Cells. 2018 Feb;36(2):252-264. doi: 10.1002/stem.2731. Epub 2017 Nov 10.

Authors

Sadhna O Piryani¹, Angel Y F Kam¹, Evelyna G Kliassov¹, Benny J Chen^{1

2}, Neil L Spector^{2

3}, John P Chute^{4

5

6}, David S Hsu^{2

3}, Nelson J Chao^{1

2}, Phuong L Doan^{1

2}

Affiliations

¹ Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, North Carolina, USA.
² Duke Cancer Institute, Duke University, Durham, North Carolina, USA.
³ Division of Medical Oncology, Duke University, Durham, North Carolina, USA.
⁴ Division of Medical Oncology, University of California, Los Angeles, Los Angeles, California, USA.
⁵ Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA.
⁶ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA.

Abstract

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^FL/FL mice). Following 5-FU, VEcadherinCre;Bax^FL/FL 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.

Keywords: Chemotherapy; Epidermal growth factor; Granulocyte colony stimulating factor; Hematopoietic regeneration; Hematopoietic stem cells (HSCs).

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Apoptosis / drug effects
Cell Cycle / drug effects
Epidermal Growth Factor / pharmacology*
ErbB Receptors / metabolism
Fluorouracil / pharmacology
Granulocyte Colony-Stimulating Factor / pharmacology*
Hematopoiesis / drug effects
Hematopoietic Stem Cells / cytology
Hematopoietic Stem Cells / drug effects
Mice
Mice, Inbred C57BL
Signal Transduction / drug effects

Substances

Granulocyte Colony-Stimulating Factor
Epidermal Growth Factor
ErbB Receptors
Fluorouracil

Abstract

Publication types

MeSH terms

Substances

Grants and funding