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Etoposide-mediated interleukin-8 secretion from bone marrow stromal cells induces hematopoietic stem cell mobilization.
BMC Cancer. 2020 Jul 02; 20(1):619.BC

Abstract

BACKGROUND

We assessed the mechanism of hematopoietic stem cell (HSC) mobilization using etoposide with granulocyte-colony stimulating factor (G-CSF), and determined how this mechanism differs from that induced by cyclophosphamide with G-CSF or G-CSF alone.

METHODS

We compared the clinical features of 173 non-Hodgkin's lymphoma patients who underwent autologous peripheral blood stem cell transplantation (auto-PBSCT). Additionally, we performed in vitro experiments to assess the changes in human bone marrow stromal cells (hBMSCs), which support the HSCs in the bone marrow (BM) niche, following cyclophosphamide or etoposide exposure. We also performed animal studies under standardized conditions to ensure the following: exclude confounding factors, mimic the conditions in clinical practice, and identify the changes in the BM niche caused by etoposide-induced chemo-mobilization or other mobilization methods.

RESULTS

Retrospective analysis of the clinical data revealed that the etoposide with G-CSF mobilization group showed the highest yield of CD34+ cells and the lowest change in white blood cell counts during mobilization. In in vitro experiments, etoposide triggered interleukin (IL)-8 secretion from the BMSCs and caused long-term BMSC toxicity. To investigate the manner in which the hBMSC-released IL-8 affects hHSCs in the BM niche, we cultured hHSCs with or without IL-8, and found that the number of total, CD34+, and CD34+/CD45- cells in IL-8-treated cells was significantly higher than the respective number in hHSCs cultured without IL-8 (p = 0.014, 0.020, and 0.039, respectively). Additionally, the relative expression of CXCR2 (an IL-8 receptor), and mTOR and c-MYC (components of IL-8-related signaling pathways) increased 1 h after IL-8 treatment. In animal studies, the etoposide with G-CSF mobilization group presented higher IL-8-related cytokine and MMP9 expression and lower SDF-1 expression in the BM, compared to the groups not treated with etoposide.

CONCLUSION

Collectively, the unique mechanism of etoposide with G-CSF-induced mobilization is associated with IL-8 secretion from the BMSCs, which is responsible for the enhanced proliferation and mobilization of HSCs in the bone marrow; this was not observed with mobilization using cyclophosphamide with G-CSF or G-CSF alone. However, the long-term toxicity of etoposide toward BMSCs emphasizes the need for the development of more efficient and safe chemo-mobilization strategies.

Authors+Show Affiliations

Division of Hematology-Oncology, Department of Internal Medicine, Korea University School of Medicine, 73, Goryeodae-ro, Seongbuk-gu, Seoul, 02841, South Korea.Institute of Stem Cell Research, Korea University, Seoul, South Korea. Department of Biomedical and Science, Graduate School of Medicine, Korea University, Seoul, South Korea.Institute of Stem Cell Research, Korea University, Seoul, South Korea. Department of Biomedical and Science, Graduate School of Medicine, Korea University, Seoul, South Korea.Division of Hematology-Oncology, Department of Internal Medicine, Korea University School of Medicine, 73, Goryeodae-ro, Seongbuk-gu, Seoul, 02841, South Korea.Division of Hematology-Oncology, Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, South Korea.Division of Hematology-Oncology, Department of Internal Medicine, Korea University School of Medicine, 73, Goryeodae-ro, Seongbuk-gu, Seoul, 02841, South Korea.Division of Hematology-Oncology, Department of Internal Medicine, Korea University School of Medicine, 73, Goryeodae-ro, Seongbuk-gu, Seoul, 02841, South Korea. kbs0309@korea.ac.kr. Institute of Stem Cell Research, Korea University, Seoul, South Korea. kbs0309@korea.ac.kr. Department of Biomedical and Science, Graduate School of Medicine, Korea University, Seoul, South Korea. kbs0309@korea.ac.kr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32615949

Citation

Kang, Ka-Won, et al. "Etoposide-mediated Interleukin-8 Secretion From Bone Marrow Stromal Cells Induces Hematopoietic Stem Cell Mobilization." BMC Cancer, vol. 20, no. 1, 2020, p. 619.
Kang KW, Lee SJ, Kim JH, et al. Etoposide-mediated interleukin-8 secretion from bone marrow stromal cells induces hematopoietic stem cell mobilization. BMC Cancer. 2020;20(1):619.
Kang, K. W., Lee, S. J., Kim, J. H., Lee, B. H., Kim, S. J., Park, Y., & Kim, B. S. (2020). Etoposide-mediated interleukin-8 secretion from bone marrow stromal cells induces hematopoietic stem cell mobilization. BMC Cancer, 20(1), 619. https://doi.org/10.1186/s12885-020-07102-x
Kang KW, et al. Etoposide-mediated Interleukin-8 Secretion From Bone Marrow Stromal Cells Induces Hematopoietic Stem Cell Mobilization. BMC Cancer. 2020 Jul 2;20(1):619. PubMed PMID: 32615949.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Etoposide-mediated interleukin-8 secretion from bone marrow stromal cells induces hematopoietic stem cell mobilization. AU - Kang,Ka-Won, AU - Lee,Seung-Jin, AU - Kim,Ji Hye, AU - Lee,Byung-Hyun, AU - Kim,Seok Jin, AU - Park,Yong, AU - Kim,Byung Soo, Y1 - 2020/07/02/ PY - 2020/01/22/received PY - 2020/06/23/accepted PY - 2020/7/4/entrez PY - 2020/7/4/pubmed PY - 2020/7/4/medline KW - Cyclophosphamide KW - Etoposide KW - G-CSF KW - Hematopoietic stem cell mobilization SP - 619 EP - 619 JF - BMC cancer JO - BMC Cancer VL - 20 IS - 1 N2 - BACKGROUND: We assessed the mechanism of hematopoietic stem cell (HSC) mobilization using etoposide with granulocyte-colony stimulating factor (G-CSF), and determined how this mechanism differs from that induced by cyclophosphamide with G-CSF or G-CSF alone. METHODS: We compared the clinical features of 173 non-Hodgkin's lymphoma patients who underwent autologous peripheral blood stem cell transplantation (auto-PBSCT). Additionally, we performed in vitro experiments to assess the changes in human bone marrow stromal cells (hBMSCs), which support the HSCs in the bone marrow (BM) niche, following cyclophosphamide or etoposide exposure. We also performed animal studies under standardized conditions to ensure the following: exclude confounding factors, mimic the conditions in clinical practice, and identify the changes in the BM niche caused by etoposide-induced chemo-mobilization or other mobilization methods. RESULTS: Retrospective analysis of the clinical data revealed that the etoposide with G-CSF mobilization group showed the highest yield of CD34+ cells and the lowest change in white blood cell counts during mobilization. In in vitro experiments, etoposide triggered interleukin (IL)-8 secretion from the BMSCs and caused long-term BMSC toxicity. To investigate the manner in which the hBMSC-released IL-8 affects hHSCs in the BM niche, we cultured hHSCs with or without IL-8, and found that the number of total, CD34+, and CD34+/CD45- cells in IL-8-treated cells was significantly higher than the respective number in hHSCs cultured without IL-8 (p = 0.014, 0.020, and 0.039, respectively). Additionally, the relative expression of CXCR2 (an IL-8 receptor), and mTOR and c-MYC (components of IL-8-related signaling pathways) increased 1 h after IL-8 treatment. In animal studies, the etoposide with G-CSF mobilization group presented higher IL-8-related cytokine and MMP9 expression and lower SDF-1 expression in the BM, compared to the groups not treated with etoposide. CONCLUSION: Collectively, the unique mechanism of etoposide with G-CSF-induced mobilization is associated with IL-8 secretion from the BMSCs, which is responsible for the enhanced proliferation and mobilization of HSCs in the bone marrow; this was not observed with mobilization using cyclophosphamide with G-CSF or G-CSF alone. However, the long-term toxicity of etoposide toward BMSCs emphasizes the need for the development of more efficient and safe chemo-mobilization strategies. SN - 1471-2407 UR - https://www.unboundmedicine.com/medline/citation/32615949/Etoposide-mediated_interleukin-8_secretion_from_bone_marrow_stromal_cells_induces_hematopoietic_stem_cell_mobilization L2 - https://bmccancer.biomedcentral.com/articles/10.1186/s12885-020-07102-x DB - PRIME DP - Unbound Medicine ER -
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