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PGE2, EGF, FLT3L and TPO in human hematopoiesis
ic stem cell transplantation (HSCT). We have already
showed that inhibition of the intrinsic apoptosis pathway
in donor cells, even when limited to a few days around
transplantation, significantly improves outcome of HSCT,
especially when only low donor cell numbers are avail- able.18,22,23
While donor stem cells used for HSCT can be manipu- lated ex vivo, the major challenge in the field of cancer treatment will be to identify substances that exclusively protect hematopoietic cells without having any beneficial effect on cancer cells. EGF, PGE2 and SCF are known to have proliferative and pro-survival activities on certain types of cancer24-26 and FLT3L has not yet been systemati- cally tested for its effects on solid tumors. As an alterna-
tive, radioprotective substances could be delivered only to healthy BM cells while sparing cancer cells to avoid thera- py resistance. Novel approaches in targeted drug delivery will hopefully soon enable such therapies to be developed.
Acknowledgments
We are grateful to Nora Fischer for excellent technical assis- tance and to Natalie Krause for animal care. We also would like to thank our colleagues from FOR2036 for insightful discussion.
Funding
This work was supported by grants from the German Research Foundation (DFG-FOR2036 to ME) and the European Research Council (ERC-StG-2014 – 638145 ApoptoMDS to ME).
References
1. Wang Y, Probin V, Zhou D. Cancer thera- py-induced residual bone marrow injury- Mechanisms of induction and implication for therapy. Curr Cancer Ther Rev. 2006;2(3):271-279.
2. Labi V, Erlacher M. How cell death shapes cancer. Cell Death Dis. 2015;6:e1675.
3. Murray LJ, Young JC, Osborne LJ, et al. Thrombopoietin, flt3, and kit ligands together suppress apoptosis of human mobilized CD34+ cells and recruit primi- tive CD34+ Thy-1+ cells into rapid divi- sion. Exp Hematol. 1999;27(6):1019-1028.
4. Varnum-Finney B, Xu L, Brashem-Stein C, et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nat Med. 2000;6(11):1278-1281.
5. Hoggatt J, Singh P, Sampath J, Pelus LM. Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and prolifera- tion. Blood. 2009;113(22):5444-5455.
6. Dygai AM, Khmelevskaya ES, Skurikhin EG, et al. Catecholamine regulation of stro- mal precursors and hemopoietic stem cells in cytostatic myelosuppression. Bull Exp Biol Med. 2012;15(6)2:723-727.
7. Cheng CW, Adams GB, Perin L, et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppres- sion. Cell Stem Cell. 2014;14(6):810-823.
8. Burdelya LG, Krivokrysenko VI, Tallant TC, et al. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science. 2008; 320(5873):226-230.
9. Porter RL, Georger MA, Bromberg O, et al.
Prostaglandin E2 increases hematopoietic stem cell survival and accelerates hematopoietic recovery after radiation injury. Stem Cells. 2013;31(2):372-383.
10. Doan PL, Himburg HA, Helms K, et al. Epidermal growth factor regulates hematopoietic regeneration after radiation injury. Nat Med. 2013;19(3):295-304.
11. Kamran MZ, Ranjan A, Kaur N, Sur S, Tandon V. Radioprotective Agents: Strategies and Translational Advances. Med Res Rev. 2016;36(3):461-493.
12. Johnke RM, Sattler JA, Allison RR. Radioprotective agents for radiation thera- py: future trends. Future Oncol. 2014;10(15):2345-2357.
13. Kollek M, Muller A, Egle A, Erlacher M. Bcl-2 proteins in development, health, and disease of the hematopoietic system. FEBS J. 2016;283(15):2779-2810.
14. Erlacher M, Labi V, Manzl C, et al. Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lym- phocyte development, in apoptosis induc- tion. J Exp Med. 2006;203(13):2939-2951.
15. Erlacher M, Michalak EM, Coultas L, et al. The BH3-only proteins Puma/bbc3 and Bim are rate-limiting for g-radiation- and glucocorticoid-induced apoptosis of lym- phoid cells in vivo. Blood. 2005; 106(13):4131-4138.
16. North TE, Goessling W, Walkley CR, et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature. 2007;447(7147):1007-1011.
17. Goessling W, Allen RS, Guan X, et al. Prostaglandin E2 enhances human cord blood stem cell xenotransplants and shows long-term safety in preclinical nonhuman primate transplant models. Cell Stem Cell. 2011;8(4):445-458.
18. Labi V, Bertele D, Woess C, et al. Haematopoietic stem cell survival and transplantation efficacy is limited by the BH3-only proteins Bim and Bmf. EMBO Mol Med. 2013;5(1):122-136.
19. Lemoli RM, Gulati SC. Effect of stem cell factor (c-kit ligand), granulocyte- macrophage colony stimulating factor and interleukin 3 on hematopoietic progenitors in human long-term bone marrow cultures. Stem Cells. 1993;11(5):435-444.
20. Labi V, Erlacher M, Krumschnabel G, et al. Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma forma- tion. Genes Dev. 2010;24(15):1602-1607.
21. Michalak EM, Vandenberg CJ, Delbridge AR, et al. Apoptosis-promoted tumorigene- sis: gamma-irradiation-induced thymic lymphomagenesis requires Puma-driven leukocyte death. Genes Dev. 2010; 24(15):1608-1613.
22. Kollek M, Voigt G, Molnar C, et al. Transient apoptosis inhibition in donor stem cells improves hematopoietic stem cell transplantation. J Exp Med. 2017; 214(10):2967-2983.
23. Afreen S, Weiss JM, Strahm B, Erlacher M. Cheating death for a better transplant. Stem Cells. 2018 Aug 29. [Epub ahead of print]
24. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene. 2000;19(56):6550-6565.
25. Huang Q, Li F, Liu X, et al. Caspase 3-medi- ated stimulation of tumor cell repopulation during cancer radiotherapy. Nat Med. 2011;17(7):860-866.
26. Cardoso HJ, Figueira MI, Socorro S. The stem cell factor (SCF)/c-KIT signalling in testis and prostate cancer. J Cell Commun Signal. 2017;11(4):297-307.
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