Abstract
The hematopoietic system is particularly vulnerable to the toxic effects of anticancer drugs. While inducing apoptosis in malignant cells, anticancer drugs cause a depletion of hematopoietic stem and progenitor cells in the bone marrow. Therapy-related anemia, neutropenia and thrombocytopenia are commonly developed by cancer patients and often result in treatment delay, reduction or interruption thus undermining the outcome of anticancer therapies. Even new targeted therapies, which are designed to eradicate the tumor with minimal damage for the organism, have often substantial side effects on normal hematopoietic cells that limit their successful clinical use. Current strategies to limit the harmful consequences of drug-induced hematotoxicity consist in post-chemotherapy administration of hematopoietic cytokines. However, this approach presents several limitations due to the inability of currently used growth factors to prevent the occurrence of chemotherapy-induced myelosuppression, non-responsiveness of a significant portion of patients and safety concerns linked to adverse effects and potential tumor-promoting activity. This chapter reviews current knowledge and recent advances on the mechanisms, cellular targets and experimental models of chemotherapy-induced myelosuppression. Improving our understanding on how normal hematopoietic cells respond to conventional and targeted drugs will lead to an increased success of antineoplastic therapies.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Antonchuk J, Hyland CD, Hilton DJ, Alexander WS (2004) Synergistic effects on erythropoiesis, thrombopoiesis, and stem cell competitiveness in mice deficient in thrombopoietin and steel factor receptors. Blood 104(5):1306–1313
Bartucci M, Dattilo R, Martinetti D, Todaro M, Zapparelli G, Di Virgilio A, Biffoni M, De Maria R, Zeuner A (2011) Prevention of chemotherapy-induced anemia and thrombocytopenia by constant administration of stem cell factor. Clin Cancer Res 17(19):6185–6191
Blaise D, Faucher C, Vey N, Caraux J, Maraninchi D, Chabannon C (2000) Rescue of haemopoiesis by a combination of growth factors including stem-cell factor. Lancet 356(9238):1325–1326
Broudy VC (1997) Stem cell factor and hematopoiesis. Blood 90(4):1345–1364
Cai S, Wang H, Bailey B, Ernstberger A, Juliar BE, Sinn AL, Chan RJ, Jones DR, Mayo LD, Baluyut AR, Goebel WS, Pollok KE (2011) Humanized bone marrow mouse model as a preclinical tool to assess therapy-mediated hematotoxicity. Clin Cancer Res 17(8):2195–2206
Chaudhary PM, Roninson IB (1991) Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 66(1):85–94
De Maria R, Zeuner A, Eram OA, Domenichelli C, Bonci D, Grignani F, Srinivasula SM, Alnemri ES, Testa U, Peschle C (1999) Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1. Nature 401(6752):489–493
Debatin KM, Krammer PH (2004) Death receptors in chemotherapy and cancer. Oncogene 23(16):2950–2966
Elting LS, Rubenstein EB, Martin CG, Kurtin D, Rodriguez S, Laiho E, Kanesan K, Cantor SB, Benjamin RS (2001) Incidence, cost, and outcomes of bleeding and chemotherapy dose modification among solid tumor patients with chemotherapy-induced thrombocytopenia. J Clin Oncol 19(4):1137–1146
Foley RN (2010) Emerging erythropoiesis-stimulating agents. Nat Rev Nephrol 6(4):218–223
Giordano FA, Sorg UR, Appelt JU, Lachmann N, Bleier S, Roeder I, Kleff V, Flasshove M, Zeller WJ, Allgayer H, Kalle C, Fruehauf S, Moritz T, Laufs S (2011) Clonal inventory screens uncover monoclonality following serial transplantation of MGMT(P140K)-transduced stem cells and dose-intense chemotherapy. Hum Gene Ther 22(6):697–710
Gurney AL, Carver-Moore K, de Sauvage FJ, Moore MW (1994) Thrombocytopenia in c-mpl-deficient mice. Science 265(5177):1445–1447
Huang E, Nocka K, Beier DR, Chu TY, Buck J, Lahm HW, Wellner D, Leder P, Besmer P (1990) The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell 63(1):225–233
Kaushansky K, Kirito K (2006) Transcriptional regulation of megakaryopoiesis: thrombopoietin signaling and nuclear factors. Curr Opin Hematol 13(3):151–156
Lévesque JP, Helwani FM, Winkler IG (2010) The endosteal ‘osteoblastic’ niche and its role in hematopoietic stem cell homing and mobilization. Leukemia 24(12):1979–1992
Levina V, Marrangoni A, Wang T, Parikh S, Su Y, Herberman R, Lokshin A, Gorelik E (2010) Elimination of human lung cancer stem cells through targeting of the stem cell factor-c-kit autocrine signaling loop. Cancer Res 70(1):338–346
Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, Kuter DJ (2001) Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 98(12):3241–3248
Liang K, Esteva FJ, Albarracin C, Stemke-Hale K, Lu Y, Bianchini G, Yang CY, Li Y, Li X, Chen CT, Mills GB, Hortobagyi GN, Mendelsohn J, Hung MC, Fan Z (2010) Recombinant human erythropoietin antagonizes trastuzumab treatment of breast cancer cells via Jak2-mediated Src activation and PTEN inactivation. Cancer Cell 18(5):423–435
Ludwig H, Van Belle S, Barrett-Lee P, Birgegård G, Bokemeyer C, Gascón P, Kosmidis P, Krzakowski M, Nortier J, Olmi P, Schneider M, Schrijvers D (2004) The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer 40(15):2293–2306
Marti Marti FM, Cullen MH, Roila F, ESMO Guidelines Working Group (2009) Management of febrile neutropenia: ESMO clinical recommendations. Ann Oncol 20(Suppl 4):166–169
Mohrin M, Bourke E, Alexander D, Warr MR, Barry-Holson K, Le Beau MM, Morrison CG, Passegué E (2010) Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell 7(2):174–185
Molineux G, Migdalska A, Haley J, Evans GS, Dexter TM (1994) Total marrow failure induced by pegylated stem-cell factor administered before 5-fluorouracil. Blood 83(12):3491–3499
Orazi A, Gordon MS, John K, Sledge G Jr, Neiman RS, Hoffman R (1995) In vivo effects of recombinant human stem cell factor treatment. A morphologic and immunohistochemical study of bone marrow biopsies. Am J Clin Pathol 103(2):177–184
Ozer H, Armitage JO, Bennett CL, Crawford J, Demetri GD, Pizzo PA, Schiffer CA, Smith TJ, Somlo G, Wade JC 3rd, Wade JL, Winn RJ, Wozniak AJ, Somerfield MR, The American Society of Clinical Oncology (2000) 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 18(20):3558–3585
Ribeil JA, Zermati Y, Vandekerckhove J, Cathelin S, Kersual J, Dussiot M, Coulon S, Moura IC, Zeuner A, Kirkegaard-Sørensen T, Varet B, Solary E, Garrido C, Hermine O (2007) Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1. Nature 445(7123):102–105
Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Somerfield MR, Temin S (2010) American society of clinical oncology/American society of hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Oncol Pract 6(6):317–320
Solar GP, Kerr WG, Zeigler FC, Hess D, Donahue C, de Sauvage FJ, Eaton DL (1998) Role of c-mpl in early hematopoiesis. Blood 92(1):4–10
Stahnke K, Fulda S, Friesen C, Strauss G, Debatin KM (2001) Activation of apoptosis pathways in peripheral blood lymphocytes by in vivo chemotherapy. Blood 98(10):3066–3073
Tong J, Gordon MS, Srour EF, Cooper RJ, Orazi A, McNiece I, Hoffman R (1993) In vivo administration of recombinant methionyl human stem cell factor expands the number of human marrow hematopoietic stem cells. Blood 82(3):784–791
Vadhan-Raj S (2010) Clinical findings with the first generation of thrombopoietic agents. Semin Hematol 47(3):249–257
Zeuner A, Pedini F, Signore M, Testa U, Pelosi E, Peschle C, De Maria R (2003) Stem cell factor protects erythroid precursor cells from chemotherapeutic agents via up-regulation of BCL-2 family proteins. Blood 102(1):87–93
Zeuner A, Signore M, Martinetti D, Bartucci M, Peschle C, De Maria R (2007) Chemotherapy-induced thrombocytopenia derives from the selective death of megakaryocyte progenitors and can be rescued by stem cell factor. Cancer Res 67(10):4767–4773
Zeuner A, Pedini F, Francescangeli F, Signore M, Girelli G, Tafuri A, De Maria R (2009) Activity of the BH3 mimetic ABT-737 on polycythemia vera erythroid precursor cells. Blood 113(7):1522–1525
Zeuner A, Francescangeli F, Signore M, Venneri MA, Pedini F, Felli N, Pagliuca A, Conticello C, De Maria R (2011) The Notch2-Jagged1 interaction mediates stem cell factor signaling in erythropoiesis. Cell Death Differ 18(2):371–380
Ziegler B, Testa U, Condorelli G, Vitelli L, Valtieri M, Peschle C (1998) Unilineage hematopoietic differentiation in bulk and single cell culture. Stem Cells 16(Suppl 1):51–73
Zsebo KM, Williams DA, Geissler EN, Broudy VC, Martin FH, Atkins HL, Hsu RY, Birkett NC, Okino KH, Murdock DC (1990) Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell 63(1):213–224
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media B.V.
About this chapter
Cite this chapter
Pedini, F., Venneri, M.A., Zeuner, A. (2012). Hematopoietic Stem/Progenitor Cells: Response to Chemotherapy. In: Hayat, M. (eds) Stem Cells and Cancer Stem Cells, Volume 6. Stem Cells and Cancer Stem Cells, vol 6. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2993-3_29
Download citation
DOI: https://doi.org/10.1007/978-94-007-2993-3_29
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-2992-6
Online ISBN: 978-94-007-2993-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)