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Chronic lymphocytic leukemia (CLL) cells feature a pronounced apoptotic resistance. The vascular endothelial growth factor (VEGF) possesses a role in this apoptotic block, although underlying functional mechanisms and the involvement of the microenvironment are unclear. In this study, the VEGF status in CLL was assessed by enzyme-linked immunosorbent assay and immunofluorescence. VEGF receptor 2 (VEGFR2) phosphorylation was determined flow cytometrically and by immunofluorescence. For co-culture, CLL cells were cultivated on a monolayer of the bone marrow-derived stromal cell (BMSC) line HS5. Secreted VEGF was neutralized using the monoclonal antibody mAb293 (R&D Systems, Minneapolis, MN, USA). To block protein secretion, we used Brefeldin A. VEGF was downregulated in BMSCs by small interfering RNA (siRNA), and we assessed survival by annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. CLL cells express and secrete VEGF and possess phosphorylated VEGFR2. This positive VEGF status is not sufficient to prevent spontaneous apoptosis in vitro. Coculture with BMSCs, which secrete vast amounts of VEGF, maintains in vitro CLL cell survival. Blockage of secreted VEGF using the monoclonal antibody mAb293 significantly reduced the survival support for cocultured CLL cells. Both general blockage of protein secretion by Brefeldin A in BMSCs, but not in CLL cells, and siRNA-mediated downregulation of VEGF in BMSCs, significantly reduced the coculture-mediated survival support for CLL cells. It can be concluded that BMSC-derived proteins and VEGF, in particular, but not CLL cell-derived VEGF, is essentially involved in the coculture-mediated survival support for CLL cells. Hence, therapeutic targeting of VEGF signaling might be a promising approach to overcome the apoptotic resistance CLL cells feature within their natural microenvironment.

Titel:	Bone marrow stromal cell-derived vascular endothelial growth factor (VEGF) rather than chronic lymphocytic leukemia (CLL) cell-derived VEGF is essential for the apoptotic resistance of cultured CLL cells.
Autor/in / Beteiligte Person:	Gehrke, I ; Gandhirajan, RK ; Poll-Wolbeck, SJ ; Hallek, M ; Kreuzer, KA
Zeitschrift:	Molecular medicine (Cambridge, Mass.), Jg. 17 (2011), Heft 7-8, S. 619-27
Veröffentlichung:	2018- : [London, United Kingdom] : BioMed Central ; <i>Original Publication</i>: Cambridge, Mass. : Blackwell Scientific Publications, c1994-, 2011
Medientyp:	academicJournal
ISSN:	1528-3658 (electronic)
DOI:	10.2119/molmed.2010.00210
Schlagwort:	Antibodies, Monoclonal pharmacology Bone Marrow Cells cytology Brefeldin A pharmacology Cell Line Cell Survival drug effects Cells, Cultured Coculture Techniques Drug Resistance, Neoplasm Flow Cytometry Fluorescent Antibody Technique Humans Leukemia, Lymphocytic, Chronic, B-Cell metabolism Leukemia, Lymphocytic, Chronic, B-Cell pathology Phosphorylation Protein Synthesis Inhibitors pharmacology RNA Interference Stromal Cells cytology Tumor Cells, Cultured Vascular Endothelial Growth Factor A genetics Vascular Endothelial Growth Factor A immunology Vascular Endothelial Growth Factor Receptor-2 metabolism Apoptosis Bone Marrow Cells metabolism Stromal Cells metabolism Vascular Endothelial Growth Factor A metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Mol Med] 2011; Vol. 17 (7-8), pp. 619-27. <i>Date of Electronic Publication: </i>2011 Apr 14. MeSH Terms: Apoptosis* ; Bone Marrow Cells / metabolism ; Stromal Cells / metabolism ; Vascular Endothelial Growth Factor A / *metabolism ; Antibodies, Monoclonal / pharmacology ; Bone Marrow Cells / cytology ; Brefeldin A / pharmacology ; Cell Line ; Cell Survival / drug effects ; Cells, Cultured ; Coculture Techniques ; Drug Resistance, Neoplasm ; Flow Cytometry ; Fluorescent Antibody Technique ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell / metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell / pathology ; Phosphorylation ; Protein Synthesis Inhibitors / pharmacology ; RNA Interference ; Stromal Cells / cytology ; Tumor Cells, Cultured ; Vascular Endothelial Growth Factor A / genetics ; Vascular Endothelial Growth Factor A / immunology ; Vascular Endothelial Growth Factor Receptor-2 / metabolism References: Br J Haematol. 2003 Nov;123(3):380-8. (PMID: 14616995) ; Acta Haematol. 1997;97(1-2):67-72. (PMID: 8999721) ; Clin Cancer Res. 2001 Apr;7(4):795-9. (PMID: 11309324) ; Br J Haematol. 1989 Mar;71(3):343-50. (PMID: 2930721) ; Leuk Lymphoma. 2002 Mar;43(3):461-6. (PMID: 12002747) ; Leuk Res. 2004 Mar;28(3):243-8. (PMID: 14687619) ; Cancer. 1985 Jul 15;56(2):328-32. (PMID: 3891066) ; Blood. 2004 Aug 1;104(3):788-94. (PMID: 14996703) ; Leukemia. 2005 Aug;19(8):1486-7. (PMID: 15959529) ; Br J Haematol. 1999 Dec;107(3):605-10. (PMID: 10583266) ; J Mol Med (Berl). 1999 Feb;77(2):282-93. (PMID: 10023781) ; Br J Haematol. 1996 Jan;92(1):97-103. (PMID: 8562418) ; Leukemia. 2005 Apr;19(4):524-30. (PMID: 15674425) ; Nature. 2002 Jun 27;417(6892):954-8. (PMID: 12087404) ; Semin Oncol. 1998 Feb;25(1):11-8. (PMID: 9482522) ; N Engl J Med. 1995 Oct 19;333(16):1052-7. (PMID: 7675049) ; Semin Oncol. 1999 Oct;26(5 Suppl 14):107-14. (PMID: 10561025) ; Blood. 1998 Apr 1;91(7):2387-96. (PMID: 9516138) ; Blood. 2001 Sep 15;98(6):1904-13. (PMID: 11535528) ; Eur J Immunol. 2002 May;32(5):1403-13. (PMID: 11981828) ; Leukemia. 2000 Aug;14(8):1414-8. (PMID: 10942237) ; Leuk Res. 2007 Jul;31(7):899-906. (PMID: 17241660) ; Leuk Lymphoma. 2004 Dec;45(12):2365-72. (PMID: 15621749) ; Eur Cytokine Netw. 2005 Jan-Mar;16(1):41-6. (PMID: 15809205) ; Clin Cancer Res. 2010 Jul 1;16(13):3390-8. (PMID: 20570929) ; Leukemia. 2005 Apr;19(4):513-23. (PMID: 15703780) ; Blood. 1996 Jun 15;87(12):4990-7. (PMID: 8652811) ; Leukemia. 2007 Sep;21(9):1977-83. (PMID: 17637809) ; Cell. 2001 Jul 13;106(1):1-4. (PMID: 11461694) ; Nat Med. 2003 Jun;9(6):669-76. (PMID: 12778165) ; Adv Cancer Res. 2000;79:157-73. (PMID: 10818680) ; Blood. 2010 Mar 4;115(9):1755-64. (PMID: 20018914) Substance Nomenclature: 0 (Antibodies, Monoclonal) ; 0 (Protein Synthesis Inhibitors) ; 0 (Vascular Endothelial Growth Factor A) ; 20350-15-6 (Brefeldin A) ; EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2) Entry Date(s): Date Created: 20110427 Date Completed: 20111227 Latest Revision: 20211020 Update Code: 20240513 PubMed Central ID: PMC3146618

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Bone marrow stromal cell-derived vascular endothelial growth factor (VEGF) rather than chronic lymphocytic leukemia (CLL) cell-derived VEGF is essential for the apoptotic resistance of cultured CLL cells.