Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are elevated in peripheral blood plasma of patients with chronic lymphocytic leukemia and decrease after intensive fludarabine-based treatment
Authors:
L. Smolej 1; C. Andrýs 2; J. Krejsek 2; D. Belada 1; P. Žák 1; O. Široký 1; J. Malý 1
Authors‘ workplace:
Oddělení klinické hematologie II. interní kliniky Lékařské fakulty UK a FN Hradec Králové, přednosta prof. MUDr. Jaroslav Malý, CSc.
1; Ústav klinické imunologie a alergologie Lékařské fakulty UK a FN Hradec Králové, přednosta prof. RNDr. Jan Krejsek, CSc.
2
Published in:
Vnitř Lék 2007; 53(11): 1171-1176
Category:
Original Contributions
Overview
Chronic lymphocytic leukemia (CLL) is characterized by extraordinary heterogeneity in terms of clinical course with overall survival ranging from several months to dozens of years. It is currently not possible to accurately predict the future clinical course in an individual patient. Angiogenesis has been recently reported as a potential prognostic factor in various hematological malignancies including CLL. The objective of the present study was to quantify plasma levels of key angiogenic activators vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients with CLL and determine their potential change after intensive fludarabine-based treatment. Peripheral blood EDTA plasma concentrations of bFGF and VEGF were measured using comercially available enzyme-linked immunosorbent assay in 73 patients with untreated CLL (43 males, 30 females, median age, 65 years, range 31–88) and 80 healthy donors serving as control group. We found statistically significant increase in concentrations in patients with chronic lymphocytic leukemia compared to the control group (p < 0.0001 for both cytokines). No differences in angiogenic factors were noted between subgroups with low vs. intermediate vs. high-risk stage according to modified Rai staging or males vs. females. In twelve patients who achieved at least partial response after intensive fludarabine-based treatment, levels of bFGF as well as VEGF decreased significantly (bFGF, p = 0.0005; VEGF, p = 0.0068); in addition, they were no more significantly different from controls (bFGF, p = 0.524; VEGF, p = 0.728). Our data showed that key angiogenic activators bFGF and VEGF were elevated in plasma of CLL patients. Furthemore, treatment with intensive fludarabinecontaining regimens resulted in significant decrease of both cytokines. These data suggest that angiogenic cytokines may indeed play a significant role in CLL biology and that treatment with combination of fludarabine, cyclophosphamide ± rituximab may exhibit antiangiogenic properties. Further studies with longer follow-up are necessary for evaluation of a possible association between angiogenic markers and progression-free survival or overall survival.
Keywords:
angiogenesis – chronic lymphocytic leukemia – bFGF – VEGF – prognosis – treatment – fludarabine
Sources
1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285: 1182-1186.
2. Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med 1995; 333: 1757-1763
3. Pour L, Hájek R, Büchler T et al. Angiogeneze a antiangiogenní léčba u nádorů. Vnitř Lék 2004; 50(12): 930-938.
4. Smolej L, Benešová P. Význam angiogeneze u maligních nádorů. Acta Medica (Hradec Králové) Suppl 2005; 48: 69-72.
5. Aguayo A, Kantarjian H, Manshouri T et al. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 2000; 96: 2240-2245.
6. Moehler TM, Ho AD, Goldschmidt H et al. Angiogenesis in hematologic malignancies. Crit Rev Oncol Hematol 2003; 45: 227-244.
7. Rajkumar SV, Witzig TE. A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma. Cancer Treat Rev 2000; 26: 351-362.
8. Salven P, Teerenhovi L, Joensuu H. A high pretreatment serum vascular endothelial growth factor concentration is associated with poor outcome in non-Hodgkin’s lymphoma. Blood 1997; 90: 3167.
9. Perez-Atayde AR, Sallan SE, Tedrow U et al. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am J Pathol 1997; 150: 815-821.
10. Shanafelt TD, Geyer SM, Kay NE. Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL. Blood 2004; 103: 1202-1210.
11. Papajík T, Jarošová M, Pikalová Z et al. Chronická B-lymfocytární leukemie. Část II: Diagnostická kritéria a význam stanovení individuální prognózy nemocného. Trans Hemat dnes 2006; 12: 132-139.
12. Kay NE, Bone ND, Tschumper RC et al. B-CLL cells are capable of synthesis and secretion of both pro- and anti-angiogenic molecules. Leukemia 2002; 16: 911-919.
13. Molica S, Vitelli G, Levato D et al. Clinicoprognostic implications of increased serum levels of vascular endothelial growth factor and basic fibroblastic growth factor in early B-cell chronic lymphocytic leukaemia. Br J Cancer 2002; 86: 31-35.
14. Menzel T, Rahman Z, Calleja E et al. Elevated intracellular level of basic fibroblast growth factor correlates with stage of chronic lymphocytic leukemia and is associated with resistance to fludarabine. Blood 1996; 87: 1056-1063.
15. Konig A, Menzel T, Lynen S et al. Basic fibroblast growth factor (bFGF) upregulates the expression of bcl-2 in B-cell chronic lymphocytic leukemia cell lines resulting in delaying apoptosis. Leukemia 1997; 11: 258-265.
16. Ferrajoli A, Manshouri T, Estrov Z et al. High levels of vascular endothelial growth factor receptor-2 correlate with shortened survival in chronic lymphocytic leukemia. Clin Cancer Res 2001; 7: 795-799.
17. Gora-Tybor J, Blonski JZ, Robak T. Cladribine decreases the level of angiogenic factors in patients with chronic lymphocytic leukemia. Neoplasma 2002; 49: 145-148.
18. Auguste P, Javerzat S, Bikfalvi A. Regulation of vascular development by fibroblast growth factors. Cell Tissue Res 200; 314: 157-166.
19. Šimíčková M, Dubská L, Kocáková I et al. Angiogeneze a antiangiogenní terapie se zaměřením na cirkulující vaskulární endotelový růstový faktor (VEGF). Klin Onkol 2006; 19: 212-216.
20. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Nat Rev Drug Discov 2004; 3: 391-400.
21. Cheson BD, Bennett JM, Grever M et al. National Cancer Institute–sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87: 4990-4997.
22. Rai KR. A critical analysis of staging in CLL. In: Gale RP, Rai KR (eds). Chronic Lymphocytic Leukemia. Recent Progress and Future Direction. New York (NY): AR Liss 1987: 253.
23. Duensing S, Atzpodien J. Increased intracellular and plasma levels of basic fibroblast growth factor in B-cell chronic lymphocytic leukemia. Blood 1995; 85: 1978-1980.
24. Molica S, Vitelli G, Levato D et al. Increased serum levels of vascular endothelial growth factor predict risk of progression in early B-cell chronic lymphocytic leukaemia. Br J Haematol 1999; 107: 605-610.
25. Bairey O, Zimra Y, Shaklai M et al. Bcl-2 expression correlates positively with serum basic fibroblast growth factor (bFGF) and negatively with cellular vascular endothelial growth factor (VEGF) in patients with chronic lymphocytic leukaemia. Br J Haematol 2001; 113: 400-406.
26. Gora-Tybor J, Blonski JZ, Robak T. Circulating proangiogenic cytokines and angiogenesis inhibitor endostatin in untreated patients with chronic lymphocytic leukemia. Mediators Inflamm 2003; 12: 167-171.
27. Gora-Tybor J, Blonski JZ, Robak T. Circulating vascular endothelial growth factor (VEGF) and its soluble receptors in patients with chronic lymphocytic leukemia. Eur Cytokine Netw 2005; 16: 41-46.
28. Wolowiec D, Dybko J, Wrobel T et al. Circulating sCD138 and some angiogenesis-involved cytokines help to anticipate the disease progression of early-stage B-cell chronic lymphocytic leukemia. Mediators Inflamm 2006; 3: 1-6.
29. Krejci P, Dvorakova D, Krahulcova E. FGF-2 abnormalities in B cell chronic lymphocytic and chronic myeloid leukemia. Leukemia 2001; 15: 228-237.
30. Werther K, Christensen IJ, Nielsen HJ. Determination of vascular endothelial growth factor (VEGF) in circulating blood: significance of VEGF in various leucocytes and platelets. Scand J Clin Lab Invest 2002; 62: 343-350.
31. Webb NJ, Bottomley MJ, Watson CJ et al. Vascular endothelial growth factor (VEGF) is released from platelets during blood clotting: implications for measurement of circulating VEGF levels in clinical disease. Clin Sci (Lond) 1998; 94: 395-404.
32. George ML, Eccles SA, Tutton MG et al. Correlation of plasma and serum vascular endothelial growth factor levels with platelet count in colorectal cancer: clinical evidence of platelet scavenging? Clin Cancer Res 2000; 6: 3147-3152.
33. Banks RE, Forbes MA, Kinsey SE et al. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br J Cancer 1998; 77: 956-964.
34. Vacca A, Iurlaro M, Ribatti D et al. Antiangiogenesis is produced by nontoxic doses of vinblastine. Blood 1999; 94: 4143-4155.
35. Kerbel KS, Viloria-Petit A, Klement G et al. “Accidental” anti-angiogenic drugs: anti-oncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as examples. Eur J Cancer 2000; 36: 1248-1257.
36. Smolej L, Andrys C, Pekova S et al. Plasma levels of basic fibroblast growth factor and vascular endothelial growth factor and their association with IgVH mutation status in patients with B-cell chronic lymphocytic leukemia. Haematologica 2006; 91: 1432-1433.
37. Chanan-Khan A, Miller KC, Takeshita K et al. Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL). Blood 2005; 106: 3348-3352.
38. Chanan-Khan A. Targeting the microenvironment: a new treatment paradigm for chronic lymphocytic leukaemia. Haematologica Reports 2006; 2: 22-27.
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