Abstract
Vascular endothelial growth factor (VEGF) and its cellular receptor VEGFR-2 have been implicated as the main endothelial pathway required for tumor neovascularization. However, the importance of the VEGF/VEGFR-2 system for angiogenesis in hematologic malignancies such as AML remains to be elucidated. In 32 patients with newly diagnosed untreated AML, we observed by immunohistochemical analysis of bone marrow biopsies significantly higher levels of VEGF and VEGFR-2 expression than in 10 control patients (P <0.001). In contrast, VEGFR-1 staining levels in AML patients were in the same range as in the controls. Expression of VEGF and VEGFR-2 was significantly higher in patients with a high degree of microvessel density compared to those with a low degree (VEGF: P =0.024; VEGFR-2: P =0.040) and correlated well with bone marrow microvessel density (rs=0.566 and 0.609, respectively; P <0.001). Furthermore, in patients who achieved a complete remission following induction chemotherapy VEGFR-2 staining levels decreased into the normal range. In conclusion, our results provide evidence for increased expression of VEGF/VEGFR-2 of leukemic blasts and correlation with angiogenesis in the bone marrow of AML patients. Thus, VEGF/VEGFR-2 might constitute promising targets for antiangiogenic and antileukemic treatment strategies in AML.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Folkman J, D'Amore PA . Blood vessel formation: what is its molecular basis? Cell 1996 87: 1153–1155
Hussong JW, Rodgers GM, Shami PJ . Evidence of increased angiogenesis in patients with acute myeloid leukemia Blood 2000 95: 309–313
Padró T, Ruiz S, Bieker R, Bürger H, Steins M, Kienast J, Büchner T, Berdel WE, Mesters RM . Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia Blood 2000 95: 2637–2644
Aguayo A, O'Brien S, Keating M, Manshouri T, Barlogie B, Koller C, Kantarjian H, Albitar M . Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes Blood 2000 96: 2240–2245
Pruneri G, Bertolini F, Soligo D, Carboni N, Cortolezzi A, Ferruci PF, Buffa R, Lambertenghi-Deliliers G, Pezzella F . Angiogenesis in myelodysplatic syndromes Br J Cancer 1999 81: 1398–1401
Vacca A, Ribatti D, Roncali L, Ranieri G, Serio G, Silvestris F, Dammacco F . Bone marrow angiogenesis and progression in multiple myeloma Br J Haematol 1994 87: 503–508
Rajkumar SV, Fonseca R, Witzig TE, Gertz MA, Greipp PR . Bone marrow angiogenesis in patients achieving complete response after stem cell transplantation for multiple myeloma Leukemia 1999 13: 469–472
Perez-Atayde AR, Sallan SE, Tedrow U, Connors S, Allred E, Folkman J . Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia Am J Pathol 1997 150: 815–821
Kini AR, Kay NE, Peterson LC . Increased bone marrow angiogenesis in B cell chronic lymphocytic leukemia Leukemia 2000 14: 1414–1418
Zwiebel JA . New agents for acute myelogenous leukemia Leukemia 2000 14: 488–490
Carmeliet P, Jain RK . Angiogenesis in cancer and other diseases Nature 2000 407: 249–257
Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z . Vascular endothelial growth factor (VEGF) and its receptors FASEB J 1999 13: 9–22
Eppenberger U, Kueng W, Schlaeppi JM, Roesel JL, Benz C, Mueller H, Matter A, Zuber M, Luescher K, Litschgi M, Schmitt M, Foekens JA, Eppenberger-Castori S . Markers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients J Clin Oncol 1998 16: 3129–3136
Linderholm B, Tavelin B, Grankvist K, Henriksson R . Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma J Clin Oncol 1998 16: 3121–3128
Linderholm B, Grankvist K, Wilking N, Johansson M, Tavelin B, Henriksson R . Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment J Clin Oncol 2000 18: 1423–1431
Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM . Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis and proliferation of human colon cancer Cancer Res 1995 55: 3964–3968
Yuan A, Yu CJ, Chen WJ, Lin FY, Kuo SH, Luh KT, Yang PC . Correlation of total VEGF mRNA and protein expression with histologic type, tumor angiogenesis, patient survival and timing of relapse in non-small-cell lung cancer Int J Cancer 2000 89: 475–483
Maeda K, Chung YS, Ogawa Y, Takatsuka S, Kang SM, Ogawa M, Sawada T, Sowa M . Prognostic value of vascular endothelial growth factor expression in gastric carcinoma Cancer 1996 77: 858–863
Paradis V, Ben Lagha N, Zeimoura L, Blanchet P, Eschwege P, Ba N, Jardin A, Bedossa P . Expression of vascular endothelial growth factor in renal carcinomas Virchows Arch 2000 436: 351–356
Smith BD, Smith GL, Carter D, Sasaki CT, Haffy BG . Prognostic significance of vascular endothelial growth factor protein levels in oral and oropharyngeal squamous cell carcinoma J Clin Oncol 2000 18: 2046–2052
Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC . Failure of blood-island formation and vasculogenesis in Flk-1 deficient mice Nature 1995 376: 62–66
Fong GH, Rossant J, Gertsenstein M, Breitman ML . Role of Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium Nature 1995 376: 66–70
Shaheen RM, Davis DW, Liu W, Zebrowski BK, Wilson MR, Bucana CD, McConkey DJ, McMahon G, Ellis LM . Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis Cancer Res 1999 59: 5412–5416
Prewett M, Huber J, Li Y, Santiago A, O'Connor W, King K, Overholser J, Hooper A, Pytowski B, Witte L, Bohlen P, Hicklin DJ . Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth on several mouse and human tumors Cancer Res 1999 59: 5209–5218
Skobe M, Rockwell P, Goldstein N, Vosseler S, Fusenig NE . Halting angiogenesis suppresses carcinoma cell invasion Nat Med 1997 3: 1222–1227
Millauer B, Schawver LK, Plate KH, Risau W, Ullrich A . Gioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant Nature 1994 367: 576–579
Fiedler W, Graeven U, Ergün S, Verago S, Kilic N, Stockschläder M, Hossfeld DK . Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia Blood 1997 89: 1870–1875
Bellamy WT, Richter L, Frutiger Y, Grogan TM . Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies Cancer Res 1999 59: 728–733
Chen H, Treweeke AT, West DC, Kathleen JT, Cawley JC, Zuzel M, Toh CH . In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells Blood 2000 96: 3181–3187
Bellamy WT, Richter L, Sirjani D, Roxas C, Glinsmann-Gibson B, Frutiger Y, Grogan TM, List AF . Vascular endothelial growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes Blood 2001 97: 1427–1434
Di Raimondo F, Azzaro MP, Palumbo GA, Bagnato S, Stagno F, Giustolisi GM, Cacciola E, Sortino G, Guglielmo P, Giustolisi R . Elevated vascular endothelial growth factor (VEGF) serum levels in idiopathic myelofibrosis Leukemia 2001 15: 976–980
Aguayo A, Estey E, Kantarjian H, Mansouri, Gidel C, Keating M, Giles F, Estrov Z, Barlogie B, Albitar M . Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia Blood 1999 94: 3717–3721
Fiedler W, Graeven U, Ergün S, Verago S, Kilic N, Stockschläder M, Hossfeld DK . Expression of FLT4 and its ligand VEGF-C in acute myeloid leukemia Leukemia 1997 11: 1234–1237
Ziegler BL, Valtieri M, Almeida Porada G, De Maria R, Müller R, Masella B, Gabbianelli M, Casella I, Pelosi E, Bock T, Zanjani ED, Peschle C . KDR receptor: a key marker defining hematopoietic stem cells Science 1999 285: 1553–1558
Katoh O, Tauchi H, Kawaishi K, Kimura A, Satow Y . Expression of the vascular endothelial growth factor (VEGF) receptor gene, KDR, in hematopoietic cells and inhibitory effect of VEGF on apoptotic cell death caused by ionizing radiation Cancer Res 1995 55: 5687–5692
Dias S, Hattori K, Zhu Z, Heissig B, Choy M, Lane W, Wu Y, Chadburn A, Hyjek E, Gill M, Hicklin DJ, Witte L, Moore MA, Rafii S . Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration J Clin Invest 2000 106: 511–521
Bennet JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C . Proposed revised criteria for the classification of acute myeloid leukemia: A report of the French–American–British Cooperative Group Ann Intern Med 1985 103: 620–625
Decaussin M, Sartelet H, Robert C, Moro D, Claraz C, Brambilla C, Brambilla E . Expression of vascular endothelial growth factor (VEGF) and its two receptors (VEGF-R1-Flt1 and VEGF-R2-Flk1/KDR) in non-small cell lung carcinomas (NSCLCs): correlation with angiogenesis and survival J Pathol 1999 188: 369–377
Gobbi H, Dupont WD, Simpson W, Plummer WD, Schuyler PA, Olson SJ, Arteaga CL, Page DL . Transforming growth factor-β and breast cancer risk in women with mammary epithelial hyperplasia J Natl Cancer Inst 1999 91: 2096–2101
Cheson BC, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD, Brunning R, Gale RP, Grever MR, Keating MJ, Sawitsky A, Stass S, Weinstein H, Woods WG . Report of the National Cancer Institute-sponsored Workshop on definitions of diagnosis and response in acute myeloid leukemia J Clin Oncol 1990 8: 813–819
Kaplan EL, Meier P . Non-parametric estimation from incomplete observations J Am Stat Assoc 1958 53: 457–481
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson U, Peto J, Smith PG . Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and example Br J Cancer 1977 35: 1–39
Büchner T, Hiddemann W, Wörmann B, Löffler H, Gassmann W, Haferlach T, Fonatsch C, Haase D, Schoch C, Hossfeld D, Lengfelder E, Aul C, Heyll A, Maschmeyer G, Ludwig WD, Sauerland MC, Heinecke A . Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group Blood 1999 93: 4116–4124
Katoh O, Takahashi T, Oguri T, Kuramoto K, Mihara K, Kobayashi M, Hirata S, Watanabe H . Vascular endothelial growth factor inhibits apoptotic death in hematopoietic cells after exposure to chemotherapeutic drugs by inducing MCL1 as an antiapoptotic factor Cancer Res 1998 58: 5565–5569
Mesters RM, Padró T, Bieker R, Steins M, Kreuter M, Göner M, Kelsey S, Scigalla P, Fiedler W, Büchner T, Berdel WE . Stable remission after administration of the receptor tyrosine kinase inhibitor SU5416 in a patient with refractory acute myeloid leukemia Blood 2001 98: 241–243
Mendel DB, Laird AD, Smolich BD, Blake RA, Liang C, Hannah AL, Shaheen RM, Ellis LM, Weitman S, Shawver LK, Cherrington JM . Development of SU5416, a selective small molecule inhibitor of VEGF receptor tyrosine kinase activity, as an antiangiogenesis agent Anticancer Drug Des 2000 15: 29–41
Dias S, Hattori K, Heissig B, Zhu Z, Wu Y, Witte L, Hicklin DJ, Tateno M, Bohlen P, Moore MAS, Rafii S . Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias Proc Natl Acad Sci USA 2001 98: 10857–10862
Bautz F, Rafii S, Kanz L, Möhle R . Expression and secretion of vascular endothelial growth factor-A by cytokine-stimulated hematopoietic progenitor cells: possible role in the hematopoietic microenvironment Exp Hematol 2000 28: 700–706
Tordjman R, Delaire S, Plouet J, Ting S, Gaulard P . Fichelson S, Roméo PH, Lemarchandel V. Erythroblasts are a source of angiogenic factors Blood 2001 97: 1968–1974
Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P, Kerbel RS . Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity J Clin Invest 2000 105: R15–R24
Browder T, Butterfield CE, Kräling BM, Shi B, Marshall B, O'Reilly MS, Folkman J . Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer Cancer Res 2000 60: 1878–1886
Fong GH, Zhang L, Bryce DM, Peng J . Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt–1 knock-out mice Development 1999 126: 3015–3025
Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, Vandendriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, Persico MG . Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions Nat Med 2001 7: 575–583
Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marmé D . Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via VEGF receptor flt-1 Blood 1996 87: 3336–3343
Clauss M, Weich H, Breier G, Knies U, Rockl W, Waltenberger J, Risau W . The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis J Biol Chem 1996 271: 17629–17634
Takakura N, Watanabe T, Suenobu S, Yamada Y, Noda T, Ito Y, Satake M, Suda T . A role for hematopoietic stem cells in promoting angiogenesis Cell 2000 102: 199–209
Donovan MJ, Lin MI, Wiegn P, Ringstedt T, Kraemer R, Hahn R, Wang S, Ibanez CF, Rafii S, Hempstead BL . Brain derived neurotrophic factor is an endothelial cell survival factor required for intramyocardial vessel stabilization Development 1999 124: 4531–4540
Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, Wu Y, Hicklin D, Zhu Z, Hackett NR, Crystal RG, Moore MAS, Hajjar KA, Manova K, Benezra R, Rafii S . Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth Nat Med 2001 7: 1194–1201
Acknowledgements
The authors are indebted to Dr Achim Heinecke (Department of Biostatistics, University of Muenster, Muenster, Germany) for his biostatistical advice and assistance.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Padró, T., Bieker, R., Ruiz, S. et al. Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute myeloid leukemia. Leukemia 16, 1302–1310 (2002). https://doi.org/10.1038/sj.leu.2402534
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2402534
Keywords
This article is cited by
-
Angiogenic signaling pathways and anti-angiogenic therapy for cancer
Signal Transduction and Targeted Therapy (2023)
-
A randomized phase 2 trial of nintedanib and low-dose cytarabine in elderly patients with acute myeloid leukemia ineligible for intensive chemotherapy
Annals of Hematology (2023)
-
Leukaemia: a model metastatic disease
Nature Reviews Cancer (2021)
-
LINC00649 underexpression is an adverse prognostic marker in acute myeloid leukemia
BMC Cancer (2020)
-
Interaction of Taspine Derivative TPD7 with Vascular Endothelial Growth Factor Receptor 2 by Cell Membrane Chromatography
Chromatographia (2019)