Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia

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Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia

AR Perez-Atayde, SE Sallan, U Tedrow, S Connors, E Allred and J Folkman
Department of Pathology, Children's Hospital, Boston, Massachusetts 02115, USA.

It has been shown that solid tumors progress in concert with an induction of tumor angiogenesis. It is not known, however, whether a similar phenomenon occurs in leukemia. Angiogenesis was characterized immunohistochemically by factor VIII staining of bone marrow biopsies and quantified by assessment of microvessel density using previously described techniques. We evaluated bone marrow biopsies from 40 children with newly diagnosed, untreated acute lymphoblastic leukemia. In 22 of the patients, we also evaluated angiogenesis after the completion of remission induction chemotherapy. Control specimens were obtained from children undergoing staging evaluations at the time of diagnosis of solid tumors and lymphomas. Microvessels were counted throughout the entire core specimen in consecutive x 200 fields, and a median count per field (cpf) was calculated. In addition, the number of microvessels in the single x 200 field with the highest microvessel density was designated as the "hot spot." Biopsies from children with leukemia and from controls showed median microvessel densities of 42 and 6 counts per field, respectively (P < or = 0.0001). Microvessel density of the hot spots of leukemia specimens and controls were also significantly different, 51 and 8, respectively (P < or = 0.0001). A computer-aided three-dimensional reconstruction model of bone marrow vascularity showed a complex, arborizing branching of microvessels in leukemic specimens compared with single, straight microvessels without branching in controls. Urinary basic fibroblast growth factor, a potent angiogenic factor, was measured in 22 of the children with newly diagnosed leukemia and in 39 normal, age-matched controls. Urinary basic fibroblast growth factor levels were increased in all 22 patients before treatment, were variable during induction chemotherapy, and demonstrated statistically insignificant decreases at the time of complete remission. These findings suggest that leukemia cells induce angiogenesis in the bone marrow and that leukemia might be angiogenesis dependent and raise the possibility for a role of antiangiogenic drugs in the treatment of leukemia.

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				S. Indraccolo, L. Stievano, S. Minuzzo, V. Tosello, G. Esposito, E. Piovan, R. Zamarchi, L. Chieco-Bianchi, and A. Amadori Interruption of tumor dormancy by a transient angiogenic burst within the tumor microenvironment. PNAS, March 14, 2006; 103(11): 4216 - 4221. [Abstract] [Full Text] [PDF]

				W. Liu, M. Guo, Y.-B. Xu, D. Li, Z.-N. Zhou, Y.-L. Wu, Z. Chen, S. C. Kogan, and G.-Q. Chen Induction of tumor arrest and differentiation with prolonged survival by intermittent hypoxia in a mouse model of acute myeloid leukemia Blood, January 15, 2006; 107(2): 698 - 707. [Abstract] [Full Text] [PDF]

				W. Fureder, M.-T. Krauth, W. R. Sperr, K. Sonneck, I. Simonitsch-Klupp, L. Mullauer, M. Willmann, H.-P. Horny, and P. Valent Evaluation of Angiogenesis and Vascular Endothelial Growth Factor Expression in the Bone Marrow of Patients with Aplastic Anemia Am. J. Pathol., January 1, 2006; 168(1): 123 - 130. [Abstract] [Full Text] [PDF]

				L. F. Costa, M. Balcells, E. R. Edelman, L. M. Nadler, and A. A. Cardoso Proangiogenic stimulation of bone marrow endothelium engages mTOR and is inhibited by simultaneous blockade of mTOR and NF-{kappa}B Blood, January 1, 2006; 107(1): 285 - 292. [Abstract] [Full Text] [PDF]

				S. Faderl, K.-A. Do, M. M. Johnson, M. Keating, S. O'Brien, I. Jilani, A. Ferrajoli, F. Ravandi-Kashani, C. Aguilar, A. Dey, et al. Angiogenic factors may have a different prognostic role in adult acute lymphoblastic leukemia Blood, December 15, 2005; 106(13): 4303 - 4307. [Abstract] [Full Text] [PDF]

				M. Chavez-MacGregor, A. Aviles-Salas, D. Green, A. Fuentes-Alburo, C. Gomez-Ruiz, and A. Aguayo Angiogenesis in the Bone Marrow of Patients with Breast Cancer Clin. Cancer Res., August 1, 2005; 11(15): 5396 - 5400. [Abstract] [Full Text] [PDF]

				Y. Shaked, D. Cervi, M. Neuman, L. Chen, G. Klement, C. R. Michaud, M. Haeri, B. J. Pak, R. S. Kerbel, and Y. Ben-David The splenic microenvironment is a source of proangiogenesis/inflammatory mediators accelerating the expansion of murine erythroleukemic cells Blood, June 1, 2005; 105(11): 4500 - 4507. [Abstract] [Full Text] [PDF]

				K. Podar and K. C. Anderson The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications Blood, February 15, 2005; 105(4): 1383 - 1395. [Abstract] [Full Text] [PDF]

				J. LeCouter, C. Zlot, M. Tejada, F. Peale, and N. Ferrara Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization PNAS, November 30, 2004; 101(48): 16813 - 16818. [Abstract] [Full Text] [PDF]

				M G Alexandrakis, F H Passam, C Dambaki, C A Pappa, and E N Stathopoulos The relation between bone marrow angiogenesis and the proliferation index Ki-67 in multiple myeloma J. Clin. Pathol., August 1, 2004; 57(8): 856 - 860. [Abstract] [Full Text] [PDF]

				S. Kumar, T. E. Witzig, and S. V. Rajkumar Thalidomide: Current Role in the Treatment of Non-Plasma Cell Malignancies J. Clin. Oncol., June 15, 2004; 22(12): 2477 - 2488. [Abstract] [Full Text] [PDF]

				H. X. Chen Expanding the Clinical Development of Bevacizumab Oncologist, June 1, 2004; 9(suppl_1): 27 - 35. [Abstract] [Full Text] [PDF]

				A. Ruddell, P. Mezquita, K. A. Brandvold, A. Farr, and B. M. Iritani B Lymphocyte-Specific c-Myc Expression Stimulates Early and Functional Expansion of the Vasculature and Lymphatics during Lymphomagenesis Am. J. Pathol., December 1, 2003; 163(6): 2233 - 2245. [Abstract] [Full Text]

				F. J. Giles, A. T. Stopeck, L. R. Silverman, J. E. Lancet, M. A. Cooper, A. L. Hannah, J. M. Cherrington, A.-M. O'Farrell, H. A. Yuen, S. G. Louie, et al. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes Blood, August 1, 2003; 102(3): 795 - 801. [Abstract] [Full Text] [PDF]

				X. Chen, Z. Ai, M. Rasmussen, P. Bajcsy, L. Auvil, M. Welge, L. Leach, S. Vangveeravong, A. J. Maniotis, and R. Folberg Three-Dimensional Reconstruction of Extravascular Matrix Patterns and Blood Vessels in Human Uveal Melanoma Tissue: Techniques and Preliminary Findings Invest. Ophthalmol. Vis. Sci., July 1, 2003; 44(7): 2834 - 2840. [Abstract] [Full Text] [PDF]

REGULAR ARTICLES

Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia

				G. Schuch, M. Machluf, G. Bartsch Jr, M. Nomi, H. Richard, A. Atala, and S. Soker In vivo administration of vascular endothelial growth factor (VEGF) and its antagonist, soluble neuropilin-1, predicts a role of VEGF in the progression of acute myeloid leukemia in vivo Blood, December 15, 2002; 100(13): 4622 - 4628. [Abstract] [Full Text] [PDF]

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				R. Koomagi, F. Zintl, A. Sauerbrey, and M. Volm Vascular Endothelial Growth Factor in Newly Diagnosed and Recurrent Childhood Acute Lymphoblastic Leukemia as Measured by Real-Time Quantitative Polymerase Chain Reaction Clin. Cancer Res., November 1, 2001; 7(11): 3381 - 3384. [Abstract] [Full Text] [PDF]