Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia

Abstract

The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. In contrast, only few data are available for hematologic neoplasms. To investigate the role of angiogenesis in acute myeloid leukemia (AML), bone marrow biopsies from 62 adults with newly diagnosed, untreated AML (day 0) were evaluated. Further studies were done after the completion of remission induction chemotherapy (day 16 of induction chemotherapy, n = 21; complete remission, n = 20). Microvessels were scored in at least 3 areas (×500 field, 0.126 mm2) of the highest microvessel density in representative sections of each bone marrow specimen using immunohistochemistry for von Willebrand factor and thrombomodulin. Microvessel counts were significantly higher in patients with AML (n = 62) compared with control patients (n = 22): median (interquartile range) 24.0 (21.0-27.8)/×500 field vs 11.2 (10.0-12.0)/×500 field, respectively (P < .001). On day 16 of induction chemotherapy, microvessel density was reduced by 60% (44-66) (P < .001) in hypoplastic marrows without residual blasts, in contrast to only 17% (0-37) reduction in hypoplastic marrows with ≥ 5% residual blasts (P < .001 for the difference between both groups). Bone marrow biopsies taken at the time of complete remission displayed a microvessel density in the same range as the controls. In conclusion, there is evidence of increased microvessel density in the bone marrow of patients with AML, which supports the hypothesis of an important role of angiogenesis in AML. Furthermore, these findings suggest that antiangiogenic therapy might constitute a novel strategy for the treatment of AML.

Angiogenesis in Liquid Tumors: An In Vitro Assay for Leukemic‐Cell‐Induced Bone Marrow Angiogenesis

“…Interestingly, at day 2 and day 3, HS5 cells cocultured with HL60 and K562 leukemic cells induced significantly greater endothelial invasion distance and invasion area and much more isolated tip cells compared to HS5 cells alone (Figure and Figure S3, Supporting Information). These observations agreed well with clinical observations of bone marrows of patients with acute myeloid leukemia, where endothelial sprouts and small microvessels without visible lumens are prevailing . For HS5 cells cocultured with K562 cells, some tip cells in fact successfully invaded through the entire width of the collagen matrix (1000 μm) and reached the leukemic channel by day 3.…”

“…Compared to angiogenesis assays with leukemic cells only (Figure A), most invading tip cells induced by HS5 cells alone were followed by multicellular stalks forming mature lumen structures in the collagen gel (Figure A). Very few isolated, single tip cells were resulted from endothelial invasion induced by HS5 cells alone, presenting a good agreement with in vivo vasculature in healthy bone marrow samples . Interestingly, at day 2 and day 3, HS5 cells cocultured with HL60 and K562 leukemic cells induced significantly greater endothelial invasion distance and invasion area and much more isolated tip cells compared to HS5 cells alone (Figure and Figure S3, Supporting Information).…”

“…In contrast to solid tumors, fewer studies so far have been conducted to examine specifically the role of angiogenesis in hematological malignancies (liquid tumors, including leukemia and lymphoma) . In fact, most hematological malignancies, such as acute and chronic leukemia, lymphoma, myelodysplastic syndromes, myeloproliferative neoplasms, and multiple myeloma, are associated with angiogenesis in the bone marrow or lymphatic organs . Histologically, angiogenesis is considered irrelevant to the pathologies of hematologic malignancies, based on the fact that these malignances do not develop compact tumor mass as solid tumors .…”

Vascularized Microfluidics and the Blood–Endothelium Interface

“…By day 3, the stromal cells alone induced significant angiogenic sprouting, and unlike the leukemic cells, these sprouts were multicellular with mature lumens rather than single, isolated ECs, in keeping with what is seen in biopsies of healthy bone marrow [172]. When co-cultured with HL60 or K562 cells, greater endothelial invasion distance and area were seen than either in isolation, but with more isolated tip cells when compared to the bone marrow fibroblasts alone, consistent with bone marrow biopsies taken from patients with acute myeloid leukemia [173]. .…”

Heparan Sulfate D‐Glucosaminyl 3‐O‐Sulfotransferase‐3B1 (HS3ST3B1) Promotes Angiogenesis and Proliferation by Induction of VEGF in Acute Myeloid Leukemia Cells

“…VEGF/VEGFRs act in an autocrine or paracrine manner on endothelial cells as well as certain malignant cells [Santos and Dias, ]. Increased VEGF production by tumor cells and higher microvessel density are highly correlated with adverse clinical outcome of AML [Padro et al, ; de Bont et al, ; Shih et al, ]. A number of in vitro and in vivo studies have examined the role of HSPG in modulation of VEGF activity, and the interaction of HS with HS‐binding growth factors is thought to be dependent on the patterns of the sulfate and hexuronic acid isoform residues [Sasisekharan et al, ; Bishop et al, ; Zhang, ].…”