Angiogenesis and acute myeloid leukemia Houda Haouas Department of Biological and Chemical Engineering, National Institute of Applied Sciences and Technology, Tunis, Tunisia Background: Angiogenesis is a word of Greek origin, ‘angeio’ refers to blood vessel, and genesis refers to creation, meaning the generation of new blood vessels. This process is essential for vertebrate development and plays a key role in human diseases. Angiogenesis is generally understood to be essential for the growth and metastasis of solid tumors and is also important in acute myeloid leukemia (AML). Methods: This review summarizes the essential features of physiological and tumoral angiogenesis and the methods used for their assessment. Results: Technologies for evaluating angiogenesis in AML are discussed and the prognostic significance of angiogenic factors is considered in the context of optimizing treatment. Conclusion: As acute myelogenous leukemia and endothelial cells depend on each other for survival and proliferation, therapy directed against several pro-angiogenic factors might help to enhance the AML outcome. Keywords: Acute leukemia, Angiogenesis, Diagnosis, Prognosis

Introduction Angiogenesis The adult human blood vasculature is constituted of about 100 000 miles of blood vessels, which if joined end to end, would circle the earth nearly four times. The importance of this system lies in its role in supplying the body with oxygen and nutrients, the removal of carbon dioxide, metabolic by-products and waste, and the circulation of cells and their products, notably hematopoietic cells allowing immune surveillance. Blood vessel formation is fundamental to development. During embryonic life, blood vessels are formed by vasculogenesis and angiogenesis. Vasculogenesis, a process of forming new blood vessels from vascular progenitor cells (angioblasts), mesoderm-derived angioblasts or endothelial progenitor cells (EPC), occurs first and provides the primitive vascular pattern.1,2 Angiogenesis, the growth of blood vessels from pre-existing ones by recruiting pre-existing endothelial cells, takes place later during embryogenesis and contributes, with vasculogenesis, to the spread of blood vessels in the body.3–5 In addition to embryogenesis, angiogenesis plays an important role after birth for wound healing, during the menstrual cycle, after tissue grafts and in response to ischemia.6,7 It contributes to physiological homeostasis and tissue integrity. Angiogenesis is also associated with Correspondence to: Houda Haouas, Department of Biological and Chemical Engineering, National Institute of Applied Sciences and Technology, Centre Urbain Nord, BP 676, 1080 Tunis, Tunisia. Email: [email protected]

© W. S. Maney & Son Ltd 2014 DOI 10.1179/1607845413Y.0000000139

human pathologies, including diabetic retinopathy, inflammatory disorders, such as rheumatoid arthritis and psoriasis, and with tumor growth and metastasis.8–13 Angiogenesis occurs by two types of mechanisms: sprouting and intussusceptive. Sprouting angiogenesis consists of the formation of blood vessels in tissues lacking vascularization (hypoxic tissues), while intussusceptive angiogenenesis, which is also called splitting angiogenesis, corresponds to the formation of blood vessels by the subdivision of existing ones.14–16 The latter process requires reorganization of existing endothelial cells and is not well understood. However, several sequential steps compose the sprouting angiogenesis: enzymatic degradation of the capillary basement membrane, proliferation of endothelial cells, directed migration of endothelial cells, tubulogenesis (endothelial cell tube formation), vessel fusion, vessel pruning and vessel stabilization by pericytes. The formation of mature blood vasculature requires endothelial cell activation, proliferation, and migration, as well as the recruitment of mural cells ( pericytes of small capillaries and vascular smooth muscle cells of the larger vessels) that stabilize the structure. The quiescence of mature blood vessels is dependent on the balance between two groups of growth factors with pro-angiogenic and anti-angiogenic activity. Dysregulation or shift of this equilibrium towards an excess of positive factors, called the angiogenic switch, induces

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neovascularization.17,18 Poorly perfused tissues respond to a hypoxic environment by secreting vascular endothelial growth factor A (VEGF-A), one of the best characterized pro-angiogenic factors that plays an important role in hypoxia-induced angiogenesis.15,19,20 Endothelial cells exposed to the highest VEGF-A concentration become tip cells, and extend by forming numerous filopodia that contain the VEGF-A receptor VEGFR2. The developing sprout then elongates by proliferation of endothelial stalk cells that follow behind the tip cell. When the tip cells from two developing sprouts converge at the source of VEGF-A secretion, they fuse and form a lumen. Perfusion of the new capillary with oxygenated blood reduces the secretion of VEGF-A that, in conjunction with pecicyte recruitment, prevents further sprouting.15 This is well documented in the Delta-Notch pathway, one of the cell–cell signaling pathways that functions as a dampening mechanism to prevent excess angiogenesis, promoting the orderly development of new vessels and selecting tip cells (Fig. 1).21–23 In fact, the Notch receptor on the stalk cell is activated by its membrane-bound ligand on tip cells, Delta-like ligand 4 or DLL4, whose expression is induced by VEGF-A. Activated stalk cells suppress their

VEGFR2 production and reduce their migration compared to tip cells. Normal, quiescent blood vessels can be activated to form vessels during wound healing and pathogenesis not only by sprouting angiogenesis but also by vasculogenesis and intussusception. However, in tumor tissues three other processes also occur and are considered tumor specific. These include vessel co-option, where tumor cells infiltrate into normal tissue and coopt the pre-existing vasculature; vascular mimicry, where tumor cells relocate to physically form vascular structures that resemble endothelial tubes; and finally differentiation of cancer stem-like cells into bona fide endothelial cells that form tumor endothelium (Fig. 2).5 Another recognized important mechanism in tumors is angiogenesis driven by blood-derived infiltrating myeloid cells, including macrophages, neutrophils, mast cells, and myeloid progenitors. These inflammatory cells of the innate immune system are recruited to the tumor cells, adapt to the tumor microenvironnement and support tumor growth by secreting stromal-cell derived factor (SDF-1), VEGF, and other pro-angiogenic factors.24 For example, tumorassociated macrophages secrete immunosuppressive factors such as IL-6 and IL-10 to block the host immune response to tumors and can also provide

Figure 1 VEGF and DLL4/Notch signaling in tumor angiogenesis. VEGF, vascular endothelial growth factor, DLL4, delta-like ligand 4. Reprinted with permission from Hicklin.21

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Figure 2 Modes of vessel formation in normal tissues (A–C) and tumors (A–F). EC, endothelial cells; EPC, endothelial progenitor cells. Reprinted with permission from Carmeliet and Jain.5

angiogenic factors, such as fibroblast growth factor 2 (FGF2), matrix metalloproteinase (MMP), and VEGF, to facilitate tumor neovessel formation. Macrophages participate in the process of anastomosis between two vascular sprouts, where they are recruited in either a Tie-2 (tyrosine-protein kinase receptor)-dependent manner via Ang-2-secreted tip cells (angiopoietine 2) or a Tie-2-independent pathway via the beta-2 integrins.25 Angiogenesis via bone-derived EPC in tumor vasculature is under debate.26,27 Many pathways and molecules have been shown to be implicated in physiological and tumor angiogenesis, and it is now apparent that the process of tumor-induced angiogenesis is far more complex than initially envisioned (Table 1).28 This process depends on cell–cell and cell–extracellular matrix interactions. Integral membrane proteins and extracellular proteases are involved in these interactions. Angiogenesis is in fact the product of evolving crosstalk between different cell types within the tumor

and its stroma. The tumor microenvironment is composed of myofibroblasts, fibroblasts, adipocytes, endothelial cells, pericytes, dentritic cells, tumor-associated macrophages, immune cells, and hematopoietic progenitor cells.29–31 From a simple point of view, angiogenesis is essential to the growth and metastatic spread of solid tumors.12 Many tumors are able to attract blood vessels from neighboring tissues, thereby allowing their transition from avascular to vascular phase.32 The transition is primarily activated when a growing tumor creates a low oxygen microenvironment.16 In response to angiogenic factors secreted by tumor cells, such as VEGF-A, endothelial cells release MMPs, which degrade the extracellular matrix. The proliferating endothelial tip cells migrate toward the tumor, followed by stalk endothelial cells, the proliferation of which is inhibited by NOTCH signaling induced by VEGF-A. The neovasculature is then stabilized by pericyte recruitment in response to PDGF secreted by endothelial cells (Fig. 3).33,34

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Table 1

Pathways and molecules involved in physiological and tumor angiogenesis

Ligand-receptor VEGF-VEGFR1 and VEGF-VEGFR2

VEGFC-VEGFR3NRP2 Notch pathway

Ephrin-B2-EPHB4

PDGF-BB-PDGFRβ

ANGPT1–TIE2 ANGPT2-TIE2 TGFβ1-TGFβRII

Putative role in physiological angiogenesis

Implicated role in tumor angiogenesis

Induce proliferation, sprouting and tube formation of endothelial cells; increase vascular permeability; suppress apoptosis for vessel stabilization; upregulate PDGFβ for mural cell recruitment Lymphatic development

Recruitment of immune cells in suppressing antitumor immune response; recruitment of immune cells in promoting tumor growth and angiogenesis; promote sustained angiogenesis Lymphatic-mediated metastasis

Negative feedback for VEGF-mediated vessel sprouting and participates in vessel fate determination (arterial compared with venous) Arterial compared with venous endothelial cell specialization determination; guides vessel branching Promotes migration, recruitment and proliferation of mural cells

DLL4 expression upregulated in cancer and DLL4 inhibition in vivo result in non-productive vasculature and inhibits tumor growth Expression and role in tumorigenesis may be cell type dependent

Faciliates EC-matrix and EC-mural cell interaction for vessel stabilization; suppresses EC apoptosis Induces EC apoptosis in absence of VEGF; participates in lymphatic patterning Promotes ECM and protease production; promotes differentiation of fibroblasts to myofibroblasts and mesenchymal cells to mural cells

Recruitment and survival of tumour- and tumour vasculature-associated stromal cells; mediates TGFβ-induced epithelial–mesenchymal transition Role in tumorigenesis may be dependent on cell type and ANGPT2 levels Recruitment of tumor-associated TEMs; promotes VEGF-mediated tumor neovascularization Promotes angiogenesis by inducing VEGF expression and pro-tumorigenic phenotypes of associated stroma cells

ANGPT, angiopoietin; DLL4, delta-like ligand 4; EC, endothelial cell; ECM, extracellular matrix; NRP2, Neuropilin 2; PDGF, plateletderived growth factor; TEMs, TIE2-expressing. Reprinted with permission from Chung and Ferrara28

Angiogenesis assays Several assays can be used to assess angiogenesis (Table 2). In vitro, they involve evaluating endothelial cell proliferation, endothelial cell migration, and endothelial tube formation, as well as microvessel sprouting in response to pro- or anti-angiogenic factors.35–38 In vivo, the visualization of neovascularization in response to implanted angiogenic molecules depends on the tissue source.36,39,40 Corneal tissue is both transparent and avascular, while the chorioallantoic membrane is highly vascularized but inexpensive and readily accessible by removal of the egg shell. Another popular assay consists of measuring the angiogenic response to tumor cells embedded in Matrigel and implanted subcutaneously in a mouse (Matrigel plug assay).41 To facilitate visualization of blood vessels, Dextran-FITC is injected intravenously before plug removal. However, as tumor vasculature is very heterogeneous and no differences are readily apparent between normal and tumor vessels, caution is necessary when extrapolating results.

Angiogenesis and leukemia Several studies reported that vascularization and/or angiogenic factor quantification in solid tumors may be of prognostic value and an indicator for cancer therapies.42 However, little is known about the importance of vascularization for leukemias or ‘liquid tumors’, which do not grow as a compact mass that requires oxygenation by vasculature development. The existence of leukemia-related angiogenesis was first suggested in 1993 by Judah Folkman, who

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found an elevated level of the pro-angiogenic factor bFGF in the urine of leukemic patients.43 bFGF was subsequently found in the bone marrow and stromal cells of leukemia patients.44 The mechanism of bone marrow angiogenesis in hematological malignancies seems to be more complex than tumor angiogenesis. The vasculature of bone marrow is unique compared to other tissues/organs and consists of small vessels, called sinusoid, that have unique structural and functional properties.45 They are devoid of smooth muscle mural cells and their endothelial cells play an important role in the homing of hematopoietic progenitor cells, promoting hematopoiesis, mobilization of stem cells, and maintenance of HSC. These events are mediated by the expression of several cytokines, cytokines receptors, and adhesion molecules.46,47 The bone marrow microenvironnement or niche, which is composed of supportive cells, extracellular growth factors, metabolic constituents, and matrix factors, can be divided in two compartments: an endosteal niche and a vascular or peri-vascular niche (Fig. 4).48–50 The endosteal niche seems to play a regulatory role in the self-renewal of hematopoietic stem cells and thus in maintaining the pool of quiescent HSC.51 In the perivascular niche, HSC expand via stimulation by NOTCH ligands and stem cell factor (angiocrines factors) secreted by endothelial cells before entering the circulation.52,53 The sinusoidal vessels are in close contact with several types of cells, including CXCL12-abundant reticular cells, which play an important role in cellular cross-talk.54 The vascular niche has been proposed to be a specialized

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Figure 3 Angiogenic sprouting. VEGF, vascular endothelial growth factor, ECM, extracellular matrix; PDGF, platelet-derived growth factor. Reprinted with permission from Oklu et al. 34

Table 2 In vitro and in vivo angiogenesis assays In vitro assays Endothelial cell proliferation Endothelial cell migration Endothelial tube formation

Sprouting microvessels

Direct cell counting, DNA synthesis (thymidine or BrdU incorporation methods), metabolic activity (MTT assay) Transfilter assay (modified classical Boyden chamber), under-agarose assay, wound healing assay, Teflon fence assay, phagokinetic track assay Plating Human umbilical vein endothelial cells (HUVEC) Or bovine aortic endothelial cells (BAEC) with Matrigel (two dimensional) or fibrin gel beads (three-dimensional) Rat and mouse aortic ring test

In vivo assays Sprouting angiogenesis

Corneal angiogenesis assay Chick chorioallantoic membrane angiogenis assay Matrigel plug assay

microenvironment that, through paracrine signaling interactions, control LSC proliferation and fate determination.55 It has been shown that in vivo transplanted human LSC home to the epiphyseal osteoblastic surface of the endosteum before dispersing to the perivascular niche.56

Methods for evaluating angiogenesis in leukemia Circulating angiogenic factors Serum/plasma or bone marrow plasma levels of proangiogenic or anti-angiogenic growth factors are measured by enzyme-linked immunosorbent assay.

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Figure 4 Organization of normal hematopoietic stem cell (HSC) and leukemic stem cell (LSC) niches in the bone marrow. Both HSCs and LSCs establish niches around the bone marrow endosteum and sinusoids. In normal hematopoiesis, the endosteal niche is formed and regulated by osteoblasts, osteoclasts, mesenchymal stromal cells (MSCs), T-regulatory cells (Tregs), and macrophages, while in leukemia, LSC associate with osteoblasts and mesenchymal stromal cells. HSCs form sinusoidal niches with sinusoidal endothelial cells and leptin receptor (lepr+)-expressing perivascular stromal cells. LSCs form sinusoidal niches with sinusoidal endothelial cells. Oxygen gradient decreases from the sinusoids to the endosteum. The normal HSC endosteal niches are hypoxic, while there is an expansion of hypoxic niches in LSC endosteal niches due to LSC proliferation. Reprinted with permission from Nwajei et al. 49

Cellular expression of angiogenic factors Cellular expression of angiogenic factors in leukemic blasts is evaluated by flow cytometry or immunohistochemistry. Intracellular angiogenic factors levels are assessed by western blot and quantitative polymerase chain reaction. Bone marrow microvessel density Angiogenesis can be estimated in leukemic patients by the measure of bone-marrow microvessel density (MVD) and hotspot density.57,58 This is done in bone marrow trephine biopsies by immunohistochemical analyses using antibodies to CD31, CD34, factor VIII-related antigen also known as von Willebrand factor, thrombomodulin, ULEX-E, smooth muscle actin (SMA), collagen type IV, and CD105.59–65

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Dynamic contrast-enhanced magnetic resonance imaging Bone marrow MVD can only be assessed in portions of the organ and therefore gives a limited indication of the overall angiogenesis in a leukemic patient. However, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measures global and functional bone marrow angiogenesis in situ. This non-invasive method allows direct quantification of blood vessel density, vascular flow, and permeability by following the pharmacokinetics of injected low-molecular-weight contrast agents through the vertebral body vasculature.66,67 It is important to note that DCE-MRI is also used to assess spatial and temporal heterogeneity in tumor angiogenesis and to predict tumor aggressiveness and treatment response.68–70

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Numbers of circulating endothelial progenitor cells Estimation of number of circulating endothelial progenitor cells (cEPCs) by flow cytometry in peripheral blood can be used as a marker for angiogenesis. Bone marrow-derived cEPCs and perivascular endothelial cells seem to contribute differently to angiogenesis. The perivascular endothelial cells function through paracrine mechanisms, such as local secretion of VEGF.24 However, cEPCs seem to home to sites of new blood vessel formation, where they merge with the growing vessel wall and differentiate into endothelial cells, amplifying the angiogenic process.33,71 Despite this, advances in the therapeutic and diagnostic use of these cells and their products have been hindered by the lack of standardized or evidence-based methods to define or identify endothelial stem/ progenitor cells.72 In contrast, total angiogenic potential of bone marrow or peripheral blast cell supernatants can be assessed by endothelial sprouting in vitro, using the chick chorioallantoic membrane assay or one of the angiogenesis assays indicated above.

Angiogenesis in acute myeloid leukemia The first studies to demonstrate an association between angiogenesis and acute myeloid leukemia (AML) found that bone marrow from AML patients exhibits an increased MVD and that MVD decreased in response to 16 days induction therapy; this was restored to normal levels upon complete remission (CR).63,73–77 Higher baseline MVD was associated with shorter overall survival.58,59 This increase of endothelial cells correlated with the production of angiogenic growth factors as in solid tumors. One of the most studied angiogenic factors is VEGF (commonly referred to as VEGF-A), which promotes endothelial cell survival, proliferation, and migration, and increases vascular permeability and adhesion molecules on endothelial cells.78 Leukemic cells express VEGF and thereby stimulate neovascularization in bone marrow.79,80 Expression of VEGF has been linked to adverse prognosis in AML. Indeed, VEGF is upregulated in AML blasts77,80,81 and represents an adverse prognostic factor.82 Patients with higher VEGF expression had shorter disease-free survival,83 and elevated VEGF plasma levels in AML have been linked with reduced survival and a lower frequency of CR.84,85 Likewise, a high level of serum VEGF correlated with poor response to chemotherapy and lower survival in AML patients.86 Nevertheless, some studies did not find elevated VEGF levels in plasma87–89 or serum90,91 in AML patients. The level of VEGF121 mRNA isoform in peripheral blood mononuclear cells from adult AML patients is a strong independent prognostic parameter. A high level of VEGF121 expression has been linked to a

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bad prognosis for either event-free survival (EFS) or overall survival.92 However, pediatric AML samples showed no relationship between VEGF expression and either overall survival or relapse-free survival.93 This study reported the co-expression of VEGF121, VEGF145, VEGF148, and VEGF165 mRNA isoforms. Yang and co-workers have shown that increased bone marrow angiogenesis, measured by DCE-MRI at diagnosis67,94 and at day 7 after induction chemotherapy,95 can independently predict adverse clinical outcome in AML. The difference between pretreatment and day 7 bone marrow DCE-MRI may permit an early assessment of treatment response and identify high-risk patients. In addition, the DCE-MRI measurement of bone marrow in AML patients in CR may also be an indicator of outcome and survival.96 High bone marrow blood flow and high tissue perfusion is related to a significantly decreased disease-free survival and overall survival.95 On the other hand, high vessel count in AML bone marrow was associated with a more immature vessel status. Differently structured networks of vessels in the bone marrow of newly diagnosed AML patients have been identified. Biopsies exhibiting a high vessel count and vessels with predominantly large lumen were related to elevated AML blast-derived VEGFA in vitro.64 Moreover, two studies showed that the number of circulating endothelial cells (CEC) is significantly higher in AML patients97,98 and correlates with disease status and response to treatment.97 The levels of activated CEC, resting CEC and endothelial progenitor cells (CEPC) in the peripheral blood of AML patients in CR were significantly lower than at diagnosis.97 Moreover, elevated CEPC levels and a low apoptotic CEC index were associated with higher probability of induction treatment failure.99 On the other hand, two different studies showed no difference in MVD between AMLs of different subtypes defined by French American British classification (FAB).63,73 Another study found similar MVD between M1/M2/M3 and M4/M5 subtypes.100 Moreover, De Bont et al. 101 reported a significant VEGF level increase in AML FAB M4/M5 versus AML patients with FAB M1/M2/M3/M4eo, who had longer duration of remission. In addition to its important role in the initiation of angiogenesis, VEGF plays a role in AML via an autocrine loop.102,103 AML cells not only produce VEGF but also express functional VEGFR, resulting in an autocrine stimulation of tumor growth. Soluble VEGFR1 and VEGFR2 (flt1, KDR, respectively) are the negative counterpoint to the VEGF signaling pathway. A recent study found that soluble VEGF, sFLT1, and sKDR concentration levels were significantly higher in AML patients at diagnosis versus healthy controls. The data indicated that sVEGF/

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sFlt1 ratio is an independent predictor of AML patient outcome and should be considered for anti-antiangiogenic therapy.104 Another study reported that plasma levels of soluble VEGFR1, but not VEGFR2, were independent prognostic factors in AML. A reverse correlation was observed between plasma soluble VEGFR1 (sVEGFR1) levels and the rate of CR in patients with AML.105 Recent studies have shown the importance of another VEGF family member, namely VEGF-C, for regulating AML blast proliferation and survival.106 VEGF-C is an independent factor for the overall survival in pediatric and adult AML patients.107 AML patients with high VEGFC mRNA expression levels at diagnosis show poor biological responses: higher blast counts on day 15 in the bone marrow and an elongated time to reach CR. Other studies found that VEGF-C protein expression levels were significantly elevated in all AML bone marrow samples.108,109 Expression of the VEGF-C receptors VEGFR2 and VEGFR3 favors autocrine and paracrine signaling in AML. The leukemic blasts can then increase vessel formation and their own stem cell maintenance. VEGFA and VEGFC can activate both AML and endothelial cells.106 bFGF is another potent and specific positive regulator of tumor angiogenesis. bFGF levels are increased during progression of some solid tumors, and its measurement, either in tumor tissue, urine, serum, or plasma, has been suggested to be clinically useful in predicting prognosis in a variety of solid tumors. Like VEGF, bFGF is overexpressed in the bone marrow of patients with newly diagnosed AML and stimulates leukemic cell proliferation in an autocrine manner. The degree of bFGF expression did not correlate with MVD.85 Other studies showed elevated plasma levels of bFGF in AML patients but found no correlation between bFGF levels and CR rates or survival.61,84 However, serum bFGF is not always elevated in AML patients.86,88,91,110 Hepatocyte growth factor (HGF) is produced mainly by mesenchymal cells and is known as a powerful angiogenesis factor.111 It also promotes proliferation and migration of blood mononuclear cells, including leukemic blasts.112 However, little is known about the role of HGF in AML. Hjorth-Hansen et al. 113 reported that the HGF levels in serum samples from newly diagnosed AML cases exhibited a statistically significant elevation, but there was no significant correlation between the HGF level and patient survival. In contrast, Kim et al. 91 found that serum HGF concentration was an independent prognostic factor to attain CR and that higher HGF concentrations were associated with lower survival in patients with AML. Verstovsek et al. also observed that increased HGF plasma concentrations correlated

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with shorter survival in AML patients. No significant correlation between HGF concentrations and CR rate or duration was found.114 Other studies have also reported significantly increased plasma levels of HGF in AML patients at diagnosis that predicted patient outcome.61,87 Moreover, HGF levels were elevated in patients who died compared to those who relapsed and to patients in CR. A recent study proposed an autocrine activation of the MET receptor tyrosine kinase (HGF receptor) in AML.115 Angiopoietins (Ang-1 and Ang-2) are extracellular ligands that bind to tie2, a receptor tyrosine kinase. Ang-1 acts as stabilizing and maturation factor for vasculature. Ang-2 is angiogenic in the presence of VEGF and anti-angiogenic in the absence of either VEGF or other mitogenic factors.116 Ang-2 works in concert with VEGF to stimulate angiogenic remodeling and sprouting. Ang-2 activates endothelial cells and destabilizes vessel structure; then VEGF promotes endothelial cell proliferation and migration, allowing the formation of new vessels. In the absence of VEGF, Ang-2 leads to vessel regression.117 Ang-2 expression correlates with clinical features and outcome of patients with breast, non small lung carcinoma and gastric cancers.118–120 As in solid tumors, Hou et al. 116 found that high pretreatment levels of Ang-2 in the bone marrow indicate an unfavorable prognosis in AML. However, two other studies showed that high expression of Ang-2 in peripheral blasts121 and in marrow blasts122 of AML patients were a prognostic indicator of good clinical outcomes. While contradictory, these results suggest an important interaction between VEGF-A and Ang-2. In fact, if the patient population is subdivided by VEGF-A expression levels, high amounts of VEGFA and Ang-2 correlated with poor outcome.123 On the other hand, pre-therapeutic levels of plasma Ang-2 were significantly higher in AML patients. Moreover, patients with high plasma levels of Ang-2 displayed a significantly worse overall survival than those with low levels.124 Likewise, Hou et al. 116 predicted poor outcome in AML patients with high level of Ang-2 in bone marrow plasma. Angiogenin (ANG) was the first angiogenic factor to be isolated from a human tumor.125 It has been evaluated in the clinical setting by several groups. Verstovsek et al. found higher plasma ANG concentrations in AML patients than in healthy individuals that correlated with prolonged survival.126 Elevated serum and plasma levels of ANG have been found in patients with AML, suggesting a role of ANG in the pathogenesis of these diseases.88,110 Patients with untreated AML had increased serum levels of ANG and intensive chemotherapy resulted in its decrease.110 However, other studies have not detected augmented serum ANG levels in AML patients.91

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Table 3 Anti-VEGF small molecules currently under clinical trials in acute myeloid leukemia Molecule

Generic name

Trade name

SU5416 SU11248 BAY 43-9006

Semaxanib (Sugen) Sunitinib (Pfizer) Sorafenib (Bayer and Onyx Pharmaceuticals)

– Sutent Nexavar

PKC 412 CEP 701 PTK787/ZK222584 AZD2171 AG-013736

Midostaurin (Novartis) Lestaurtinib (Cephalon) Vatalanib (Bayer Shering and Novartis) Cediranib (AstraZeneca) Axitinib (Pfizer)

– – – Recentin Inlyta

Target VEGFR-1,2, KIT, FLT3 VEGFR-1,2,3, PDGFRs. KIT, FLT3, RET, M-CSFR VEGFR-2,3, PDGFR- β, FGFR, FLT3, KIT, MCSFR RAF kinase VEGFR2, PDGFRs, KIT, FLT3 PKCα. VEGFR-2, PDGFR- β, KIT, FLT3, JAK2, M-CSFR VEGFR-1, 2,3, PDGFR- β, KIT, M-CSFR VEGFR-1, 2,3, PDGFR- β, KIT VEGFR-1, 2,3, PDGFR, KIT

KIT, tyrosine-protein-kinase kit, CD117 or stem cell growth factor receptor; FLT-3, CD135 or receptor-type tyrosine protein kinase FLT3 or Fms-like tyrosine kinase 3; RET, glial cell line-derived neurotrophic factor receptor; PDGFR, platelet-derived growth factor receptors; PKCα, protein-kinase C alpha; M-CSFR, macrophage-colony stimulating factor receptor; FGFR, fibroblast growth factor receptor.

Endostatin is the C-terminal anti-angiogenic fragment of the extracellular matrix protein collagen XVIII that is generated by tumour-derived proteases.127,128 Its level and prognostic relevance in AML were evaluated in several studies with controversial results. Endostatin serum levels did not significantly differ between diagnosed patients and healthy individuals. Elevated endostatin levels at AML diagnosis indicated longer patient survival.129 Glenjen et al. 110 and Wrobel et al. 130 observed increased serum endostatin levels in untreated AML patients, in whom baseline endostatin levels were significantly lower than after CR.130 Untreated AML patients with increased levels of endostatin and endostatin levels maintained this after intensive chemotherapy.110 In contrast, Lai et al. found no significant differences in the median plasma endostatin (PE) levels between AML patients and controls. Patients in CR had a significantly lower median PE level. PE is a prognostic factor for AML. High PE levels correlate with poor clinical outcome. High PE patients survived for significantly shorter time than low PE patients.131 Moreover, endostatin serum levels did not correlate with diseasefree survival.63,82,110,130,131 High serum TNF-alpha level is an adverse prognostic factor for survival and EFS in patients with untreated AML.132 However, several other studies showed that neither TNF alpha nor other angiogenic factors were increased in AML patient serum or plasma.61,76,91

Conclusion Taken together, several studies revealed that MVD enumeration in bone marrow of AML patients might be an additional prognostic factor, as well as CEC, and some angiogenic factors. However, the results are sparse because of the different characteristics and the limited number of AML patient cohorts, and the different measurement methods used to assess bone marrow angiogenesis. Notably, intracellular levels of angiogenic factors may not reflect their blood levels

and serum cytokines levels may not precisely reflect the bone marrow vasculature.133,134 Although, antiVEGF antibodies have been used for therapy in AML, the outcome is still poor. Bevacizumab (Avastin, Genentech/Roche), a VEGF-A-specific, humanized monoclonal antibody, has been shown to have no clinical effect in patients with relapsed or refractory AML.135 Nevertheless, the combination with chemotherapy had shown a slightly enhanced anti-tumoral activity compared to either agent alone.136 A recent study reported that the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of older AML patients.137 A second generation of drugs: small molecules targeting the VEGF pathway has been developed as antiangiogenic and is in clinical trials alone and in combined therapy with cytostatic agents in AML (Table 3). VEGF-targeted therapy in AML patients could inhibit autocrine VEGF signaling in AML cells, as well as aberrant vessel formation by vascular endothelial cells. So far, in the clinic these molecules have shown limited anti-angiogenic effect when used as monotherapy. The response is confined to certain subgroups of AML patients and is frequently short-lived.138–140 For example, Sunitinib, a VEGF RTK (receptor tyrosine kinase) inhibitor also inhibits KIT, FLT-3, PDGFRs, KIT and M-CSFRinitiated signaling. It has a limited effect in AML, with complete or partial remissions of short duration limited to a minority of patients.141 Additional benefit to standard therapy is not always observed when combining chemotherapy with these molecules.142,143 Noteworthy, several clinical trials using these molecules in some cancers have shown that tumor acquire resistance via a compensatory mechanism with short-term tumor stabilization rather than long-term survival benefits.144 Consequently, antiangiogenic therapy targeting one pro-angiogenic factor might have no or little effect and combination of two or more blocking antiangiogenic pathways might be more effective.138–140,145 As angiogenesis is

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a complex process involving the interplay of different angiogenic growth factors, the simultaneous analysis of their expression in the same AML pretreatment samples might give insights into their relative relevance for the disease process. An angiogenic profile for each patient should help identify the prognostic and make decision for an optimal treatment by the selection of the appropriate angiogenic therapy directed against more than one angiogenic factor. For this purpose, a universal method should be defined and used in multi-center studies.

Acknowledgement This work was supported by DGRS (General Direction of Scientific Research, Tunis, Tunisia).

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