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Page 10 of 17 Testa et al. J Cancer Metastasis Treat 2020;6:53 I http://dx.doi.org/10.20517/2394-4722.2020.111

higher than that observed in AML [60,61] . These studies failed to demonstrate a significant increase in serum/
plasma VEGF levels in AML patients [60,61] .

As reported above, the analysis of plasma/serum VEGF levels in AML patients showed conflicting results
[59]
as not all studies showed an increase of VEGF levels in these patients . These discrepancies may be
related to the variable sensitivities of the immunodetection assays used to quantify VEGF levels and the
heterogeneity of AML patients (de novo or relapsed AMLs) included in these studies. However, the majority
of these studies showed increased VEGF levels in plasma/serum of AML patients, a conclusion supported
[63]
[62]
by a recent large meta-analysis performed by Song et al. . A meta-analysis carried out by Guo et al.
showed that high VEGF expression in AML was associated with worse event-free survival and poor overall
[64]
survival. In this context, two studies are particularly interesting. Aguayo et al. showed that VEGF levels
were similarly elevated in AML and MDS patients: in AMLs, but not in MDSs, elevated plasmatic VEGF
[65]
levels were associated with reduced survival and reduced remission rate. De Bont et al. evaluated the
release of VEGF by leukemic blasts of pediatric AMLs, and the levels of this endothelial growth factor
release by leukemic cells are an independent prognostic factor for relapse-free survival.

[59]
As mentioned above, some studies have shown that the increased MVD in AML is a negative prognostic
[66]
factor. This conclusion was confirmed by other studies. Rabitsch et al. analyzed bone marrow MVD in
38 younger AML patients undergoing standard chemotherapy treatment and consecutive allogeneic bone
marrow transplantation: at diagnosis, the MVD was markedly higher in AML patients than in normal
2
2
controls (30/mm vs. 7/mm ); in patients who failed to achieve a complete response following induction
2
chemotherapy, the MVD was higher at diagnosis than in those achieving complete remission (41.5/mm
2
vs. 28.5/mm ); and patients with high MVD displayed a shorter overall survival and a higher risk of relapse
than patients with lower MVD. Similarly, studies carried out in myelodysplastic syndromes, conditions
frequently preceding AMLs, have shown that increased MVD was associated with a shorter survival
time .
[67]
Myeloid sarcoma, also known as granulocytic sarcoma or chloroma, is a tissue extramedullary mass form
of AML composed of myeloid blasts [68,69] . Myeloid sarcoma may occur de novo, may precede or coincide
with AML, or may correspond to a blastic transformation of a preceding myeloproliferative neoplasm
or myelodysplastic syndrome [68,69] . Myeloid sarcoma may occur as a manifestation of relapse in an AML
patient, even after allogeneic stem cell transplantation . Piccaluga et al. explored the bone marrow
[70]
[71]
MVD in 60 myeloid sarcomas and showed that these tumors have an increased MVD compared to normal
bone marrow. The MVD observed in myeloid sarcomas was similar to that observed in AMLs. Among
myeloid sarcomas, those with a monocytic morphology displayed a significantly higher MVD than those
with blastic appearance . In these patients, higher MVD was associated with a reduced overall survival in
[71]
[71]
multivariate analysis .
MOLECULAR MECHANISMS RESPONSIBLE FOR STIMULATION OF ANGIOGENESIS
Recent studies have explored the molecular mechanisms involved in the stimulation of angiogenesis
in some AML subtypes and have defined a link between leukemia-specific genetic abnormalities and
enhanced angiogenesis.

Initial studies by Hiramatsu and coworkers showed that, among the various AML subtypes, AML M3,
corresponding to APL, having the translocation t(15;17) generating the fusion protein Promyelocytic/
[72]
Retinoic Acid Receptor Alfa (PML/RARA), showed the highest expression of VEGF and VEGF-R1 . The
AML subtype characterized by the specific t(8;21) translocation, generating the fusion protein AML1/ETO
[72]
(Eight-Twenty-One), displayed high expression of VEGF and VEGF-R2 .