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Testa et al. J Cancer Metastasis Treat 2020;6:53 I http://dx.doi.org/10.20517/2394-4722.2020.111 Page 13 of 17

displayed a significantly reduced overall survival compared to that observed in patients with low plasmatic
[93]
Ang2 levels . The discrepancy observed in these two studies may be tentatively related to some relevant
differences: the first study evaluated bone marrow expression of Ang2, while the second study evaluated
plasmatic Ang2 levels and the source of circulating Ang2 is not only related to leukemic blasts, but also
[93]
reflects the production by other cell types, including endothelial cells .

[94]
Loges et al. explored VEGF-A, VEGF-C, Ang1, Ang2, and Tie2 mRNA levels in a cohort of 90 patients
with de novo AML. This study showed that high Ang2 levels have a good prognostic impact on patient’s
survival: sub-analysis according to the levels of other endothelial growth factors showed that the prognostic
impact of Ang2 mRNA expression was most evident in AML subgroups with low VEGF-C and Ang1
[94]
levels .

Riccioni and coworkers reported a detailed immunophenotypic analysis of AMLs expressing high levels
[92]
of Tie2 . In this study carried out in 111 de novo adult AML patients, 35% displayed high levels and
20% moderate levels of Tie2. Tie2 expression on leukemic blasts was associated with the expression of
monocytic markers. Furthermore, Tie2 expression was associated with concomitant expression of other
[95]
endothelial growth factors such as VEGF-R1, VEGF-R2, and VEGF-R3 . Highly-expressing Tie2 AMLs
[95]
were characterized by high blast cell counts at diagnosis and frequent FLT3 mutations . According to
these findings, it was suggested that AMLs exhibiting high Tie2 expression resemble Tie2-expressing
[96]
monocytes, a subpopulation of monocytes playing a role in promotion of tumor angiogenesis .
About 30% of adult AMLs display FLT3 mutations; in addition, 10%-15% of AMLs exhibit high FLT3
expression, in the absence of FLT3 mutations. This last group of AMLs is characterized by recurrent
[97]
expression of receptors for endothelial growth factors, including Tie2 .

The possible clinical efficacy of Tie2 inhibitors was not yet explored in AML patients. Pexmetinib, a dual
[98]
inhibitor of Tie2 and p38 MAPK, showed antileukemic activity in preclinical models of AML .

Recent studies support a role for epidermal growth factor ligand 7 (EGFL7) as a pro-angiogenic factor
promoting angiogenesis in AMLs. This secreted angiogenic factor possesses the unique property to be
almost exclusively expressed by endothelial cells. EGFL7 is maximally expressed in proliferating endothelial
[99]
cells and acts on endothelial cells . Interestingly, microRNA-126, an endothelial cell-specific miRNA, is
located in intron 7 of the EGFL7 gene. EGFL7 interacts with the extracellular domain of NOTCH, resulting
[99]
in an antagonistic effect on NOTCH activation . EGFL7 is a potent angiogenic factor, playing a key role
in the control of vascular angiogenesis during embryogenesis [100] . EGFL7 is aberrantly overexpressed in
solid tumors. A recent study showed that EGFL7 mRNA and EGFL7 protein levels are increased in blasts of
AMLs compared to normal bone marrow cells: in AML patients with cytogenetically normal AMLs, high
EGFL7 mRNA levels associate with decreased overall survival rates [101] . In vitro studies showed that EGFL7
stimulates the proliferation of leukemic blasts, whereas high EGFL7 expression predicts poor prognosis
in AML patients undergoing allogeneic stem cell transplantation [102] . Functional studies have shown that
EGFL7 inhibits NOTCH signaling in AML blasts antagonizing canonical NOTCH ligand binding; anti-
EGF7L treatment resulted in reactivation of NOTCH signaling in AML cells, increased differentiation, and
apoptosis, thus suggesting that it may represent a therapeutic strategy [103] .

CONCLUSION
Endothelial cells are intimately associated with HSCs throughout the life of the stem cell, from peculiar
endothelial cells (hemogenic endothelium) that give rise to HSCs, to the perivascular niche endothelial
cells that regulate HSC homeostasis. Endothelial cells as constituents of bone marrow vascular niches play
a key role in the control of HSC homing, migration, and maintenance. Bone marrow endothelial cells