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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 9 of 17
[49]
+
survival . In fact, it was shown that binding of BCR-ABL1 CML cells to E-selectin in the vascular niche
[49]
stimulates cell cycle progression and response to imatinib treatment . For CML cells, the E-selectin CD44
[50]
receptor and not CD162 seems to be involved in the mediation of E-selectin induced effects .
ANGIOGENESIS IN AML BONE MARROW: MICROVESSEL DENSITY
The technique currently used to evaluate the extent of angiogenesis at the level of bone marrow biopsies
consists in staining of the histological sections with specific endothelial cell markers and then evaluation
with a microscope of the density of microvessels present in these tissue sections (the number of vessels per
millimeter length of bone marrow core biopsy is evaluated). This technique provides a score of MVD. Using
this approach, two different groups of investigators in 2000 provided evidence that the MVD was increased
(approximately doubled) in AML specimens compared to normal bone marrow [51,52] . Examination of AML
bone marrow specimens after induction of disease remission was associated with a clear decrease of bone
marrow MVD; in patients not achieving remission following chemotherapy treatment, no decrease of bone
[53]
marrow MVD was observed [51,52] .Kini et al. reported that the MVD and hot spot density were particularly
increased in bone marrow biopsies of acute promyelocytic leukemia patients compared with normal bone
marrow specimens; treatment with retinoic acid induced disease remission and a clear decrease of MVD.
Other studies have evaluated whether the increased MVD observed in AML bone marrow was associated
[54]
with an increased production of VEGF. Padrò et al. showed, through the immunohistochemical analysis
of 32 AML bone marrow samples, higher VEGF and VEGF-R2 expression than in control normal bone
marrow: expression of VEGF and VEGF-R2 was clearly higher in patients with a high degree of MVD,
compared to those observed with lower MVD. A direct correlation was observed between VEGF expression
[54]
and MVD . Ghannadan and coworkers explored VEGF expression in the bone marrow of 41 AMLs and
observed positive expression in all AML subtypes classified according to the FAB classification, with the
[55]
expression of most immature FAB M0 AMLs, expressing undetectable or only low levels of VEGF . VEGF
was detectable in immature elements, whereas it was undetectable or expressed at very low levels in mature
[55]
hematopoietic elements .

Other studies confirmed the increased MVD in AML bone marrow and showed also a correlation between
the increase of MVD and the proliferation index of leukemic blasts and the association between increased
[56]
MVD and increased bone marrow VEGF levels, both parameters decreasing in patients who achieved
[57]
disease remission following induction therapy .
[58]
Kuzu et al. showed a higher MVD in AML patients compared to controls, independent of cellularity
or blast percentage; higher baseline MVD values in AML patients were associated with a shorter overall
survival and thus are a negative prognostic factor.

Interestingly, Weidenaar and coworkers explored the vascular morphology within AML bone marrow
[59]
biopsies . The analysis of a pericyte marker (smooth muscle actin) provided evidence that in AML bone
marrow at diagnosis only 35% of vessels were pericyte-coated, compared to 73% in the normal bone
marrow and 55% in AML patients in remission. Furthermore, the percentage of pericyte-coated vessels was
significantly higher in the group of AML patients with “low vessel count” compared with that observed in
[59]
AML patients with “high vessel count” . Two different patterns of vascular morphology were observed
in AML bone marrow biopsies: high number of vessels with a large lumen and thin walls and a high vessel
count with a network of small vessels with thin walls, narrow lumen, and branching. The first vessel pattern
was associated with high secreted vascular endothelial growth factor A (VEGFA) protein levels .
[59]

Other investigators have reported a comparative analysis of bone marrow MVD in various hematological
malignancies, confirming the higher values of MVD in AML compared to normal bone marrow. These
studies also showed an increase of MVD in Acute Lymphoblastic Leukemia (ALL) and CML, at a level