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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 3 of 17

The mechanisms through which tumors stimulate angiogenesis are complex and heterogeneous in the
various tumors implying different molecular and cellular processes; however, it is evident that in all tumors
a major determinant of angiogenesis is related to the tumor microenvironment [11,12] . Tumor angiogenesis is
also a key determinant of tumor heterogeneity in that the level of proximity of cancer cells to blood vessels
[13]
in a tumor greatly influences phenotype and functional and metabolic properties of tumor cells .

The present paper analyzes the angiogenic mechanisms occurring in acute myeloid leukemia focusing
on the analysis of changes in vessel density, architecture, and functional properties and on the direct
contribution of bone marrow endothelial cells to the development of leukemia progression, promoting
leukemic cell homing, survival and proliferation of leukemic cells, and resistance to therapy. As discussed
below, a better understanding of the complex interactions occurring between leukemic cells and bone
marrow vascular niches may contribute to the development of new therapeutic approaches, including the
targeting of leukemic endothelium.

ROLE OF ENDOTHELIAL CELLS IN LEUKEMIA DEVELOPMENT
Role of bone marrow endothelial cells in the control of hematopoiesis
The bone marrow capillary network exhibits a complex structure and shows a linear columnar organization
at the level of the metaphysis and endosteum and a sinusoidal organization forming a network of
fenestrated, highly branched sinusoidal vessels at the level of the bone cavity; columnar and sinusoidal
vessels are interconnected, thus generating a single capillary network, providing a unique and fundamental
[14]
structure for supporting hematopoiesis . The columnar and sinusoidal vessels can be distinguished
according to the pattern of expression of some endothelial cell surface markers, such as endomucin and
CD31: due to the high expression of these markers, columnar vessels are defined as type H vessels, whereas
[15]
sinusoidal vessels are defined as type L vessels for the low expression of these markers . These phenotypic
differences between type H and type L vessels correspond also to important functional differences in that
[16]
columnar vessels exhibit a higher oxygen pressure and blood flow than sinusoidal vessels . The lower
endothelial permeability of columnar vessels induces the generation of a microenvironment characterized
[17]
by low reactive oxygen species (ROS) . These differences between type H and type L vessels have
important consequences at the tissue level, contributing to the generation of different microenvironments;
thus, type H vessels connect to arterioles, are surrounded by osteoprogenitors, release factors that promote
osteogenesis, and create a local microenvironment promoting the survival and quiescence of HSCs, while
type L vessels lack arteriolar connections and association with osteo-progenitors and generate a local
microenvironment more permissive of the differentiation of HSCs and Hemopoietic Progenitor Cells
[14]
(HPCs) [Figure 1].
Type H endothelial cells display high proliferation rate and mediate vascular growth in bone; regulators of
vessel growth are highly expressed in type H endothelial cells, such as neuropilin1, plexin D1, and vascular
endothelial growth factor-receptor 3 (VEGF-R3), compared to the low levels of these regulators observed
in sinusoid type L endothelial cells. The generation of type H bone marrow vessels is promoted by NOTCH
activation in endothelial cells, a surprising finding given the inhibitory effects on angiogenesis of NOTCH
[18]
signaling exerted in other tissues .
Blood flow was shown to be crucial for the formation of type H capillaries and angiogenic growth of the
bone marrow vasculature; a pharmacologically-induced reduction of blood flow resulted in the inhibition
[19]
of angiogenesis, osteogenesis, and NOTCH activity in the endothelium . With aging, there is a decline of
[19]
both blood flow and NOTCH endothelial activity .
Type H endothelial cells are essential for maintaining HSC number and vitality. A major determinant of
this effect is represented by the production of the cytokine stem cell factor (SCF) selectively produced by