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

Vascular bone marrow permeability is also affected by inflammatory and infectious processes. In fact,
studies carried out in the context of infectious experimental models have shown a key role of endothelial
[35]
bone marrow cells as mediators of stimuli enhancing granulopoiesis during acute infection . Using a
model of inflammatory response induced by interferon a (IFNa), a cytokine rapidly produced in response
to infection, the induction of a rapid stimulation of endothelial cells bone marrow cells in vivo was shown,
[36]
resulting in an increase of endothelium activation, vascular permeability, and vascularity . This IFNa-
mediated activation of bone marrow endothelial cells is in part dependent on an increased production of
[36]
VEGF by bone marrow cells .

[27]
Passaro et al. explored the bone marrow vasculature using intravital two-photon microscopy in acute
myeloid leukemia (AML) patient-derived xenografts; this approach allowed defining changes in bone
marrow vascularity since the first stages of leukemic cells engraftment in bone marrow of recipient animals.
Using this approach, it was shown that: (1) AML engraftment induced a leukemic-specific expansion of the
endothelial compartment among the non-hematopoietic stroma, associated with an increase of microvessel
density (MVD) and an alteration of the architecture of bone marrow vasculature with loss of sinusoidal
structures, reduction of the mean diameter of vessels, and an increase of tissue hypoxia; (2) increased
vascular leakiness in bone marrow; (3) induction of remission with chemotherapy failing to induce a
recovery of vascular architecture and permeability in bone marrow; (4) analysis of molecular signatures in
vascular endothelial cells showed a consistent deregulation of various pathways involved in permeability
regulation and cell adhesion; (5) importantly, among the genes hyperexpressed in vascular endothelial cells,
there are the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) gene, encoding
A NADPH, which, in response to hypoxia, increases ROS levels in the vascular cells and the endothelial
nitric oxide synthetase (eNOS), responsible for the production of nitric oxide (NO) molecules; (6) as a
consequence of the deregulated Nox4 and eNOS expression, all leukemic vascular niches express high ROS
and NO levels; and (7) combined treatment with chemotherapy and genetic or pharmacological inhibitors
of eNOS resulted in an improvement of the antileukemic effects and a restoration of bone marrow
[27]
vasculature .

[37]
Duarte et al. analyzed by intravital microscopy (IVM) the changes in bone marrow vasculature induced
by the engraftment of primary AML cells; the consistent advantage of this technique is related to its
minimal invasiveness and its compatibility with longitudinal observations of cellular dynamics. These
studies showed that following AML engraftment in bone marrow blood vessels appeared damaged: most
vessels were narrower than those in control mice; limited and abnormal sprouting of bone marrow vessels;
progressive decrease of vessels in the endosteum and metaphysis; endosteal vessels are progressively lost
high
high
at intermediate and advanced disease stages; and the number of CD31 /Endomucin was significantly
[37]
reduced . These changes in bone marrow (BM) vasculature are accompanied by a concomitant
progressive depletion of bone marrow stroma. This endosteal remodeling correlated with a loss of normal
hematopoiesis, further supporting the evidence that the vascular endosteal system is structurally and
[37]
functionally damaged by the leukemic process . Importantly, endosteal areas represent the major site for
initiation of AML relapse. Finally, studies in genetically engineered mice provided evidence that rescue of
[37]
endosteal vessels improves the efficacy of standard antileukemic chemotherapy .

Other components of the endothelial niche play a key role in the control of normal hematopoiesis and
in AML development. Osteoblasts are an important component of the endosteal niche and regulate
[38]
hematopoiesis through the secretion of various factors, such as osteopontin (OPN) . OPN is a cytokine
involved in many physiological processes, including angiogenesis. In adult bone marrow, OPN production
[38]
is restricted to endosteal region, where this cytokine is required for HSC homing and quiescence . In
the endosteal niche, a truncated form of OPN, trOPN, interacts with a b and a b integrins expressed on
4 1
9 1
[39]
HSCs and inhibits their proliferation and differentiation . Interestingly, OPN expression is increased both