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Page 8 of 14 Tosato et al. J Cancer Metastasis Treat 2021;7:52 https://dx.doi.org/10.20517/2394-4722.2021.120

marrow mesenchymal cells, altering niche support functions for the normal bone marrow HSC, and
promoting growth in the malignant cells.

Vascular reprogramming
The density of blood vessels is markedly increased in MDS, de novo AML, and MPN compared to the
normal bone marrow [76-80] . Morphologically, these vessels are altered showing increased tortuosity, increased
permeability, and focal vascular damage with loss of the endothelial monolayer, all of which are vascular
features commonly observed in solid tumors [68,81,82] . In mouse models of AML, vascular abnormalities are
associated with poor vessel perfusion and bone marrow hypoxia, particularly surrounding the tumor cells,
and these deficiencies are thought to limit proper delivery of anti-cancer drugs [68,82] . AML cells and other cell
[83]
types in the leukemic bone marrow secrete VEGF (also identified as vascular permeability factor, VPF) .
Hypoxia is a principal regulator of VEGF expression through stabilization of the hypoxia-inducible factors
HIF-1α and HIF-2α. Increased oxygen consumption by rapidly proliferating tumor cells contributes to bone
marrow hypoxia, and increased VEGF expression from different cell sources in the bone marrow
microenvironment likely contributes to increased vascularization and vascular permeability in the leukemic
[84]
bone marrow . Circulating levels of the pro-angiogenic factors VEGF and angiopoietin-2 are abnormally
increased in mice with AML and other leukemias [68,83,85] . In addition, increased systemic levels of the
endothelial growth factors VEGF, FGF2, and hepatocyte growth factor (HGF) directly correlated with
increased bone marrow vascularization in MDS, AML, and MPN [76,77,79,81] . However, the contribution of
tumor hypoxia to bone marrow leukemogenesis is currently unclear since different studies show contrasting
results in different mouse models of AML [86-88] . Certain leukemic cells express functional VEGFR2 and
respond to VEGF with increased proliferation [83,89] . VEGF/VEGFR2-activated endothelial cells and
potentially other responsive cells in the bone marrow microenvironment can accelerate AML progression,
through increased adhesion to AML cells and secretion of cytokines and growth factors that promote
leukemic cell growth and viability, including Kitl/SCF, granulocyte-macrophage colony stimulating factor
(GMCSF), granulocyte colony-stimulating factor (G-CSF), and IL-6 [82,90,91] . RNA profiling of endothelial cells
retrieved from the bone marrow of mice with AML detected evidence of increased expression of adhesion
molecules, particularly integrins associated with activation of Fak signaling . One of the most expressed
[82]
genes was Nox4, a NADPH oxidase involved in the response to hypoxia leading to the production of
reactive oxygen species, activation of nitric oxide synthase 3, and release of nitric oxide (NO) . Consistent
[82]
with these experimental models, NO was abnormally elevated in bone marrow aspirates of patients with
[82]
AML . Thus, the bone marrow with MDS, AML and MPN is more vascularized than normal bone
marrow, but the vessels are morphologically and functionally altered as they are leaky and poorly perfused
[Figure 1]. However, we do not know if the process is diffused throughout the bone marrow or limited to
specific areas and vascular beds. VEGF constitutively produced by the tumor cells or induced by hypoxia in
tumor cells or non-malignant bone marrow cells may be the driver of angiogenesis, as observed in many
solid tumor types. Other proangiogenic factors and inflammatory cytokines likely contribute to altering
bone marrow vessels and their function, but this remains an area of investigation.

Tumor-promoting effects of the niche and therapeutic targeting
Current approaches to treatment of patients with MDS evaluate the risk of AML development through a
variety of prognostic scoring systems. MDS is most prevalent in the elderly. Lower-risk patients die more
frequently from complications of bone marrow failure than from transformation into AML. Consequently,
the goal of treatment in these lower-risk patients is symptom relief rather than cure or complete remission.
The only curative treatment for MDS with a high or very high risk of transformation into AML is allogeneic
bone marrow transplantation. Choice of this treatment is based on assessing medical fitness and on other
criteria. No drug intended specifically to target niche deficiencies is currently approved for the treatment of
MDS/AML. However, lenalinomide, which is FDA approved for lower-risk MDS and is particularly