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Page 2 of 17 Testa et al. J Cancer Metastasis Treat 2020;6:53 I http://dx.doi.org/10.20517/2394-4722.2020.111

supply oxygen and nutrients to tissues, but are also involved in specialized functions to support tissue-
[1]
specific homeostasis, through tissue-specific endothelial cells .

A deregulation of angiogenetic mechanisms is involved in many diseases, characterized by excessive
angiogenetic processes, as observed in many malignant tumors or dysfunctional angiogenetic processes,
[1]
such as in diabetic microvasculopathies . Historically, the occurrence of a vascular phase of tumor
development was first demonstrated for solid tumors, characterized by an angiogenic capability required
to promote new vessel formation to sustain tumor growth . Only more recently the occurrence of tumor-
[2,3]
related angiogenic mechanisms was reported also for hematological malignancies, although some doubts
were raised about the role of angiogenesis in the progression of hematological malignancies. However,
numerous studies have shown that the degree of angiogenesis or the level of endothelial growth factors
correlate with stage of disease, prognosis, or response to therapy, thus suggesting that angiogenesis
induction in hematological malignancies has a physiological role in the mechanisms responsible for disease
progression .
[4,5]

The terms angiogenesis and vasculogenesis underline two different biologic processes involving new blood
vessel formation: the first one describes the formation of new blood vessels starting from pre-existing
vessels, while the second one identifies the de novo formation of blood vessels and mostly occurs during
embryonic and fetal life.

Blood vasculature forms a closed circulatory system involved in the circulation of blood from heart to all
peripheral tissues; this complex function requires a highly articulated network composed of different types
of vessels, including arteries, veins, and capillaries; the inner layer of vessels is constituted by endothelial
cells, a unique and typical component of vessels. There is growing evidence that endothelial cells exert
a number of complex biological functions not limited to the generation of a barrier between blood and
tissues, but also consisting in specialized functions, such as the creation of a stem cell niche, a function
[6]
particularly important at the level of bone marrow .

Endothelial cells originate from the mesoderm layer of the early embryo and subsequently a subset of
[7]
endothelial cells, the hemogenic endothelium, gives rise to hematopoietic stem cells (HSCs) . At the
level of hemogenic endothelium, the hemangioblast, a mesoderm-derived stem cell, gives rise to both
the angioblast, the progenitor of endothelial cells, and hematopoietic stem cells, the progenitors of
hematopoietic cells. During embryogenesis, endothelial cells undergo a process of specification, necessary
to generate the peculiar features of distinct vessel subtypes (arteries, veins, capillaries, and lymphatic
[7]
vessels) to provide essential support to tissue morphogenesis . During tissue and organ formation,
endothelial cells undergo an additional process of tissue- and organ-characteristic specification.

However, recent studies indicate that the relationship between endothelial cells and hematopoietic
lineage during embryonic life is more complex. During embryonic life, some mesoderm cells located
in the extraembryonic organ called the yolk sac generate a population of HSCs, called erythro-myeloid
progenitors (EMPs); EMPs migrate from the yolk sac into embryo and generate a population of primitive
hematopoietic cells, but they also differentiate into endothelial cells, contributing to the vasculature of
[8]
several organs . Interestingly, the percentage of endothelial cells that originate from EMPs ranges from
30% in the brain to 60% in the liver . Further studies will be required to demonstrate to which extent these
[8]
observations made in mice apply also to humans; however, these studies strongly support the existence of a
strong link between endothelial and hematopoietic cell lineages.

Recent studies support the existence of endothelial stem/progenitor cells located at the level of the
endothelium of vessels of various tissues; under steady-state conditions, the endothelial stem cells are in a
state of quiescence, but they can be activated by stimuli requiring a tissue regenerative response [9,10] .