The endothelium in graft-versushost disease and graft-versusleukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 479

the liver, ileum, and colon during GVHD. E4G10-treated HSCT recipients
had better survival, less target organ damage, reduced numbers of tissue-
infiltrating CD3 + T cells, and lower clinical GVHD scores in various murine
GVHD models. The mechanism of how the inhibition of neovascularization
reduces inflammation has not been formally demonstrated experimentally.
However, the most convincing hypothesis is the impaired recruitment of
proinflammatory cells migrating via the blood vessels to inflammatory sites.

In patients with cancer (not undergoing allo-HSCT) the inhibition of tumor
neovascularization has become a standard therapy, and anti-VEGF antibod-
ies are used as first-line drugs. In contrast, specific therapeutic strategies
to inhibit neovascularization have not been studied in patients under-
going allo-HSCT. However, preliminary preclinical studies suggest that
anti-VEGFR1/2 antibodies might inhibit hematopoietic reconstitution after
allo-HSCT [46] . Therefore, more detailed preclinical results on the effect of
anti-VEGF drugs in allo-HSCT recipients have to be collected in order to
assess the risk in this setting. Interestingly, standard drugs being used as
GVHD prophylaxis, including cyclosporin A and methotrexate, inhibit neo-
vascularization, raising the possibility that this capacity contributes to the
clinical efficacy in the prevention of GVHD [57] .

485

The endothelium in graft-versus-leukemia
Neovascularization and its inhibition in hematologic
malignancies

It was discovered in the early 1970s that angiogenesis by capillary sprout-
ing of host vessels is important for growth and metastasis of solid malignant
tumors [58] . The inhibition of neovascularization to inhibit tumor growth
is a therapeutic concept that was demonstrated to be effective in clinical
studies. Currently, several agents that inhibit neovascularization, such as
the humanized anti-VEGF-A antibody bevacizumab, as well as the tyrosine
kinase inhibitors sorafenib and sunitinib, are used as single agents or in com-
bination with chemotherapy to treat patients with solid malignant diseases.

An increased vascular density in the bone marrow has been demonstrated
to be associated with various hematologic malignancies such as acute and
chronic leukemias, myelodysplastic syndromes, and multiple myeloma
[59-62] . However, until recently it was not known if neovascularization is
important exclusively for the growth and metastasis of solid tumors or if
it also plays a role in the pathophysiology of hematological malignancies,
which are more relevant for allo-HSCT. Current evidence indicates that the
growth of hematologic malignancies, similar to the survival of solid tumor
cells, depends on neovascularization as summarized in more detail in a
review by Schmidt and Carmeliet [63] .

In a study using primary leukemic blasts, VEGFR-2 expression as well as
VEGF production was detected in 23 of 33 patients with acute myeloid
leukemia (AML) [64] . Rafii and co-workers [65] demonstrated that certain
leukemias not only produce VEGF but also express functional VEGFR-2
in vivo and in vitro, resulting in the generation of an autocrine loop that
may support leukemic cell survival and proliferation. Furthermore, the