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Table 1
Human tumors which express Epo and/or EpoR
Tumor
Reference
Breast carcinoma
(
22
)
Lung carcinoma
(
12
)
Gastric carcinoma
(
25
)
Hepatocellular carcinoma
(
26
)
Uterine cervix carcinoma
(
27
)
Renal carcinoma
(
28
)
Neuroblastoma
(
29
)
Pediatric tumors
(
30
)
Hemangioblastoma
(
31
)
Lymphoid malignancies
(
32
)
Glioma
(
33
)
and human breast cancer and lymphoma models (
9
). Moreover,
Epo stimulates postnatal neovascularization by increasing EPC
mobilization from the bone marrow (
10
).
Several tumor cell lines express Epo and EpoR regardless that
they secrete a very small amount of Epo individually and that most
of them respond to hypoxic stimuli by enhanced secretion of Epo
(
11
). Kayser and Gabius (
12
) first suggested that human tumors
may express EpoR. In their study 81% of human lung carcinoma
tissues possessed Epo-binding site, detected by the use of biotiny-
lated rhEpo. Epo and EpoR mRNA and/or EpoR protein have
been detected in several human tumors (Table
1
).
Epo favors tumor progression through effects on angiogenesis
and it may be considered as an endogenous stimulator of vessel
growth during tumor progression through an autocrine/paracrine
loop (
13
). Tumor cell can directly release increasing amounts of vas-
cular endothelial growth factor (VEGF) and placental growth factor
(PlGF) in response to Epo (
14
). In cerebral endothelial cell cultures,
rhuEPO enhanced angiogenesis by increasing VEGF levels and this
effect was inhibited by anti-Epo antibody and a specific VEGF recep-
tor (VEGFR) antagonist (
15
). In an experimental model of femoral
artery legation using EpoR-null mice, blood flow recovery, activa-
tion of VEGF/VEGFR system, and mobilization of EPC were all
impaired in EpoR-null mice as compared with wild-type mice (
16
).
In a Lewis lung carcinoma xenograft model, subcutaneous
administration of Epo promoted tumor growth through enhance-
ment of angiogenesis (
17
). In the dorsal skin-fold window cham-
bers, the co-injection of Epo with labeled rodent mammary
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