Erythropoietin regulates tumour growth of human malignancies.
In addition to the chief function of erythropoietin (Epo) in promoting erythropoiesis, some other roles have been found in the brain and uterus. We have reported that signalling pathways of Epo and Epo receptor (EpoR) are involved in the tumourigenesis of ovarian and uterine cancers. To determine whether Epo plays a similar role in other malignancies, we studied the expression of Epo in several malignant human cell lines. We found that 24 malignant human cell lines examined express Epo and EpoR regardless of their origins, types, genetic characteristics and biological properties and secrete a very small amount of Epo individually and that most of them respond to hypoxic stimuli by enhanced secretion of Epo. To determine whether the Epo-EpoR pathway operates in tumours of these cell lines, we transplanted several cell lines into nude mice and confirmed the presence of Epo-responsive sites in xenografts in which the phosphorylation of the STAT5 (signal transducer and activator of transcription) is detectable. Furthermore, in nude mice we blocked the Epo signalling in xenografts of two representative cell lines, stomach choriocarcinoma and melanoma, by i.p. injections of EpoR antagonist and found inhibition of angiogenesis and survival of tumour cells leading to destruction of tumour masses and disturbances of phosphorylation of STAT5. In contrast, Epo mimetic peptide promotes angiogenesis and tumour cell survival. These findings suggest that Epo is indispensable for the growth and viability of malignant tumour and also that the deprivation of Epo signalling may be a promising therapy for human malignancy.
Yasuda
Yoshiko
Y
Department of Anatomy, Division 1, Kinki University School of Medicine, Osaka-Sayama, Japan. y1126yas@med.kindai.ac.jp
Fujita
Yoshihiko
Y
Matsuo
Takuya
T
Koinuma
Satoshi
S
Hara
Satoshi
S
Tazaki
Akira
A
Onozaki
Mie
M
Hashimoto
Mitsuhiro
M
Musha
Terunaga
T
Ogawa
Kazuhiro
K
Fujita
Hiroyoshi
H
Nakamura
Yukio
Y
Shiozaki
Hitoshi
H
Utsumi
Hiroshi
H
D002455:Cell Division; D004921:Erythropoietin / Q000032:analysis / Q000502:physiology*; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000209:etiology; D017467:Receptors, Erythropoietin / Q000032:analysis; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D017467:Receptors, Erythropoietin; D004921:Erythropoietin