Journal Article

Erythropoietin regulates tumour growth of human malignancies

Yoshiko Yasuda, Yoshihiko Fujita, Takuya Matsuo, Satoshi Koinuma, Satoshi Hara, Akira Tazaki, Mie Onozaki, Mitsuhiro Hashimoto, Terunaga Musha, Kazuhiro Ogawa, Hiroyoshi Fujita, Yukio Nakamura, Hitoshi Shiozaki and Hiroshi Utsumi

in Carcinogenesis

Volume 24, issue 6, pages 1021-1029
Published in print June 2003 | ISSN: 0143-3334
Published online June 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg060
Erythropoietin regulates tumour growth of human malignancies

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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.

Keywords: ADC, adenocarcinoma; E2, estradiol-17β; EMP1, erythropoietin mimetic peptide 1; EMP9, erythropoietin mimetic peptide 9; Epo, erythropoietin; EpoR, erythropoietin receptor; HIF, hypoxia-inducible factor; IdU, 5-iodo-2′-deoxyuridine; STAT5, signal transducer and activator of transcription; TdT, terminal deoxy nucleotidyl transferase.

Journal Article.  6471 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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