Recombinant human erythropoietin α targets intratumoral blood vessels, improving chemotherapy in human xenograft models

J. Tóvári, Réka Gilly, E. Rásó, S. Paku, Bíborka Bereczky, Norbert Varga, Ágnes Vágó, J. Tímár

Research output: Contribution to journalArticle

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Abstract

Recombinant human erythropoietin (rHuEPO) is widely used for correction of hemoglobin level in cancer patients. However, apart from hematopoiesis, rHuEPO reportedly has an effect on endothelial cells. We describe here how rHuEPOα can modulate tumor vasculature in human squamous cell (A431) and colorectal carcinoma (HT25) xenograft models. In vivo rHuEPO treatment of xenografts at human-equivalent dose significantly increased the proliferation index of the tumor-associated endothelial cells and the size of CD31-positive intratumoral blood vessels, whereas the pericyte coverage became fragmented. Moreover, rHuEPO administration resulted in decreased expression of vascular endothelial growth factor both by cancer cells and tumor stroma, measured by quantitative PCR. Due to the morphologic alterations in tumoral microvessels, DNA-binding agents (Hoechst and Doxorubicin) labeled significantly larger areas in the tumor mass. Furthermore, rHuEPO treatment led to a significantly improved efficacy of 5-fluorouracil (5-FU) chemotherapy in the case of both tumor xenografts. Meanwhile, rHuEPO had no effect on the in vitro proliferation of erythropoietin receptor-positive tumor cells, and did not interfere with the effects of 5-FU either. These data reveal a new effect of rHuEPO administration: remodeling tumoral microvessels, suppressing vascular endothelial growth factor expression, thereby augmenting antitumor effects of a cancer drug, 5-FU, even in erythropoietin receptor-positive human cancer xenografts.

Original languageEnglish
Pages (from-to)7186-7193
Number of pages8
JournalCancer Research
Volume65
Issue number16
DOIs
Publication statusPublished - Aug 15 2005

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Erythropoietin
Heterografts
Blood Vessels
Drug Therapy
Neoplasms
Fluorouracil
Erythropoietin Receptors
Microvessels
Vascular Endothelial Growth Factor A
Endothelial Cells
Pericytes
Hematopoiesis
Cell Size
Doxorubicin
Squamous Cell Carcinoma
Colorectal Neoplasms
Hemoglobins
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Recombinant human erythropoietin α targets intratumoral blood vessels, improving chemotherapy in human xenograft models. / Tóvári, J.; Gilly, Réka; Rásó, E.; Paku, S.; Bereczky, Bíborka; Varga, Norbert; Vágó, Ágnes; Tímár, J.

In: Cancer Research, Vol. 65, No. 16, 15.08.2005, p. 7186-7193.

Research output: Contribution to journalArticle

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