Erythropoietin and erythropoietin receptor expression in head and neck cancer: relationship to tumor hypoxia.
OBJECTIVE
Erythropoietin, an oxygen-regulated glycoprotein hormone, is a hematopoietic cytokine that stimulates erythropoiesis by binding to its cellular receptor [erythropoietin receptor (EPOR)]. The recombinant form of human erythropoietin is used to prevent or treat anemia in cancer patients. However, in a recent randomized, placebo-controlled trial involving patients receiving curative radiotherapy for squamous cell carcinoma of the head and neck, erythropoietin treatment was associated with poorer locoregional progression-free survival. The purpose of our study was to determine whether EPOR and its ligand erythropoietin are expressed in primary head and neck cancer. We also investigated the hypothesis that erythropoietin expression in malignant cells may be associated with the presence of tumor hypoxia, an important factor involved in resistance to radiation treatment, tumor aggressiveness, and poor prognosis.


METHODS
Twenty-one patients received an i.v. infusion of the hypoxia marker pimonidazole hydrochloride before multiple tumor biopsies. Contiguous sections from 74 biopsies were analyzed by immunohistochemistry for EPOR and erythropoietin expression and pimonidazole binding.


RESULTS
EPOR expression was present in tumor cells in 97% of the biopsies. Coexpression of erythropoietin was observed in 90% of biopsies. Erythropoietin and pimonidazole adduct staining did not always colocalize within tumors, but there was a significant positive correlation between levels of microregional erythropoietin expression and pimonidazole binding.


CONCLUSIONS
The coexpression of erythropoietin and EPOR in tumor cells suggests that erythropoietin may potentially function as an autocrine or paracrine factor in head and neck cancer. The expression of the hypoxia-inducible protein erythropoietin in tumor cells correlates with levels of tumor hypoxia.
Arcasoy
Murat O
MO
Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27710, USA. arcas001@mc.duke.edu
Amin
Khalid
K
Chou
Shu-Chuan
SC
Haroon
Zishan A
ZA
Varia
Mahesh
M
Raleigh
James A
JA
D018572:Disease-Free Survival; D004921:Erythropoietin / Q000096:biosynthesis* / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D000860:Hypoxia; D007150:Immunohistochemistry; D008024:Ligands; D009593:Nitroimidazoles / Q000494:pharmacology; D011379:Prognosis; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D017467:Receptors, Erythropoietin / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000737:chemistry; D013997:Time Factors
D008024:Ligands; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin; C033815:pimonidazole