Survival and invasiveness of astrocytomas promoted by erythropoietin.
OBJECTIVE
The hypoxia-inducible pleiotropic hormone, erythropoietin (EPO), has recently been found to promote the development and survival of neurons and astrocytes. Since hypoxia has been implicated in the malignant progression of some human cancers, the authors investigated whether EPO signaling influenced the malignant properties of human astrocytoma cells.


METHODS
Reverse transcriptase-polymerase chain reaction, Western blot analysis, and immunohistochemical studies were used to measure EPO and its receptor (EPOR). Cell viability, Matrigel invasion assays, metalloprotease assays, EPO neutralizing antibodies, and EPOR overexpression were used to study the biological actions of EPO. Expression of both EPO and EPOR was observed in the hypoxic regions and invasive margins of glioma specimens obtained at biopsy, and expression of EPOR correlated with the stage of the tumor. The EPOR was also functionally upregulated by hypoxia in cultured glioblastoma multiforme (GBM) cells. Both hypoxia and EPO protected cultured GBM cells from cisplatin cytotoxicity and promoted the invasiveness of GBM cells through Matrigel by potentiating metalloprotease activity. Hypoxia-enhanced cell invasion was attenuated in cells that overexpressed a nonfunctional EPOR.


CONCLUSIONS
Hypoxia-inducible autocrine and paracrine EPO signaling participates in the malignant progression of GBMs.
Mohyeldin
Ahmed
A
Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
Dalgard
Clifton L
CL
Lu
Huasheng
H
Mcfate
Thomas
T
Tait
A Sasha
AS
Patel
Viral C
VC
Wong
Kondi
K
Rushing
Elizabeth
E
Roy
Subhojit
S
Acs
Geza
G
Verma
Ajay
A
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000502:physiology* / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006397:Hematinics / Q000627:therapeutic use; D006801:Humans; D009361:Neoplasm Invasiveness; D051381:Rats; D017208:Rats, Wistar; D017467:Receptors, Erythropoietin / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000502:physiology
D000970:Antineoplastic Agents; D006397:Hematinics; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa; D002945:Cisplatin