Analysis of HIF-1a and its regulator, PHD2, in retroperitoneal sarcomas: clinico-pathologic implications.
Hypoxia is known to play important role in cancer biology.  In sarcomas, hypoxia-induced protein biomarkers such as Hypoxia Inducible Factor-1a (HIF-1a), vascular endothelial growth factor (VEGF), and Erythropoietin (Epo) have been previously reported in only a few studies.  Moreover, the biologic significance and relationship to tumorigenesis of these hypoxia-induced biomarkers is not well understood in the context of sarcoma. The HIF negative regulator, Prolyl Hydroxylase Domain protein 2 (PHD2) has not been evaluated in sarcomas.  We examined the expression of PHD2, HIF-1a, and several other hypoxia induced biomarkers in a series of clinically characterized, retroperitoneal sarcomas with immunohistochemical methods.  Expression of these proteins was analyzed and correlated with clinical outcome.  Increased HIF-1a expression was associated with shorter overall and disease free survival.  PHD2 expression was detected in the majority of sarcoma cases, with increased expression correlating with high tumor grade but not with survival.  Though changes in PHD2 expression alone did not correlate with overall and disease free survival, reduced/absent PHD2 expression in the presence of HIF-1a expression was associated with shorter overall and disease-free survival than that of other HIF-1a/PHD2 expression profiles.  These observations suggest that regulation and expression of both PHD2 and HIF-1a are important to the biology of sarcomas, and that loss of PHD2 function has an additional adverse effect in the prognosis of sarcomas in tumors expressing HIF-1a.  The biologic and therapeutic implications of HIF-1a and PHD2 expression in retroperitoneal sarcomas warrant further investigation.
Huang
Jui-Han
JH
Department of Pathology and Laboratory Medicine University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Lee
Frank S
FS
Department of Pathology and Laboratory Medicine University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Pasha
Theresa L
TL
Department of Pathology and Laboratory Medicine University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Sammel
Mary D
MD
Department of Biostatistics and Epidemiology University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Karakousis
Giorgos
G
Department of Surgery University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Xu
George
G
Department of Pathology and Laboratory Medicine University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Fraker
Douglas
D
Department of Surgery University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Zhang
Paul J
PJ
Department of Pathology and Laboratory Medicine University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015687:Cell Hypoxia; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010534:Peritoneal Neoplasms / Q000378:metabolism* / Q000473:pathology; D012509:Sarcoma / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases