title: Prognostic significance of erythropoietin in pancreatic adenocarcinoma.
abstract: BACKGROUND
  Erythropoietin (Epo) administration has been reported to have tumor-promoting effects in anemic cancer patients. We investigated the prognostic impact of endogenous Epo in patients with pancreatic ductal adenocarcinoma (PDAC).
  
  
  METHODS
  The clinico-pathological relevance of hemoglobin (Hb, n = 150), serum Epo (sEpo, n = 87) and tissue expression of Epo/Epo receptor (EpoR, n = 104) was analyzed in patients with PDAC. Epo/EpoR expression, signaling, growth, invasion and chemoresistance were studied in Epo-exposed PDAC cell lines.
  
  
  RESULTS
  Compared to donors, median preoperative Hb levels were reduced by 15% in both chronic pancreatitis (CP, p<0.05) and PDAC (p<0.001), reaching anemic grade in one third of patients. While inversely correlating to Hb (r = -0.46), 95% of sEPO values lay within the normal range. The individual levels of compensation were adequate in CP (observed to predicted ratio, O/P = 0.99) but not in PDAC (O/P = 0.85). Strikingly, lower sEPO values yielding inadequate Epo responses were prominent in non-metastatic M0-patients, whereas these parameters were restored in metastatic M1-group (8 vs. 13 mU/mL; O/P = 0.82 vs. 0.96; p<0.01)--although Hb levels and the prevalence of anemia were comparable. Higher sEpo values (upper quartile ≥ 16 mU/ml) were not significantly different in M0 (20%) and M1 (30%) groups, but were an independent prognostic factor for shorter survival (HR 2.20, 10 vs. 17 months, p<0.05). The pattern of Epo expression in pancreas and liver suggested ectopic release of Epo by capillaries/vasa vasorum and hepatocytes, regulated by but not emanating from tumor cells. Epo could initiate PI3K/Akt signaling via EpoR in PDAC cells but failed to alter their functions, probably due to co-expression of the soluble EpoR isoform, known to antagonize Epo.
  
  
  CONCLUSIONS
  Higher sEPO levels counteract anemia but worsen outcome in PDAC patients. Further trials are required to clarify how overcoming a sEPO threshold ≥16 mU/ml by endogenous or exogenous means may predispose to or promote metastatic progression.
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Welsch
authors.forename: Stefanie
authors.initials: S
authors.lastname: Zschäbitz
authors.forename: Verena
authors.initials: V
authors.lastname: Becker
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.forename: Frank
authors.initials: F
authors.lastname: Bergmann
authors.forename: Ulf
authors.initials: U
authors.lastname: Hinz
authors.forename: Shereen
authors.initials: S
authors.lastname: Keleg
authors.forename: Anette
authors.initials: A
authors.lastname: Heller
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.forename: Ursula
authors.initials: U
authors.lastname: Klingmüller
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Jens
authors.initials: J
authors.lastname: Werner
authors.forename: Nathalia A
authors.initials: NA
authors.lastname: Giese
mesh_terms: D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000276:immunology; D001483:Base Sequence; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology / Q000503:physiopathology*; D017931:DNA Primers; D004921:Erythropoietin / Q000235:genetics / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D017931:DNA Primers; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D004921:Erythropoietin