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Prognostic Significance of Erythropoietin in Pancreatic Adenocarcinoma

Authors
Journal
PLoS ONE
1932-6203
Publisher
Public Library of Science
Publication Date
Volume
6
Issue
8
Identifiers
DOI: 10.1371/journal.pone.0023151
Keywords
  • Research Article
  • Biology
  • Biochemistry
  • Proteins
  • Plasma Proteins
  • Genetics
  • Gene Expression
  • Dna Transcription
  • Gene Function
  • Histology
  • Immunology
  • Immunologic Techniques
  • Molecular Cell Biology
  • Cellular Types
  • Endothelial Cells
  • Epithelial Cells
  • Medicine
  • Clinical Immunology
  • Immune System
  • Cytokines
  • Clinical Research Design
  • Observational Studies
  • Gastroenterology And Hepatology
  • Gastrointestinal Cancers
  • Pancreas
  • Oncology
  • Basic Cancer Research
  • Metastasis
  • Tumor Physiology
  • Cancer Treatment
  • Cytokine Therapy
  • Cancers And Neoplasms
  • Gastrointestinal Tumors
  • Pancreatic Cancer
  • Cancer Risk Factors
Disciplines
  • Biology
  • Medicine

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). Methodology 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. Conclusion/Significance 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.

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