Prognostic significance of erythropoietin in pancreatic adenocarcinoma

• Published in: PloS one Vol. 6; no. 8; p. e23151
• Main Authors: Welsch, Thilo, Zschäbitz, Stefanie, Becker, Verena, Giese, Thomas, Bergmann, Frank, Hinz, Ulf, Keleg, Shereen, Heller, Anette, Sipos, Bence, Klingmüller, Ursula, Büchler, Markus W, Werner, Jens, Giese, Nathalia A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-08-2011; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenocarcinoma; Adult; Aged; AKT protein; Analysis; Anemia; Autoantibodies - immunology; Base Sequence; Biology; Blotting, Western; Breast cancer; Cancer metastasis; Cancer patients; Capillaries; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Pancreatic Ductal - physiopathology; Chemoresistance; Chemotherapy; Clinical trials; Cytokines; Cytotoxicity; DNA Primers; Erythropoietin; Erythropoietin - genetics; Erythropoietin - physiology; Female; Flow Cytometry; Genes; Hemoglobin; Hemoglobins; Hepatocytes; Hospitals; Humans; Immunohistochemistry; Immunoprecipitation; Liver; Liver cancer; Lung cancer; Male; Medical research; Medicine; Metastases; Middle Aged; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - physiopathology; Pancreatitis; Pathology; Patients; Prognosis; Proteins; Real-Time Polymerase Chain Reaction; Receptors, Erythropoietin - genetics; Receptors, Erythropoietin - immunology; RNA, Messenger - genetics; Signal transduction; Signaling; Stem cells; Surgery; Tumor cells; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0023151

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).
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.
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.
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.