Prognostic significance of Erythropoietin in pancreatic adenocarcinoma

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= 20.46), 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.