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      Prognostic Significance of Erythropoietin in Pancreatic Adenocarcinoma

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          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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          Most cited references52

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          Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial.

          Anaemia is associated with poor cancer control, particularly in patients undergoing radiotherapy. We investigated whether anaemia correction with epoetin beta could improve outcome of curative radiotherapy among patients with head and neck cancer. We did a multicentre, double-blind, randomised, placebo-controlled trial in 351 patients (haemoglobin <120 g/L in women or <130 g/L in men) with carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received curative radiotherapy at 60 Gy for completely (R0) and histologically incomplete (R1) resected disease, or 70 Gy for macroscopically incompletely resected (R2) advanced disease (T3, T4, or nodal involvement) or for primary definitive treatment. All patients were assigned to subcutaneous placebo (n=171) or epoetin beta 300 IU/kg (n=180) three times weekly, from 10-14 days before and continuing throughout radiotherapy. The primary endpoint was locoregional progression-free survival. We assessed also time to locoregional progression and survival. Analysis was by intention to treat. 148 (82%) patients given epoetin beta achieved haemoglobin concentrations higher than 140 g/L (women) or 150 g/L (men) compared with 26 (15%) given placebo. However, locoregional progression-free survival was poorer with epoetin beta than with placebo (adjusted relative risk 1.62 [95% CI 1.22-2.14]; p=0.0008). For locoregional progression the relative risk was 1.69 (1.16-2.47, p=0.007) and for survival was 1.39 (1.05-1.84, p=0.02). Epoetin beta corrects anaemia but does not improve cancer control or survival. Disease control might even be impaired. Patients receiving curative cancer treatment and given erythropoietin should be studied in carefully controlled trials.
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            JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin.

            Erythropoietin (EPO) regulates the proliferation and differentiation of erythroid cells through interaction with its receptor (EPOR). Although EPOR is a member of the cytokine receptor superfamily and lacks a kinase domain, EPO induces tyrosine phosphorylation, which is correlated with gene transcription and mitogenesis. Here we demonstrate that EPO induces tyrosine phosphorylation of JAK2 kinase and activates its in vitro autophosphorylation. Using EPOR mutants, phosphorylation and activation of kinase activity correlate with the induction of mitogenesis. Furthermore, JAK2 physically associates with a membrane-proximal region of the EPOR cytoplasmic domain that is required for biological activity. The results support the hypothesis that JAK2 is the kinase that couples EPO binding to tyrosine phosphorylation and mitogenesis.
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              Turning cells red: signal transduction mediated by erythropoietin.

              Erythropoietin (EPO) is the crucial cytokine regulator of red blood-cell production. Since the discovery of EPO in 1985 and the isolation of its cognate receptor four years later, there has been significant interest in understanding the unique ability of this ligand-receptor pair to promote erythroid mitogenesis, survival and differentiation. The development of knockout mice has elucidated the precise role of the ligand, receptor and downstream players in murine erythroid development. In this review, we summarize EPO-mediated signaling pathways and examine their significance in vivo.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                1 August 2011
                : 6
                : 8
                : e23151
                Affiliations
                [1 ]Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
                [2 ]Division Systems Biology of Signal Transduction, German Cancer Research Center and Bioquant, Heidelberg University, Heidelberg, Germany
                [3 ]Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
                [4 ]Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
                [5 ]Institute of Pathology, University Hospital Tübingen, Tübingen, Germany
                University of Nebraska Medical Center, United States of America
                Author notes

                Conceived and designed the experiments: TW SZ NAG. Performed the experiments: SZ VB UK TG SK AH. Analyzed the data: TW SZ VB TG UH SK AH FB BS UK NAG. Contributed reagents/materials/analysis tools: VB UK TG UH. Wrote the paper: TW SZ NAG. Collected samples and provided critical comments: MWB JW.

                [¤a]

                Current address: Department of Preventive Oncology, National Center of Tumor Diseases/NCT, University Hospital Heidelberg, Heidelberg, Germany

                [¤b]

                Current address: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America

                Article
                PONE-D-11-07397
                10.1371/journal.pone.0023151
                3148251
                21829709
                ec4c4cb3-978a-449e-8900-f1cb38ea1df4
                Welsch et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 27 April 2011
                : 7 July 2011
                Page count
                Pages: 12
                Categories
                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
                Gene Expression
                Medicine
                Clinical Immunology
                Immune System
                Cytokines
                Immunologic Techniques
                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

                Uncategorized
                Uncategorized

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