Prognostic Impact of Erythropoietin Expression and Erythropoietin Receptor Expression on Locoregional Control and Survival of Patients Irradiated for Stage II/III Non-Small-Cell Lung Cancer

Rades, Dirk; Setter, Cornelia; Dahl, Olav; Schild, Steven E.; Noack, F.

doi:10.1016/j.ijrobp.2010.02.003

Cited by 17 publications

(14 citation statements)

References 33 publications

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“…Several studies indicated increased EPO expression as prognostic factor for reduced overall survival (120, 177) or vice versa, no EPO expression as prognostic factor for increased overall survival (178, 179). Furthermore, increased EPOR expression was identified as prognostic factor for reduced overall survival, more aggressive tumor behavior, and progression-free survival (57, 73, 120, 180–182).…”

Section: Action Of Epo On Non-hematopoietic Cellsmentioning

confidence: 99%

Erythropoietin and Cancer: The Unintended Consequences of Anemia Correction

2014

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Until 1990, erythropoietin (EPO) was considered to have a single biological purpose and action, the stimulation of red blood cell growth and differentiation. Slowly, scientific and medical opinion evolved, beginning with the discovery of an effect on endothelial cell growth in vitro and the identification of EPO receptors (EPORs) on neuronal cells. We now know that EPO is a pleiotropic growth factor that exhibits an anti-apoptotic action on numerous cells and tissues, including malignant ones. In this article, we present a short discussion of EPO, receptors involved in EPO signal transduction, and their action on non-hematopoietic cells. This is followed by a more detailed presentation of both pre-clinical and clinical data that demonstrate EPO’s action on cancer cells, as well as tumor angiogenesis and lymphangiogenesis. Clinical trials with reported adverse effects of chronic erythropoiesis-stimulating agents (ESAs) treatment as well as clinical studies exploring the prognostic significance of EPO and EPOR expression in cancer patients are reviewed. Finally, we address the use of EPO and other ESAs in cancer patients.

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Section: Action Of Epo On Non-hematopoietic Cellsmentioning

confidence: 99%

Erythropoietin and Cancer: The Unintended Consequences of Anemia Correction

2014

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“…Like other cancer types, co-expression of EPO and EPOR has been reported in NSCLC and was associated with poor survival of NSCLC patients [ 21 – 25 ]. However, several studies have denied EPOR expression and functionality in NSCLC [ 26 – 28 ]. So far, this disagreement remains unchanged.…”

Section: Introductionmentioning

confidence: 99%

Local blockage of self-sustainable erythropoietin signaling suppresses tumor progression in non-small cell lung cancer

Hao

et al. 2017

Oncotarget

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Functional significance of co-expressed erythropoietin (EPO) and its receptor (EPOR) in non-small cell lung cancer (NSCLC) had been under debate. In this study, co-overexpression of EPO/EPOR was confirmed to be positively associated with poor survival in NSCLC. The serum EPO in 14 of 35 enrolled NSCLC patients were found elevated significantly and decreased to normal level after tumor resection. With primary tumor cell culture and patient-derived tumor xenograft (PDX) mouse model, the EPO secretion from the tumors of these 14 patients was verified. Then, we proved the patient derived serum EPO was functionally active and had growth promotion effect in EPO/EPOR overexpressed but not in EPO/EPOR under-expressed NSCLC cells. We also illustrated EPO promoted NSCLC cell proliferation through an EPOR/Jak2/Stat5a/cyclinD1 pathway. In xenograft mouse model, we proved local application of EPO neutralizing antibody and short hairpin RNA (shRNA) against EPOR effectively inhibited the growth of EPO/EPOR overexpressed NSCLC cells and prolonged survivals of the mice. Finally, EPO/EPOR/Jak2/Stat5a/cyclinD1 signaling was found to be a mediator of hypoxia induced growth in EPO/EPOR overexpressed NSCLC. Our results illustrated a subgroup of NSCLC adapt to hypoxia through self-sustainable EPO/EPOR signaling and suggest local blockage of EPO/EPOR as potential therapeutic method in this distinct NSCLC population.

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“…On the other hand, recent evidence also suggests that EPOR downregulation in NSCLC is compromised due to the lack of EPOR ubiquitination following EPO stimulation [13] and that increased pre-operative plasma EPO levels are associated with reduced survival in NSCLC patients [14]. EPO expression and EPO/EPOR co-expression were also found to be associated with poor loco-regional control and survival in irradiated stage II/III NSCLC patients [15]. Overall, because these findings warrant additional research of EPOR signaling in NSCLC, our aim was to examine the association between EPOR expression and the course of disease in human lung ADC.…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin Receptor Expression Is a Potential Prognostic Factor in Human Lung Adenocarcinoma

et al. 2013

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Recombinant human erythropoietins (rHuEPOs) are used to treat cancer-related anemia. Recent preclinical studies and clinical trials, however, have raised concerns about the potential tumor-promoting effects of these drugs. Because the clinical significance of erythropoietin receptor (EPOR) signaling in human non-small cell lung cancer (NSCLC) also remains controversial, our aim was to study whether EPO treatment modifies tumor growth and if EPOR expression has an impact on the clinical behavior of this malignancy. A total of 43 patients with stage III–IV adenocarcinoma (ADC) and complete clinicopathological data were included. EPOR expression in human ADC samples and cell lines was measured by quantitative real-time polymerase chain reaction. Effects of exogenous rHuEPOα were studied on human lung ADC cell lines in vitro. In vivo growth of human ADC xenografts treated with rHuEPOα with or without chemotherapy was also assessed. In vivo tumor and endothelial cell (EC) proliferation was determined by 5-bromo-2’-deoxy-uridine (BrdU) incorporation and immunofluorescent labeling. Although EPOR mRNA was expressed in all of the three investigated ADC cell lines, rHuEPOα treatment (either alone or in combination with gemcitabine) did not alter ADC cell proliferation in vitro. However, rHuEPOα significantly decreased tumor cell proliferation and growth of human H1975 lung ADC xenografts. At the same time, rHuEPOα treatment of H1975 tumors resulted in accelerated tumor endothelial cell proliferation. Moreover, in patients with advanced stage lung ADC, high intratumoral EPOR mRNA levels were associated with significantly increased overall survival. This study reveals high EPOR level as a potential novel positive prognostic marker in human lung ADC.

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Prognostic Impact of Erythropoietin Expression and Erythropoietin Receptor Expression on Locoregional Control and Survival of Patients Irradiated for Stage II/III Non-Small-Cell Lung Cancer

Cited by 17 publications

References 33 publications

Erythropoietin and Cancer: The Unintended Consequences of Anemia Correction

Erythropoietin and Cancer: The Unintended Consequences of Anemia Correction

Local blockage of self-sustainable erythropoietin signaling suppresses tumor progression in non-small cell lung cancer

Erythropoietin Receptor Expression Is a Potential Prognostic Factor in Human Lung Adenocarcinoma

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