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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) has been linked to inflammation- and cancer-related anemia, which reduces both quality of life and prognosis of patients. The aim of this study was to reveal molecular mechanisms linked to the inhibition of erythroid differentiation by TNFalpha. In this study, we showed that the inhibition of erythropoietin (Epo)-mediated differentiation by TNFalpha lead to a downregulation of hemoglobin synthesis and was correlated to a modulation of key erythroid transcription factors. Thus, a reverse of the transcription factor GATA-1/GATA-2 balance normally present during erythropoiesis, as well as a downregulation of the cofactor of GATA-1, friend of GATA-1 (FOG-1), and the coregulating transcription factor nuclear factor erythroid 2 (NF-E2) was observed after TNFalpha treatment. Moreover, we showed a reduction of GATA-1/FOG-1 interaction due to a reduced transcription of GATA-1 and a proteasome-dependent FOG-1 degradation after TNFalpha treatment. These changes led to an inhibition of erythroid gene expression including Epo receptor (EpoR), alpha- and gamma-globin, erythroid-associated factor (ERAF), hydroxymethylbilane synthetase (HMBS), and glycophorin A (GPA). An analysis of distinct signaling pathway activations then revealed an activation of p38 by TNF, as well as a corresponding involvement of this mitogen-activated protein kinase (MAPK) in the cytokine-dependent inhibition of erythroid differentiation. Indeed the p38 inhibitor, SB203580, abrogated the inhibitory effect of TNFalpha on the major erythroid transcription factor GATA-1 as well as erythroid marker expression in Epo-induced TF-1 cells. Overall, these data contribute to a better understanding of cytokine-dependent anemia, by giving first hints about key erythroid transcription factor modulations after TNFalpha treatment as well as an involvement of p38 in the inhibition of erythroid differentiation.
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PMID:Tumor necrosis factor alpha inhibits erythroid differentiation in human erythropoietin-dependent cells involving p38 MAPK pathway, GATA-1 and FOG-1 downregulation and GATA-2 upregulation. 1880 1

Recombinant human erythropoietin (Epo) is used to prevent and treat tumor-related anemia and improve quality of life in cancer patients. Recent evidence suggested that Epo may adversely affect the survival of selected cancer patients by promoting tumor growth, inhibition of apoptosis, and induction of migration. Epo unfolds its effect on the Epo receptor (EpoR). We show--to the best of our knowledge for the first time--significantly increased EpoR expression in clinical melanoma metastases and primary melanomas in comparison with different sets of nevi by quantitative real-time reverse transcriptase-PCR, immunohistochemistry, and western blot analysis. When assessing the functionality of the EpoR-signaling pathway, recombinant human Epo led to the phosphorylation of JAK-2, signal transducers and activators of transcription 3 (STAT3), and ERK1/2 in several of the melanoma cell lines that were analyzed. Besides, Epo counteracted cisplatin-induced cell death in BLM and MV3 cells. Finally, Epo promoted cell migration of MV3 cells, whereas inhibition of the JAK/STAT and ERK1/2 pathways reduced Epo-mediated migration. In summary, we show the overexpression of functional EpoR expression in about half of the analyzed clinical melanoma metastasis specimens and show anti-apoptotic as well as pro-migratory effects of Epo, which is of importance for the treatment of anemia in advanced melanoma.
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PMID:Role of erythropoietin receptor expression in malignant melanoma. 1953 48

Despite the prevalence of anemia in cancer, recombinant erythropoietin (Epo) has declined in use because of recent Phase III trials showing more rapid cancer progression and reduced survival in subjects randomized to Epo. Since Epo receptor (EpoR), Jak2, and Hsp70 are well-characterized mediators of Epo signaling in erythroid cells, we hypothesized that Epo might be especially harmful in patients whose tumors express high levels of these effectors. Because of the insensitivity of immunohistochemistry for detecting low level EpoR protein, we developed assays to measure levels of EpoR, Jak2 and Hsp70 mRNA in formalin-fixed paraffin-embedded (FFPE) tumors. We tested 23 archival breast tumors as well as 136 archival head and neck cancers from ENHANCE, a Phase III trial of 351 patients randomized to Epo versus placebo concomitant with radiotherapy following complete resection, partial resection, or no resection of tumor. EpoR, Jak2, and Hsp70 mRNA levels varied >30-fold, >12-fold, and >13-fold across the breast cancers, and >30-fold, >40-fold, and >30-fold across the head and neck cancers, respectively. Locoregional progression-free survival (LPFS) did not differ among patients whose head and neck cancers expressed above- versus below-median levels of EpoR, Jak2 or Hsp70, except in the subgroup of patients with unresected tumors (n = 28), where above-median EpoR, above-median Jak2, and below-median Hsp70 mRNA levels were all associated with significantly poorer LPFS. Our results provide a framework for exploring the relationship between Epo, cancer progression, and survival using archival tumors from other Phase III clinical trials.
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PMID:Evaluating erythropoietin-associated tumor progression using archival tissues from a phase III clinical trial. 1954 71

Erythropoietin (Epo) may be considered as an endogenous stimulator of vessel growth during tumor progression through an autocrine and/or paracrine loop. The vascular effects of Epo would be relevant in tumor angiogenesis and the negative effect of Epo on tumor growth may be aggravated by its angiogenic activity. The mechanism of tumor growth in the context of Epo is not completely clarified, and it is still not clear whether there is a direct effect of Epo in tumor cells as opposed to exogenous effect on angiogenesis. It is also possible that the effect of Epo is multifactorial depending on the type of tumor and level of functionality of Epo receptor expression in tumor cells, as well other variables such as hypoxic stress, degree of anemia, chemotherapy, radiotherapy of surgical intervention.
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PMID:Erythropoietin and tumor angiogenesis. 1988 90

Erythropoietin (Epo) has been used in the treatment of anemia resulting from numerous etiologies, including renal disease and cancer. However, its effects are controversial and the expression pattern of the Epo receptor (Epo-R) is debated. Using in vivo lineage tracing, we document that within the hematopoietic and mesenchymal lineage, expression of Epo-R is essentially restricted to erythroid lineage cells. As expected, adult mice treated with a clinically relevant dose of Epo had expanded erythropoiesis because of amplification of committed erythroid precursors. Surprisingly, we also found that Epo induced a rapid 26% loss of the trabecular bone volume and impaired B-lymphopoiesis within the bone marrow microenvironment. Despite the loss of trabecular bone, hematopoietic stem cell populations were unaffected. Inhibition of the osteoclast activity with bisphosphonate therapy blocked the Epo-induced bone loss. Intriguingly, bisphosphonate treatment also reduced the magnitude of the erythroid response to Epo. These data demonstrate a previously unrecognized in vivo regulatory network coordinating erythropoiesis, B-lymphopoiesis, and skeletal homeostasis. Importantly, these findings may be relevant to the clinical application of Epo.
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PMID:Erythropoietin couples erythropoiesis, B-lymphopoiesis, and bone homeostasis within the bone marrow microenvironment. 2161 7

Erythropoietin (Epo) is widely used clinically to treat anemia associated with various clinical conditions including cancer. Data from several clinical trials suggest significant adverse effect of Epo treatment on cancer patient survival. However, controversy exists whether Epo receptor (EpoR) is functional in cancer cells. In this study, we demonstrated that EpoR mRNA expression was detectable in 90.1% of 65 melanoma cell lines, and increased copy number of the Epo and EpoR loci occurred in 30 and 24.6% of 130 primary melanomas, respectively. EpoR knockdown in melanoma cells resulted in diminished ERK phosphorylation in response to Epo stimulation, decreased cell proliferation and increased response to the inhibitory effect of hypoxia and cisplatin in vitro. EpoR knockdown significantly decreased melanoma xenograft size and tumor invasion in vivo. On the contrary, constitutive activation of EpoR activated cell proliferation pathways in melanoma cells and resulted in increased cell proliferation and resistance to hypoxia and cisplatin treatment in vitro. EpoR activation resulted in significantly larger xenografts with increased tumor invasion of surrounding tissue in vivo. Daily administration of recombinant Epo fails to stimulate melanoma growth in vivo, but the treatment increased vascular size in the xenografts. Increased local recurrence after excision of the primary tumors was observed after Epo treatment. Epo induced angiogenesis in Matrigel plug assays, and neutralization of Epo secreted by melanoma cells results in decreased angiogenesis. These data support that EpoR is functional in melanoma and EpoR activation may promote melanoma progression, and suggest that Epo may stimulate angiogenesis and increase survival of melanoma cells under hypoxic condition in vivo.
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PMID:Erythropoietin receptor contributes to melanoma cell survival in vivo. 2186 Apr 24

Erythropoietin (Epo) is a critical regulator of erythroid cell proliferation, differentiation and apoptosis. In the form of a recombinant protein, it is widely used to treat various forms of anemia, including that associated with cancer and with the myelosuppressive effects of chemotherapy. Studies of ovarian cancer cell lines have demonstrated the presence of the Epo receptor (EpoR), but there are disagreements regarding its localization and functionality in these cells. Using fluorescence microscopy, we were not able to identify the EpoR on the surface of A2780 cells, in contrast to the positive control K562 cells. Flow cytometry did reveal a weak surface EpoR signal in A2780 cells. Interestingly, most of the EpoR in A2780 cells was found in the cytoplasm, more abundantly as an intracellular membrane-associated protein than a soluble one. Silencing EpoR expression by lentiviral-mediated shRNA resulted in reduced A2780 proliferation as well as reduction in Epo-induced phosphorylation of Erk1/2. Our findings provide important insights into the biology of the EpoR in ovarian cancer cells.
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PMID:Location and the functionality of erythropoietin receptor(s) in A2780 cells. 2255 16

Erythropoietin (Epo) is an essential hormone that binds and activates the Epo receptor (EpoR) resident on the surface of erythroid progenitor cells, thereby promoting erythropoiesis. Recombinant human erythropoietin has been used successfully for over 20 years to treat anemia in millions of patients. In addition to erythropoiesis, Epo has also been reported to have other effects, such as tissue protection and promotion of tumor cell growth or survival. This became of significant concern in 2003, when some clinical trials in cancer patients reported increased tumor progression and worse survival outcomes in patients treated with erythropoiesis-stimulating agents (ESAs). One of the potential mechanisms proffered to explain the observed safety issues was that functional EpoR was expressed in tumors and/or endothelial cells, and that ESAs directly stimulated tumor growth and/or antagonized tumor ablative therapies. Since then, numerous groups have performed further research evaluating this potential mechanism with conflicting data and conclusions. Here, we review the biology of endogenous Epo and EpoR expression and function in erythropoiesis, and evaluate the evidence pertaining to the expression of EpoR on normal nonhematopoietic and tumor cells.
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PMID:The effect of erythropoietin on normal and neoplastic cells. 2284 49

Erythropoietin (Epo) is a low-molecular weight glycoprotein hormone stimulator of erythropoiesis synthesized in the fetal liver and in the adult kidney. Moreover, Epo is a pleiotropic cytokine that exerts diverse biological effects in non-hematopoietic tissues, and angiogenesis is indicated as one of its extra-hematopoietic functions. The involvement of Epo in angiogenesis may be considered as subset of its role in improving overall tissue oxygenation and of its anti-apoptotic role. In this context, Epo may be considered as an endogenous stimulator of vessel growth during tumor progression, and inhibition of Epo signaling might be suggested as a new antiangiogenic therapeutic approach. It is conceivable suppose that the effect of Epo is multifactorial, depending on the type of tumor and level of functionality of Epo receptor expression in tumor cells, as well as on other variables, such as hypoxic stress and degree of anemia.
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PMID:Angiogenic effects of erythropoietin. 2295 4

Lyn is involved in erythropoietin (Epo)-receptor signaling and erythroid homeostasis. Downstream pathways influenced following Lyn activation and their significance to erythropoiesis remain unclear. To address this, we assessed a gain-of-function Lyn mutation (Lyn(up/up)) on erythropoiesis and Epo receptor signaling. Adult Lyn(up/up) mice were anemic, with dysmorphic red cells (spherocyte-like, acanthocytes) in their circulation, indicative of hemolytic anemia and resembling the human disorder chorea acanthocytosis. Heterozygous Lyn(+/up) mice became increasingly anemic with age, indicating that the mutation was dominant. In an attempt to overcome this anemia, extramedullary erythropoiesis was activated. As the mice aged, the levels of different immature erythroid populations changed, indicating compensatory mechanisms to produce more erythrocytes were dynamic. Changes in Epo signaling were observed in Lyn(+/up) erythroid cell lines and primary CD71(+) Lyn(up/up) erythroblasts, including significant alterations to the phosphorylation of Lyn, the Epo receptor, Janus kinase 2, Signal Transducer and Action of Transcription-5, GRB2-associated-binding protein-2, Akt, and Forkhead box O3. As a consequence of altered Lyn signaling, Lyn(+/up) cells remained viable in the absence of Epo but displayed delayed Epo-induced differentiation. These data demonstrate that Lyn gene dosage and activity are critical for normal erythropoiesis; constitutively active Lyn alters Epo signaling, which in turn produces erythroid defects.
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PMID:Gain-of-function Lyn induces anemia: appropriate Lyn activity is essential for normal erythropoiesis and Epo receptor signaling. 2369 55


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