The Role of Hepcidin in Anemia of Cancer

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3835-3835
Author(s):  
Seth Rivera ◽  
Airie Kim ◽  
Tomas Ganz
Keyword(s):  
Knockout Mice ◽  
Iron Absorption ◽  
Anemia Of Chronic Disease ◽  
Qrt Pcr ◽  
Syngeneic Mouse ◽  
Induced Tumors ◽  
Syngeneic Mouse Model ◽  
Hepcidin Mrna ◽  
Anemia Of Inflammation

Abstract Anemia is a common occurrence in a wide variety of malignancies. When the anemia is not due to bleeding, bone marrow infiltration or chemotherapy, it is termed anemia of cancer (AC). AC is presumed to be a form of anemia of inflammation (AI, aka anemia of chronic disease). By limiting the availability of iron absorption from diet and release from stores, hepcidin causes AI. To test whether hepcidin contributes to AC, we created two syngeneic mouse models of lung cancer (TC-1 and LLC) and a syngeneic mouse model of melanoma (B16-F10). In all three models, significant anemia developed (Hgb 10.9±2.0, 9.1±2.0, 7.8±2.0 for TC-1, LLC, and B16-F10 vs. 13.7±1.2 for controls; p<0.001 for all compared to controls). There was no evidence of bleeding in the tumors or intraperitoneally. The anemia was microcytic in TC-1 mice but not LLC or B16-F10. Hepcidin mRNA (hepatic production measured by qRT-PCR) was increased in TC-1 mice but not LLC or B16-F10. To test whether hepcidin was necessary for the development of anemia in the TC-1 model, we generated tumors in hepcidin knockout mice. Hgb did not fall significantly in hepcidin knockout mice with TC-1 induced tumors (Hgb 14.5±2.4 vs. 15.5±2.2, p=0.3). CONCLUSIONS: Hepcidin is necessary for the development of AC when hepcidin production is induced by the tumor and microcytosis is present. However, AC is likely a heterogenous disease; experiments are underway to determine whether hepcidin plays a role in cancers that do not upregulate hepcidin production or cause microcytosis.

scholarly journals Unexplained Aspects of Anemia of Inflammation

2010 ◽  
Vol 2010 ◽  
pp. 1-5 ◽  
Author(s):  
Elizabeth A. Price ◽  
Stanley L. Schrier
Keyword(s):  
Inflammatory Diseases ◽  
Deficiency Anemia ◽  
Red Cell ◽  
Regulatory Peptide ◽  
Anemia Of Chronic Disease ◽  
Erythropoietin Production ◽  
Red Cell Survival ◽  
Anemia Of Chronic Inflammation ◽  
Anemia Of Inflammation

Anemia of inflammation (AI), also known as anemia of chronic inflammation or anemia of chronic disease was described over 50 years ago as anemia in association with clinically overt inflammatory disease, and the findings of low plasma iron, decreased bone marrow sideroblasts and increased reticuloendothelial iron. Pathogenic features underlying AI include a mild shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the marrow to erythropoietin, and impaired iron metabolism mediated by inflammatory cytokines and the iron regulatory peptide, hepcidin. Despite marked recent advances in understanding AI, gaps remain, including understanding of the pathogenesis of AI associated with “noninflammatory” or mildly inflammatory diseases, the challenge of excluding iron deficiency anemia in the context of concomitant inflammation, and understanding more precisely the contributory role of hepcidin in the development of AI in human inflammatory diseases.

Hepcidin Contributes to Anemia of Malignancy by Causing Sequestration of Iron in Hepatic Stores.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3197-3197
Author(s):  
Seth Rivera ◽  
Lide Liu ◽  
Elizabeta Nemeth ◽  
Victoria Gabayan ◽  
Tomas Ganz
Keyword(s):  
Serum Iron ◽  
Dry Weight ◽  
Lower Serum ◽  
Anemia Of Chronic Disease ◽  
Liver Iron ◽  
Median Serum ◽  
The Face ◽  
Bone Marrow Iron ◽  
Hepcidin Mrna ◽  
Anemia Of Inflammation

Abstract The iron regulatory hormone hepcidin is presumed to be the central mediator of anemia of inflammation (AI, anemia of chronic disease). Hepcidin is an acute phase protein which restricts iron absorption and release of iron from stores. Patients with hepatic adenomas producing large amounts of hepcidin had severe AI that resolved when the tumors were resected (Weinstein et al, 2002). In order to study the effects of hepcidin in anemia of malignancy, we created tumor xenografts in SCID mice, some of which were engineered to secrete large amounts of hepcidin (33 mice with control tumors, 30 with hepcidin producing tumors). Hepcidin producing tumors expressed 2000-times more hepcidin mRNA which also correlated with increased levels of hepcidin peptide detected in urine of these mice. Mice with hepcidin producing tumors were significantly more anemic (median hemoglobin = 10.4 vs. 8.4 g/dL, p=0.02) and had significantly lower serum iron values (median serum iron = 242 vs. 96 mg/dL, p<0.001). Liver iron was significantly higher in mice with hepcidin producing tumors (mean liver iron 199 vs. 142 mg/100 mg dry weight, p<0.001) even in the face of anemia and hypoferremia. Splenic and bone marrow iron levels were unchanged. Hepcidin contributes to the anemia of malignancy by sequestering iron predominately in hepatic stores, similar to the pattern seen in AI.

scholarly journals The role of blood in early endometrial-peritoneal interactions in a syngeneic mouse model of endometriosis

2010 ◽  
Vol 10 (1) ◽  
pp. 15-20 ◽  
Author(s):  
Ayako Kobayashi ◽  
Masahiko Maegawa ◽  
Satoshi Yamamoto ◽  
Natsuyo Ugumori ◽  
Yuka Kasai ◽  
...  
Keyword(s):  
Mouse Model ◽  
Syngeneic Mouse ◽  
Syngeneic Mouse Model

Targeting Hepcidin with Antisense Oligonucletides Improves Anemia Endpoints in Mice.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 269-269 ◽  
Author(s):  
Jeffrey R. Crosby ◽  
William A. Gaarde ◽  
Jarrett Egerston ◽  
Robert McKay ◽  
Yingqing Sun ◽  
...  
Keyword(s):  
Serum Iron ◽  
Cell Function ◽  
Iron Absorption ◽  
Mrna Levels ◽  
Erythroid Progenitor ◽  
Primary Mouse ◽  
Progenitor Cell Proliferation ◽  
Hepcidin Mrna

Abstract Anemia is one of the more common blood disorders and is associated with a number of diseases, including chronic kidney disease, chronic inflammation, and certain types of cancer. Under these conditions iron is essential as it is required for erythroid progenitor cell proliferation and red cell function. Hepcidin is a liver-derived growth factor that regulates iron absorption in the GI tract and iron absorption and release in tissues. Furthermore, hepcidin overexpression has been strongly linked mechanistically as a mediator of decreased iron availability and anemia. We have utilized an antisense approach to investigate the role of hepcidin in animal models of anemia and as a potential therapeutic approach for the treatment of this disorder in humans. Second-generation 2′-O-methoxyethyl chimeric antisense oligonucleotides (ASOs) were screened in isolated primary mouse hepatocytes, followed by in vivo screening in mice, for the ability to reduce hepcidin mRNA levels. ASO treatment resulted in a reduction of hepcidin mRNA in liver which was associated with a significant increase in serum iron levels. The best hepcidin ASO was then tested in a mouse model of turpentine induced hypoferremia and anemia to determine the role of hepcidin in regulating serum iron and anemia endpoints. Mice were treated (I.P. twice/weekly) with hepcidin or control ASO for two weeks at varying doses prior to a single subcutaneous injection of turpentine. Turpentine treatment 16 hours post-injection produced a significant reduction in serum iron levels and at two weeks resulted in reduced RBC numbers, hematocrit and hemoglobin levels. Treatment with the hepcidin ASO resulted in a dose dependent improvement in all of these endpoints while the control oligonucleotide had no effect. Studies are in progress to further characterize the pharmacological activity of hepcidin ASO in additional models of anemia and results from these on-going studies will also be presented.

IL-6 and Anemia of Inflammation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 144-144 ◽  
Author(s):  
Seth Rivera ◽  
Victoria Gabayan ◽  
Tomas Ganz
Keyword(s):  
Microcytic Anemia ◽  
Anemia Of Chronic Disease ◽  
Iron Restriction ◽  
The Difference ◽  
Acute And Chronic Inflammation ◽  
Hepcidin Mrna ◽  
Deficient Mice ◽  
Anemia Of Inflammation

Abstract BACKGROUND: Anemia of inflammation (AI, anemia of chronic disease) is an iron-restricted anemia caused by hepcidin limiting the supply of iron for erythropoiesis. We had previously shown that IL-6 was necessary for the induction of hepcidin and the development of hypoferremia during acute inflammation in vivo (Nemeth E et al, JCI, 2004). In vitro, IL-1 (Lee P et al, PNAS, 2005) and TGF-β (unpublished data) can also stimulate hepcidin production in primary murine hepatocytes in an IL-6 independent fashion. METHODS: We sought to determine whether IL-6 was necessary for the development of AI using a model of chronic peritonitis in IL-6 deficient mice and wild type (WT) controls. RESULTS: IL-6 deficient mice developed anemia of similar severity as their WT counterparts. WT mice developed microcytic anemia consistent with inflammation-induced iron restriction. In contrast, the inflamed IL-6 deficient mice developed mild macrocytosis indicating markedly different erythrocyte iron metabolism. Hepcidin mRNA increased in WT mice but not IL-6 deficient mice in response to inflammation. CONCLUSION: IL-6 is the principal regulator of hepcidin during acute and chronic inflammation. However, anemia still occurs in the absence of IL-6. The difference in mean corpuscular volume implies that the mechanism of anemia in IL-6 deficient mice is likely different than in WT mice.

The Role of Interleukin-6 and Bone-Marrow Derived Cell Production of Hepcidin In Anemia of Inflammation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 167-167
Author(s):  
Thomas M. Renaud ◽  
Stefano Rivella
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Knockout Mice ◽  
Interleukin 6 ◽  
Wild Type ◽  
Erythroid Progenitor ◽  
Cell Production ◽  
Time Points ◽  
Anemia Of Inflammation

Abstract Abstract 167 Anemia of inflammation is the second most common form of anemia in the general population, and its impact on patient well-being is largely underestimated. Anemia cause by inflammation is multi-factorial and includes hepcidin-induced iron restricted erythropoiesis as well as direct cytokine effects on the bone marrow, erythropoietin production and efficacy, and on the lifespan of red cells. Many murine models of anemia of inflammation are unreliable or cumbersome, but a new model introduced by Sasu et al (Blood, 2010) using a single intraperitoneal injection of heat-killed brucella abortus antigen (HKBA) has proven reproducible and robust. We have used this model to explore the role of interleukin-6 and bone marrow derived cell production of hepcidin in anemia of inflammation (AI). First, we sought to explore the effect this model of AI in wild type mice, iterleukin-6 knockout mice (IL6-KO) and hepcidin knockout mice (Hamp-KO) (n≥15 for each group). We followed these mice for 7 weeks with weekly CBC's to observe the severity and time to recovery from anemia. Wild type mice were most affected 2 weeks after injection and slowly recovered over 7 weeks (HgB at 2 week = 6.4g/dl ± 1.2). IL6-KO mice were equally affected initially, with similar hemoglobin values at 2 weeks (6.9g/dl ± 1.3) and recovered by 6 weeks. Hamp-KO mice were less affected throughout the course of anemia, with hemoglobin values of 10.8g/dl ± 0.7 at 2 weeks with resolution by week 4. IL6-KO mice began to recover more quickly than wild type mice by week three, with hemoglobin values of 10.9g/dl ± 1.5 at that time, compared to wild type mice at 3 weeks with hemoglobin values of 7.4g/dl ± 0.7 (p= 0.0001). We believe that this demonstrates that interleukin-6 and hepcidin do coordinate to contribute to anemia of inflammation, but that there may be independent effects or additional factors. To address these questions, we are currently evaluating iron-related gene expression in these groups of mice as well as evaluating iron stores at multiple time points. We also evaluated serum cytokine levels in each of these groups of mice. We found similar elevations TNF-alpha and interferon gamma in all three groups at 6 and 24 hours. We found similar elevations of IL-6 in wild type and Hamp-KO mice at 6 and 24 hours. Bone marrows and spleens form each group of mice were evaluated at 2 weeks by flow cytometry using ter119 and CD44 to evaluate specific effects on erythroid maturation. This evaluation demonstrated a a profound inhibitory effect on erythropoiesis and, in particular, on the production of erythroid progenitor cells, showing a similar profile by flow cytometry between the three groups. In vitro studies have suggested that macrophage production of hepcidin is important in the development of AI (Theurl et al 2008). We evaluated the importance of bone marrow derived cell production of hepcidin on the development of AI using bone marrow chimeras. Using 600cGy × 2 as a preparative regimen, we transplanted wild type mice with bone marrow from Hamp-KO mice. We also irradiated Hamp-KO mice and transplanted them with wild type marrow. We injected these two groups of mice as well as wild type and Hamp-KO controls, we followed them for a period of 4 weeks with weekly CBC's to evaluate the degree of anemia. Hemoglobin values of wild type mice transplanted with Hamp-KO marrow were statistically indistinguishable from those of non-transplanted wild type mice during the follow-up period (HgB values at 1 week = 6.8g ± 0.7 vs 7.29g ± 1.1; at 2 weeks = 7.3 ± 0.6 vs 6.4 ± 1.2; at 3 weeks = 8.5 ± 1.8 vs 7.4 ± 0.5; at 4 weeks = 9.1 v 1.9 vs 8.6 ± 0.5; p<0.02 for all time points). Hamp-KO mice with wild-type bone marrow were statistically indistinguishable from non-transplanted Hamp-KO mice (Hgb values at 1 week = 9.9 ± 2.4 vs 10.8 ± 0.7; at 2 weeks = 10.6 ± 1.5 vs 10.3 ± 1.0; at 3 weeks = 12.8 ± 1.2 10.8 ± 0.7; at 4 weeks 12.6 ± 1.2 vs. 13.6 ± 1.0; p<0.02 for all time points). This suggests that the production of hepcidin by bone marrow derived cells dose not play a physiologically important role in the development of anemia of inflammation. Disclosures: No relevant conflicts of interest to declare.

Role of the Microenvironment in Tumourigenesis: Focus on Virus-Induced Tumors

2015 ◽  
Vol 22 (8) ◽  
pp. 958-974 ◽  
Author(s):  
Maria Chiantore ◽  
Giorgio Mangino ◽  
Maria Zangrillo ◽  
Marco Iuliano ◽  
Elisabetta Affabris ◽  
...  
Keyword(s):  
Induced Tumors

Overexpression of Pygo2 Increases Differentiation of Human Umbilical Cord Mesenchymal Stem Cells into Cardiomyocyte-like Cells

2020 ◽  
Vol 20 (4) ◽  
pp. 318-324 ◽  
Author(s):  
Lei Yang ◽  
Shuoji Zhu ◽  
Yongqing Li ◽  
Jian Zhuang ◽  
Jimei Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Heart Function ◽  
Critical Role ◽  
Human Umbilical Cord ◽  
Stem Cell Markers ◽  
Quantitative Real Time Pcr ◽  
Qrt Pcr

Background: Our previous studies have shown that Pygo (Pygopus) in Drosophila plays a critical role in adult heart function that is likely conserved in mammals. However, its role in the differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs) into cardiomyocytes remains unknown. Objective: To investigate the role of pygo2 in the differentiation of hUC-MSCs into cardiomyocytes. Methods: Third passage hUC-MSCs were divided into two groups: a p+ group infected with the GV492-pygo2 virus and a p− group infected with the GV492 virus. After infection and 3 or 21 days of incubation, Quantitative real-time PCR (qRT-PCR) was performed to detect pluripotency markers, including OCT-4 and SOX2. Nkx2.5, Gata-4 and cTnT were detected by immunofluorescence at 7, 14 and 21 days post-infection, respectively. Expression of cardiac-related genes—including Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin—were analyzed by qRT-PCR following transfection with the virus at one, two and three weeks. Results : After three days of incubation, there were no significant changes in the expression of the pluripotency stem cell markers OCT-4 and SOX2 in the p+ group hUC-MSCs relative to controls (OCT-4: 1.03 ± 0.096 VS 1, P > 0.05, SOX2: 1.071 ± 0.189 VS 1, P > 0.05); however, after 21 days, significant decreases were observed (OCT-4: 0.164 ± 0.098 VS 1, P < 0.01, SOX2: 0.209 ± 0.109 VS 1, P < 0.001). Seven days following incubation, expression of mesoderm specialisation markers, such as Nkx2.5, Gata-4, MEF2c and KDR, were increased; at 14 days following incubation, expression of cardiac genes, such as Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin, were significantly upregulated in the p+ group relative to the p− group (P < 0.05). Taken together, these findings suggest that overexpression of pygo2 results in more hUCMSCs gradually differentiating into cardiomyocyte-like cells. Conclusion: We are the first to show that overexpression of pygo2 significantly enhances the expression of cardiac-genic genes, including Nkx2.5 and Gata-4, and promotes the differentiation of hUC-MSCs into cardiomyocyte-like cells.

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