ABSTRACT
Disease relapse remains a major factor limiting the survival of cancer patients. In the plasma cell malignancy multiple myeloma (MM), nearly all patients ultimately succumb to disease relapse and progression despite new therapies that have improved remission rates. Tumor regrowth indicates that clonogenic growth potential is continually maintained, but the determinants of self-renewal in MM are not well understood. Normal stem cells are regulated by extrinsic niche factors, and the tumor microenvironment (TME) may similarly influence tumor cell clonogenic growth and self-renewal. Growth differentiation factor 15 (GDF15) is aberrantly secreted by bone marrow stromal cells (BMSCs) in MM. We found that GDF15 is produced by BMSCs after direct contact with plasma cells and enhances the tumor-initiating potential and self-renewal of MM cells in a protein kinase B- and SRY (sex-determining region Y)-box-dependent manner. Moreover, GDF15 induces the expansion of MM tumor-initiating cells (TICs), and changes in the serum levels of GDF15 were associated with changes in the frequency of clonogenic MM cells and the progression-free survival of MM patients. These findings demonstrate that GDF15 plays a critical role in mediating the interaction among mature tumor cells, the TME, and TICs, and strategies targeting GDF15 may affect long-term clinical outcomes in MM.
Subject(s)
Growth Differentiation Factor 15/metabolism , Multiple Myeloma/metabolism , Animals , Cell Line, Tumor , Cell Proliferation , Growth Differentiation Factor 15/blood , Humans , Mice , Mice, Inbred C57BL , Multiple Myeloma/blood , Multiple Myeloma/pathology , Proto-Oncogene Proteins c-akt/metabolism , SOXB1 Transcription Factors/metabolism , Signal TransductionABSTRACT
In thalassemia, deficient globin-chain production during erythropoiesis results in anemia. Thalassemia may be further complicated by iron overload (frequently exacerbated by blood transfusion), which induces numerous endocrine diseases, hepatic cirrhosis, cardiac failure and even death. Accumulation of iron in the absence of blood transfusions may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism. To test this hypothesis, we examined erythroblast transcriptome profiles from 15 healthy, nonthalassemic donors. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-beta superfamily, showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 +/- 50 pg/ml. In comparison, individuals with beta-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 +/- 9,600 pg/ml; range 4,800-248,000 pg/ml; P < 0.05) that were positively correlated with the levels of soluble transferrin receptor, erythropoietin and ferritin. Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. These results suggest that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression.
Subject(s)
Antimicrobial Cationic Peptides/genetics , Cytokines/blood , Gene Expression Regulation , Thalassemia/blood , Thalassemia/genetics , Gene Expression Profiling , Growth Differentiation Factor 15 , Hepcidins , Humans , Polymerase Chain Reaction , RNA, Messenger/genetics , Reference Values , Transcription, GeneticABSTRACT
Major challenges such as nuclease degradation, rapid renal clearance, non-specific delivery, poor cellular uptake and inflammatory response have limited the clinical application of small RNA-mediated gene silencing. To overcome these challenges, we designed a novel targeting small RNA delivery platform comprising of three oligonucleotides: (1) a guide RNA sequence, (2) part of a passenger sequence linked to a DNA aptamer via a PEG linker, and (3) another passenger sequence conjugated to cholesterol, which assemble through complementary base pair annealing. Remarkably, in the presence of magnesium, this molecule self-assembled into a nanoparticle with a hydrophobic cholesterol core, hydrophilic RNA oligonucleotide shell and PEG-linked DNA aptamer flare. The nanoparticles conferred protection to the RNA oligonucleotides against nuclease degradation, which increased bioavailability, and reduced systemic inflammatory responses. The aptamer allowed targeted delivery of RNA therapeutics through cell-specific surface markers, and once inside the cell, the nanoparticles induced lysosomal leakage that released the RNA oligonucleotides into the cytosol to achieve gene silencing. We created a c-Kit-targeting miR-26a delivery particle that specifically accumulated in c-Kit+ breast cancer, significantly increased T cell recruitment, and inhibited tumor growth. Regression of large established tumors were achieved when the nanoparticle was used in combination with anti-CTLA-4 monoclonal antibody.
ABSTRACT
In thalassemia and other iron loading anemias, ineffective erythropoiesis and erythroid signaling molecules are thought to cause inappropriate suppression of a small peptide produced by hepatocytes named hepcidin. Previously, it was reported that the erythrokine GDF15 is expressed at very high levels in thalassemia and suppresses hepcidin expression. In this study, erythroblast expression of a second molecule named twisted gastrulation (TWSG1) was explored as a potential erythroid regulator of hepcidin. Transcriptome analyses suggest TWSG1 is produced during the earlier stages of erythropoiesis. Hepcidin suppression assays demonstrated inhibition by TWSG1 as measured by quantitative polymerase chain reaction (PCR) in dosed assays (1-1000 ng/mL TWSG1). In human cells, TWSG1 suppressed hepcidin indirectly by inhibiting the signaling effects and associated hepcidin up-regulation by bone morphogenic proteins 2 and 4 (BMP2/BMP4). In murine hepatocytes, hepcidin expression was inhibited by murine Twsg1 in the absence of additional BMP. In vivo studies of Twsg1 expression were performed in healthy and thalassemic mice. Twsg1 expression was significantly increased in the spleen, bone marrow, and liver of the thalassemic animals. These data demonstrate that twisted gastrulation protein interferes with BMP-mediated hepcidin expression and may act with GDF15 to dysregulate iron homeostasis in thalassemia syndromes.
Subject(s)
Antimicrobial Cationic Peptides/physiology , Cytokines/physiology , Erythropoiesis/physiology , Proteins/physiology , Animals , Antimicrobial Cationic Peptides/genetics , Bone Morphogenetic Protein 2/physiology , Bone Morphogenetic Protein 4/physiology , Cytokines/genetics , Erythropoiesis/genetics , Female , Growth Differentiation Factor 15/genetics , Growth Differentiation Factor 15/physiology , Hepatocytes/cytology , Hepatocytes/physiology , Hepcidins , Homeostasis , Humans , Iron/metabolism , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Proteins/genetics , Smad Proteins/physiology , Thalassemia/blood , Thalassemia/genetics , Thalassemia/pathology , Thalassemia/physiopathologyABSTRACT
Therapeutic regulation of globin genes is a primary goal of translational research aimed toward hemoglobinopathies. Signal transduction was used to identify chromatin modifications and transcription factor expression patterns that are associated with globin gene regulation. Histone modification and transcriptome profiling were performed using adult primary CD34(+) cells cultured with cytokine combinations that produced low versus high levels of gamma-globin mRNA and fetal hemoglobin (HbF). Embryonic, fetal, and adult globin transcript and protein expression patterns were determined for comparison. Chromatin immunoprecipitation assays revealed RNA polymerase II occupancy and histone tail modifications consistent with transcriptional activation only in the high-HbF culture condition. Transcriptome profiling studies demonstrated reproducible changes in expression of nuclear transcription factors associated with high HbF. Among the 13 genes that demonstrated differential transcript levels, 8 demonstrated nuclear protein expression levels that were significantly changed by cytokine signal transduction. Five of the 8 genes are recognized regulators of erythropoiesis or globin genes (MAFF, ID2, HHEX, SOX6, and EGR1). Thus, cytokine-mediated signal transduction in adult erythroid cells causes significant changes in the pattern of globin gene and protein expression that are associated with distinct histone modifications as well as nuclear reprogramming of erythroid transcription factors.
Subject(s)
Cytokines/metabolism , Erythroid Cells/metabolism , Fetal Hemoglobin/biosynthesis , Histones/metabolism , Protein Processing, Post-Translational , Transcription Factors/metabolism , Adult , Antigens, CD34 , Cells, Cultured , Erythroid Cells/cytology , Gene Expression Profiling , Gene Expression Regulation , Hemoglobinopathies/metabolism , Humans , RNA Polymerase II/metabolism , Signal Transduction , Transcription, GeneticABSTRACT
PURPOSE OF REVIEW: Growth differentiation factor 15 (GDF15) was identified as a hepcidin-suppression factor that is expressed at high levels in patients with ineffective erythropoiesis. This review addresses the regulation, expression and potential functions of GDF15 in the context of erythroid biology. RECENT FINDINGS: GDF15 expression during late erythroid differentiation was discovered as part of an erythroblast transcriptome project. As GDF15 expression is associated with cellular stress or apoptosis, further investigation of the cytokine was focused upon its involvement in ineffective erythropoiesis. Remarkably high serum levels were detected in patients with thalassemia syndromes, congenital dyserythropoiesis and some acquired sideroblastic anemias. High-level GDF15 expression is not a feature of normal erythropoiesis, or erythroid recovery after bone-marrow transplantation. As GDF15 is a transforming growth factor-beta superfamily member, it was investigated as an effector of ineffective erythropoiesis that suppresses hepcidin expression despite iron overloading. SUMMARY: In contrast to the low levels of GDF15 expressed during normal erythropoiesis, ineffective erythropoiesis causes high-level expression of GDF15. In patients with thalassemia and related anemias, GDF15 expression may contribute to iron overloading or other features of the disease phenotype.
Subject(s)
Anemia/metabolism , Erythropoiesis/physiology , Growth Differentiation Factor 15/metabolism , Iron Overload/metabolism , Thalassemia/metabolism , Anemia/pathology , Animals , Humans , Iron Overload/pathology , Thalassemia/pathologyABSTRACT
Congenital dyserythropoietic anemia (CDA) is a rare group of red blood cell disorders characterized by ineffective erythropoiesis and increased iron absorption. To determine whether growth differentation factor 15 (GDF15) hyper-expression is associated with the ineffective erythropoiesis and iron-loading complications of CDA type I (CDA I), GDF15 levels and other markers of erythropoiesis and iron overload were studied in blood from 17 CDA I patients. Significantly higher levels of GDF15 were detected among the CDA I patients (10 239 +/- 3049 pg/mL) compared with healthy volunteers (269 +/- 238 pg/mL). In addition, GDF15 correlated significantly with several erythropoietic and iron parameters including Hepcidin-25, Ferritin, and Hepcidin-25/Ferritin ratios. These novel results suggest that CDA I patients express very high levels of serum GDF15, and that GDF15 contributes to the inappropriate suppression of hepcidin with subsequent secondary hemochromatosis.
Subject(s)
Anemia, Dyserythropoietic, Congenital/etiology , Growth Differentiation Factor 15/blood , Antimicrobial Cationic Peptides/blood , Biomarkers/blood , Case-Control Studies , Erythropoiesis , Female , Ferritins/blood , Hepcidins , Humans , Iron/metabolism , Iron Overload , Israel , MaleABSTRACT
BACKGROUND: Low serum hepcidin levels provide a physiologic response to iron demand in patients with iron deficiency (ID). Based on a discovery of suppressed hepcidin expression by a cytokine named growth differentiation factor 15 (GDF15), it was hypothesized that GDF15 may suppress hepcidin expression in humans with ID due to blood loss. STUDY DESIGN AND METHODS: To test this hypothesis, GDF15 and hepcidin levels were measured in peripheral blood from subjects with iron-deficient erythropoiesis before and after iron supplementation. RESULTS: Iron variables and hepcidin levels were significantly suppressed in iron-deficient blood donors compared to healthy volunteers. However, ID was not associated with elevated serum levels of GDF15. Instead, iron-deficient subjects' GDF15 levels were slightly lower than those measured in the control group of subjects (307 +/- 90 and 386 +/- 104 pg/mL, respectively). Additionally, GDF15 levels were not significantly altered by iron repletion. CONCLUSIONS: ID due to blood loss is not associated with a significant change in serum levels of GDF15.
Subject(s)
Blood Donors , Growth Differentiation Factor 15/blood , Iron Deficiencies , Antimicrobial Cationic Peptides/analysis , Ferritins/blood , Hepcidins , Humans , Transferrin/analysisABSTRACT
Crosstalk between malignant and neighboring cells contributes to tumor growth. In East Asia, infection with the liver fluke is a major risk factor for cholangiocarcinoma (CCA). The liver fluke Opisthorchis viverrini secretes a growth factor termed liver fluke granulin, a homologue of the human progranulin, which contributes significantly to biliary tract fibrosis and morbidity. Here, extracellular vesicle (EV)-mediated transfer of mRNAs from human cholangiocytes to naïve recipient cells was investigated following exposure to liver fluke granulin. To minimize the influence of endogenous progranulin, its cognate gene was inactivated using CRISPR/Cas9-based gene knock-out. Several progranulin-depleted cell lines, termed ΔhuPGRN-H69, were established. These lines exhibited >80% reductions in levels of specific transcript and progranulin, both in gene-edited cells and within EVs released by these cells. Profiles of extracellular vesicle RNAs (evRNA) from ΔhuPGRN-H69 for CCA-associated characteristics revealed a paucity of transcripts for estrogen- and Wnt-signaling pathways, peptidase inhibitors and tyrosine phosphatase related to cellular processes including oncogenic transformation. Several CCA-specific evRNAs including MAPK/AKT pathway members were induced by exposure to liver fluke granulin. By comparison, estrogen, Wnt/PI3K and TGF signaling and other CCA pathway mRNAs were upregulated in wild type H69 cells exposed to liver fluke granulin. Of these, CCA-associated evRNAs modified the CCA microenvironment in naïve cells co-cultured with EVs from ΔhuPGRN-H69 cells exposed to liver fluke granulin, and induced translation of MAPK phosphorylation related-protein in naïve recipient cells in comparison with control recipient cells. Exosome-mediated crosstalk in response to liver fluke granulin promoted a CCA-specific program through MAPK pathway which, in turn, established a CCA-conducive disposition.
Subject(s)
Bile Duct Neoplasms/pathology , Cholangiocarcinoma/pathology , Granulins/metabolism , Opisthorchis/metabolism , Animals , Bile Duct Neoplasms/genetics , Bile Ducts/cytology , Cell Line , Cell Proliferation/drug effects , Cell Proliferation/genetics , Cell Transformation, Neoplastic/pathology , Cholangiocarcinoma/genetics , Clustered Regularly Interspaced Short Palindromic Repeats , Extracellular Vesicles/metabolism , Gene Expression Regulation, Neoplastic , Granulins/toxicity , Mutation , Opisthorchis/pathogenicity , Progranulins/genetics , Progranulins/metabolism , Progranulins/pharmacology , RNA, Messenger/metabolism , Tumor MicroenvironmentABSTRACT
CRISPR/Cas9-based genome editing has yet to be reported in species of the Platyhelminthes. We tested this approach by targeting omega-1 (ω1) of Schistosoma mansoni as proof of principle. This secreted ribonuclease is crucial for Th2 polarization and granuloma formation. Schistosome eggs were exposed to Cas9 complexed with guide RNA complementary to ω1 by electroporation or by transduction with lentiviral particles. Some eggs were also transfected with a single stranded donor template. Sequences of amplicons from gene-edited parasites exhibited Cas9-catalyzed mutations including homology directed repaired alleles, and other analyses revealed depletion of ω1 transcripts and the ribonuclease. Gene-edited eggs failed to polarize Th2 cytokine responses in macrophage/T-cell co-cultures, while the volume of pulmonary granulomas surrounding ω1-mutated eggs following tail-vein injection into mice was vastly reduced. Knock-out of ω1 and the diminished levels of these cytokines following exposure showcase the novel application of programmed gene editing for functional genomics in schistosomes.
Subject(s)
Gene Editing , Ribonucleases/genetics , Schistosoma mansoni/enzymology , Schistosoma mansoni/genetics , Animals , Base Sequence , CRISPR-Cas Systems/genetics , Cell Line , Chromosomes/genetics , DNA Repair/genetics , Exons/genetics , Gene Expression Regulation , Genetic Loci , Granuloma/pathology , Homologous Recombination/genetics , Humans , Inflammation/pathology , Lung/parasitology , Lung/pathology , Mice , Mutation/genetics , Ovum/enzymology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Th2 Cells/immunology , TransgenesABSTRACT
Three slit genes, slit1 to slit3, have been cloned to date. Slit1 and slit2 act as chemorepellent factors for axon guidance. Slit3 is involved in the formation of the diaphragm and kidney during embryogenesis. However, its molecular function remains unclear. We found that slit3 expression was induced by lipopolysaccharide (LPS)-stimulation in macrophages and that it was localized in the mitochondria and along the plasma membrane. Silencing of slit3 expression by RNA interference reduced cell motility and Rac/Cdc42 activation. These results suggest that slit3 functions as an intracellular signaling molecule for cell motility as part of the LPS-induced signaling cascade.
Subject(s)
Lipopolysaccharides/pharmacology , Macrophages/drug effects , Macrophages/physiology , Membrane Proteins/physiology , cdc42 GTP-Binding Protein/metabolism , rac GTP-Binding Proteins/metabolism , Animals , Base Sequence , Cell Line , Cell Movement/drug effects , Cell Movement/physiology , Cells, Cultured , DNA Primers/genetics , Membrane Proteins/genetics , Mice , RNA, Messenger/genetics , RNA, Messenger/metabolism , Subcellular Fractions/metabolismABSTRACT
The efficacy of traditional chemotherapy is limited by its toxicity, especially with regard to hematopoiesis. Here we show that miR-26a plays a critical role in protecting mice against chemotherapy-induced myeloid suppression by targeting a proapoptotic protein (Bak1) in hematopoietic stem/progenitor cells (HSPCs). Because c-Kit is expressed at high levels in HSPCs, we designed a microRNA-aptamer chimera that contains miR-26a mimic and c-Kit-targeting aptamer and successfully delivered miR-26a into HSPCs to attenuate toxicity of 5' fluorouracil (5-FU) and carboplatin. Meanwhile, our in silico analysis revealed widespread and prognosis-associated downregulation of miR-26a in advanced breast cancer and also showed that KIT is overexpressed among basal-like breast cancer cells and that such expression is associated with poor prognosis. Importantly, the miR-26a aptamer effectively repressed tumor growth in vivo and synergized with 5-FU or carboplatin in cancer therapy in the mouse breast cancer models. Thus, targeted delivery of miR-26a suppresses tumor growth while protecting the host against myelosuppression by chemotherapy.
ABSTRACT
Slit, a secreted protein, functions as a chemorepellent factor in axon guidance and neuronal migration and as an inhibitor in leukocyte chemotaxis. In humans, slit2 protein attracts endothelial cells and promotes tube formation in the tumor angiogenic mechanism. In this study, we cloned a part of the canine slit subfamily and examined the expression of slit subfamily mRNAs in 3 normal canine mammary glands and 11 mammary tumor samples by RT-PCR. The cloned part of the slit gene sequences showed high similarity to those of the human, mouse, and rat. The mRNAs were expressed at low levels in the normal mammary gland. The expression levels of slit1 mRNA were low in both the normal and tumor tissues. In contrast, the expression of slit2 mRNA increased in most of the malignant mammary tumors, and an increase in slit3 mRNA expression was observed in 2 of the malignant mixed tumors. These results suggest that the expression of slit2 plays an important role in tumor angiogenesis in canine mammary gland tumors and that slit2 can be a putative marker for malignancy diagnosis of these tumors.
Subject(s)
Dog Diseases/metabolism , Gene Expression , Glycoproteins/metabolism , Mammary Neoplasms, Animal/metabolism , Nerve Tissue Proteins/metabolism , RNA, Messenger/metabolism , Animals , Base Sequence , Cloning, Molecular , DNA Primers , Dog Diseases/genetics , Dogs , Mammary Neoplasms, Animal/genetics , Molecular Sequence Data , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNASubject(s)
Erythropoiesis , Gene Expression , Growth Differentiation Factor 15/metabolism , Hematologic Diseases/blood , Hematologic Diseases/genetics , Iron Overload/blood , Iron Overload/genetics , Antimicrobial Cationic Peptides/metabolism , Erythroblasts/metabolism , Erythropoiesis/physiology , Growth Differentiation Factor 15/physiology , Hepcidins , Humans , Iron/metabolism , Liver/metabolism , Proteins/metabolism , Proteins/physiologyABSTRACT
Slits are large molecular and extracellular glycoproteins that may function as chemorepellents in axon guidance and neural cell migration. The heterogeneity of the mRNA for slit has been described. Its variants indicate considerable potential for alternative splicing, resulting in the generation of multiple protein isoforms. We examined the regions in which these isoforms are expressed, and identified the highest expression of a splicing product for slit1 in rat brain rather than in other organs. The splicing product, Slit1alpha, arises through alternative splicing at the C-terminus of Slit1, causing defects in the cysteine knot domain. We show that slit1alpha exists in the hippocampus and cerebral cortex in rat brain by in situ hybridization, and that it acts as a chemorepellent in olfactory bulb axon guidance in vitro. These findings suggest that Slit1alpha is an active Slit1 protein specific in the vertebrate nervous system.
Subject(s)
Alternative Splicing , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/physiology , Animals , Brain/metabolism , COS Cells , Chlorocebus aethiops , Gene Expression , Genetic Variation , Protein Isoforms/genetics , Protein Isoforms/physiology , RNA, Messenger/genetics , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
The Hedgehog (Hh) signaling pathway is aberrantly activated in a wide variety of human cancers, and recent clinical studies have demonstrated that pathway inhibitors are effective in advanced basal cell carcinoma (BCC). The majority of these agents have been designed to target SMOOTHENED (SMO), a transmembrane regulator of Hh signaling, but subsequent mutations in SMO have been found to generate drug resistance. In other cancers, oncogenic events that bypass SMO may activate canonical Hh signaling, and SMO antagonists have not demonstrated significant activity in several diseases. Therefore, alternative strategies targeting the Hh pathway downstream of SMO may have clinical utility. Liver X receptors (LXR) regulate cholesterol and fatty acid homeostasis, and LXR activation can inhibit the Hh pathway in normal mouse embryonic fibroblasts. We examined the effects of LXR activation on Hh signaling in human multiple myeloma cells and found that LXR agonists inhibited Hh pathway activity and clonogenic tumor growth in vitro. LXR activation also inhibited putative multiple myeloma cancer stem cells in vivo leading to the loss of tumor initiating and self-renewal potential. Finally, Hh signaling was inhibited downstream of SMO, suggesting that LXR agonists may represent a novel strategy to target pathogenic Hh signaling as well as treat multiple myeloma.
Subject(s)
Hedgehog Proteins/antagonists & inhibitors , Hydrocarbons, Fluorinated/pharmacology , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Orphan Nuclear Receptors/agonists , Sulfonamides/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/physiology , Cell Survival/physiology , Clone Cells , Humans , Liver X Receptors , Mice , Mice, Inbred NOD , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Orphan Nuclear Receptors/genetics , Orphan Nuclear Receptors/metabolism , Signal Transduction/drug effects , TransfectionABSTRACT
The bis-benzylidine piperidone RA190 covalently binds to cysteine 88 of ubiquitin receptor RPN13 in the 19S regulatory particle and inhibits proteasome function, triggering rapid accumulation of polyubiquitinated proteins. Multiple myeloma (MM) lines, even those resistant to bortezomib, were sensitive to RA190 via endoplasmic reticulum stress-related apoptosis. RA190 stabilized targets of human papillomavirus (HPV) E6 oncoprotein, and preferentially killed HPV-transformed cells. After oral or intraperitoneal dosing of mice, RA190 distributed to plasma and major organs except the brain and inhibited proteasome function in skin and muscle. RA190 administration profoundly reduced growth of MM and ovarian cancer xenografts, and oral RA190 treatment retarded HPV16(+) syngeneic mouse tumor growth, without affecting spontaneous HPV-specific CD8(+) T cell responses, suggesting its therapeutic potential.
Subject(s)
Membrane Glycoproteins/antagonists & inhibitors , Neoplasms/drug therapy , Piperidones/pharmacology , Proteasome Inhibitors/pharmacology , Animals , Boronic Acids/pharmacology , Bortezomib , Cell Line, Tumor , Endoplasmic Reticulum Stress , Female , Genes, p53 , Humans , Intracellular Signaling Peptides and Proteins , Membrane Glycoproteins/chemistry , Membrane Glycoproteins/physiology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neoplasms/pathology , Proteasome Inhibitors/pharmacokinetics , Pyrazines/pharmacology , UbiquitinationABSTRACT
In many human cancers, tumorigenic potential is not equally shared by all cells but is restricted to phenotypically distinct subpopulations termed cancer stem cells. Cancer stem cells are also capable of both self-renewal and differentiation, and these functional properties have been suggested to play major roles in tumor initiation and progression. The factors responsible for the development of cancer stem cells and their subsequent regulation are unclear, but several chronic inflammatory states have been associated with an increased risk of malignancy. Therefore, it is possible that specific processes associated with chronic inflammation, as well as the adaptation to cellular stress, regulate cancer stem cells. Several factors associated with chronic inflammation, including cytokines, oxidative stress, and hypoxia, induce the activation of specific cellular response programs that can affect the survival, proliferation, metabolism, and differentiation of cancer cells, as well as the self-renewal and quiescence of normal stem cells. In this review, we discuss how these adaptive processes potentially become subverted to enhance the development and function of cancer stem cells.
Subject(s)
Inflammation/pathology , Neoplastic Stem Cells/pathology , Chronic Disease , Humans , Oxidative Stress , Regeneration , Wound HealingABSTRACT
Erythropoiesis describes the hematopoietic process of cell proliferation and differentiation that results in the production of mature circulating erythrocytes. Adult humans produce 200 billion erythrocytes daily, and approximately 1 billion iron molecules are incorporated into the hemoglobin contained within each erythrocyte. Thus, iron usage for the hemoglobin production is a primary regulator of plasma iron supply and demand. In many anemias, additional sources of iron from diet and tissue stores are needed to meet the erythroid demand. Among a subset of anemias that arise from ineffective erythropoiesis, iron absorption and accumulation in the tissues increases to levels that are in excess of erythropoiesis demand even in the absence of transfusion. The mechanisms responsible for iron overloading due to ineffective erythropoiesis are not fully understood. Based upon data that is currently available, it is proposed in this review that loading and overloading of iron can be regulated by distinct or combined mechanisms associated with erythropoiesis. The concept of erythroid regulation of iron is broadened to include both physiological and pathological hepcidin suppression in cases of ineffective erythropoiesis.