Abstract
ObjectivesAnemia is a common complication of malignancy, which could result from either compromised erythropoiesis or decreased lifespan of circulating erythrocytes. Premature suicidal erythrocyte death, characterized by cell shrinkage and phosphatidylserine (PS) externalization, decreases erythrocyte lifespan and could thus cause anemia. Here, we explored whether accelerated eryptosis participates in the pathophysiology of anemia associated with lung cancer (LC) and its treatment.MethodsErythrocytes were drawn from healthy volunteers and LC patients with and without cytostatic treatment. PS exposure (annexin V-binding), cell volume (forward scatter), cytosolic Ca2+ (Fluo3 fluorescence), reactive oxygen species (ROS) production (DCFDA fluorescence) and ceramide formation (anti-ceramide antibody) were determined by flow cytometry.ResultsHemoglobin concentration and hematocrit were significantly lower in LC patients as compared to healthy controls, even though reticulocyte number was higher in LC (3.0±0.6%) than in controls (1.4±0.2%). The percentage of PS-exposing erythrocytes was significantly higher in LC patients with (1.4±0.1%) and without (1.2±0.3%) cytostatic treatment as compared to healthy controls (0.6±0.1%). Erythrocyte ROS production and ceramide abundance, but not Fluo3 fluorescence, were significantly higher in freshly drawn erythrocytes from LC patients than in freshly drawn erythrocytes from healthy controls. PS exposure of erythrocytes drawn from healthy volunteers was significantly more pronounced following incubation in plasma from LC patients than following incubation in plasma from healthy controls.ConclusionAnemia in LC patients with and without cytostatic treatment is paralleled by increased eryptosis, which is triggered, at least in part, by increased oxidative stress and ceramide formation.
Highlights
Anemia is a common clinical condition in malignancy [1], which may result from blood loss [1], impaired erythropoiesis due to inadequate production or efficacy of erythropoietin [2, 3], decreased availability of iron [1, 4, 5] or from decreased life span of circulating erythrocytes [6]
Hemoglobin concentration and hematocrit were significantly lower in lung cancer (LC) patients as compared to healthy controls, even though reticulocyte number was higher in LC (3.0±0.6%) than in controls (1.4±0.2%)
The percentage of PS-exposing erythrocytes was significantly higher in LC patients with (1.4±0.1%) and without (1.2±0.3%) cytostatic treatment as compared to healthy controls (0.6±0.1%)
Summary
Anemia is a common clinical condition in malignancy [1], which may result from blood loss [1], impaired erythropoiesis due to inadequate production or efficacy of erythropoietin [2, 3], decreased availability of iron [1, 4, 5] or from decreased life span of circulating erythrocytes [6]. Phosphatidylserine exposing erythrocytes www.impactjournals.com/oncotarget are recognized by phagocytosing cells, engulfed and cleared from circulating blood [9, 10]. Signaling eventually leading to eryptosis includes oxidative stress [9, 11,12,13], increase of cytosolic Ca2+ activity ([Ca2+]i) [14], ceramide formation [9], energy depletion [15] and caspase activation [9]. Eryptosis may be triggered by activation of casein kinase 1α, CDK4, or p38 kinase and by pharmacological or genetic knockout of AMP-activated kinase AMPK, cGMP-dependent protein kinase as well as sorafenib- and sunitinibsensitive kinases [9]
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