Enhanced eryptosis contributes to anemia in lung cancer patients

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.

Inhibition of Suicidal Erythrocyte Death by Reversine

“…Enhanced eryptosis is observed in diverse clinical conditions including iron deficiency [33], dehydration [92], hyperphosphatemia [93], vitamin D excess [94], chronic kidney disease (CKD) [95-100], hemolytic-uremic syndrome [101], diabetes [102], hepatic failure [103, 104], malignancy [33, 105, 106], sepsis [107], sickle-cell disease [33], beta-thalassemia [33], Hb-C and G6PD-deficiency [33], as well as Wilson´s disease [107]. The enhanced eryptosis leads to rapid clearance of the phosphatidylserine exposing erythrocytes from circulating blood [33].…”

Diffusely Increased Splenic Fluorodeoxyglucose Uptake in Lung Cancer Patients

“…Extramedullary hematopoiesis is active, especially in the fetal life, but can also be activated during chronic anemic processes [2]. The impaired erythropoietin production in cancer patients who have anemia may be partly because of the production of inflammatory cytokines in response to the tumor [7,8]. Such cytokines also could distort the ability of BM to respond the circulating erythropoietin.…”

Stimulation of Eryptosis by Afatinib

“…Several substances inhibit eryptosis [113][114][115][116]. Enhanced eryptosis is observed in diverse clinical conditions including iron deficiency [58], vitamin D excess [117], chronic kidney disease (CKD) [118][119][120][121][122][123], hemolytic-uremic syndrome [124], autoimmune hemolytic anemia [125], diabetes [126], hypertension and dyslipidemia [127], hepatic failure [128], malignancy [129][130][131], arteritis [132], systemic lupus erythematosus [133], sepsis [134,135], malaria [58,136,137], sicklecell disease [58], beta-thalassemia [58], Hb-C and G6PD-deficiency [58], Wilsons disease [134], as well as advanced age [138]. Eryptosis further increases following storage for transfusion [67,68,83,139] and is enhanced in erythrocytes from newborns exposed to oxidative stress [58,140].…”