Department of Molecular Medicine II, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
Department of Internal Medicine III, Eberhard-Karls-University of Tübingen, Tübingen, Germany.
Int J Cancer. 2017 Oct 15;141(8):1522-1528. doi: 10.1002/ijc.30800. Epub 2017 Jun 21.
In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis characterized by cell shrinkage and cell membrane scrambling. Eryptotic erythrocytes are rapidly cleared from circulating blood and may adhere to the vascular wall. Stimulation of eryptosis thus impairs microcirculation and leads to anemia as soon as the loss of erythrocytes cannot be fully compensated by enhanced erythropoiesis. Signaling stimulating eryptosis includes increase of cytosolic Ca -activity, ceramide, caspases, calpain, p38-kinase, protein-kinase C, Janus-activated kinase 3, casein-kinase 1α, and cyclin-dependent kinase 4. Eryptosis is inhibited by AMP-activated kinase, p21-activated kinase 2, cGMP-dependent protein-kinase, mitogen- and stress-activated kinase, and sorafenib- and sunitinib-sensitive tyrosine-kinases. Eryptosis is triggered by complement, hyperosmotic shock, energy-depletion, oxidative stress, multiple xenobiotics including diverse cytostatic drugs, diabetes, hepatic failure, iron-deficiency, chronic kidney disease, hemolytic-uremic-syndrome, fever, systemic lupus erythematosus, infections, sepsis, sickle cell anemia, thalassemia, glucose-6-phosphate-dehydrogenase deficiency, and Wilson´s disease. Compelling evidence points to a decisive role of eryptosis in anemia of malignancy. As shown for lung cancer, eryptosis inducing plasma components accumulate in cancer patients and trigger oxidative stress and ceramide. The tumor-induced eryptosis leads to anemia despite increased erythropoiesis. The stimulation of eryptosis in malignancy is compounded by cytostatic treatment, as a large number of cytostatic agents trigger eryptosis. Inhibiting eryptosis may be a useful strategy in reducing tumor-induced anemia and impaired microcirculation. Inhibitors of eryptosis may, however, be harmful, if they similarly interfere with death of tumor cells. Clearly, additional experimental effort is required to achieve killing of tumor cells with simultaneous avoidance of stimulated eryptosis.
类似于有核细胞的细胞凋亡，红细胞可发生红细胞皱缩和细胞膜无序化的红细胞形凋亡。发生红细胞形凋亡的红细胞迅速从循环血液中清除，并可黏附于血管壁。因此，只要红细胞的丢失不能通过增强的红细胞生成得到完全代偿，刺激红细胞形凋亡就会损害微循环并导致贫血。刺激红细胞形凋亡的信号转导包括胞浆 Ca 2+ 活性、神经酰胺、半胱天冬酶、钙蛋白酶、p38-激酶、蛋白激酶 C、Janus 激活激酶 3、酪蛋白激酶 1α和细胞周期蛋白依赖性激酶 4 的增加。AMP 激活的蛋白激酶、p21 激活的蛋白激酶 2、cGMP 依赖性蛋白激酶、有丝分裂原和应激激活的蛋白激酶以及索拉非尼和舒尼替尼敏感的酪氨酸激酶抑制红细胞形凋亡。补体、高渗休克、能量耗竭、氧化应激、多种外源性化合物（包括多种细胞毒性药物）、糖尿病、肝衰竭、缺铁、慢性肾脏病、溶血尿毒综合征、发热、系统性红斑狼疮、感染、败血症、镰状细胞贫血、地中海贫血、葡萄糖-6-磷酸脱氢酶缺乏症和威尔逊病可触发红细胞形凋亡。大量证据表明红细胞形凋亡在恶性肿瘤相关性贫血中起决定性作用。如肺癌所示，诱导红细胞形凋亡的血浆成分在癌症患者中积累，并触发氧化应激和神经酰胺。肿瘤诱导的红细胞形凋亡导致贫血，尽管红细胞生成增加。细胞毒性治疗会加剧恶性肿瘤中的红细胞形凋亡，因为大量细胞毒性药物会触发红细胞形凋亡。抑制红细胞形凋亡可能是减少肿瘤相关性贫血和改善微循环受损的有用策略。然而，如果抑制剂同样干扰肿瘤细胞的死亡，则可能对患者有害。显然，需要进一步的实验努力来实现肿瘤细胞的杀伤，同时避免刺激的红细胞形凋亡。
