Pediatric tumor cells express erythropoietin and a functional erythropoietin receptor that promotes angiogenesis and tumor cell survival
Pediatric tumor cells express erythropoietin and a functional erythropoietin receptor that promotes angiogenesis and tumor cell survival
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DOI：
10.1097/01.lab.0000090156.94795.48
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发表时间：
2003-10-01
影响因子：
5
通讯作者：
Malik, P
中科院分区：
文献类型：
--
作者：
Batra, S;Perelman, N;Malik, P
促红细胞生成素传统上被认为是红细胞限制性细胞因子，但最近的证据表明，它在非造血组织，特别是在神经发育中发挥更广泛的作用。儿童实体瘤大多起源于发育，超过50%的实体瘤起源于神经。我们发现促红细胞生成素受体和促红细胞生成素在常见的儿科肿瘤细胞中表达：神经母细胞瘤、尤文氏肉瘤家族肿瘤、儿科脑肿瘤（成神经管细胞瘤、星形细胞瘤和室管膜瘤）、肾母细胞瘤、横纹肌肉瘤和肝母细胞瘤（n = 24），以及来自其中一些肿瘤的细胞系（n = 25）。促红细胞生成素在肿瘤细胞系中的表达是缺氧诱导的。在表达促红细胞生成素受体的肿瘤细胞系中加入外源性促红细胞生成素可增加核因子κ B的核DNA结合活性，并增加抗凋亡基因bcl-1、bcl-xL和mcl-1的表达。此外，外源性促红细胞生成素增加肿瘤细胞系的血管生成生长因子、血管内皮生长因子或胎盘生长因子的产生和分泌，从而促进内皮细胞增殖和趋化性。促红细胞生成素受体表达促进肿瘤细胞存活和释放血管生成生长因子在儿科肿瘤中以前没有描述。因此，在儿科肿瘤的异种移植模型中，需要在体内仔细评估促红细胞生成素的影响，然后在患有癌症的儿科患者中进行评估。
Erythropoietin was traditionally considered an erythroid-restricted cytokine, but recent evidence indicates a broader role for it in nonhematopoietic tissues, specifically in neural development. Pediatric solid tumors are mostly developmental in origin, and more than 50% of the solid tumors are neural in origin. We found erythropoietin receptor and erythropoietin expression in common pediatric tumor cells: neuroblastomas, Ewing's sarcoma family of tumors, pediatric brain tumors (medulloblastoma, astrocytoma, and ependymoma), Wilms tumors, rhabdomyosarcomas, and hepatoblastomas (n = 24), and in cell lines derived from some of these tumors (n = 25). Expression of erythropoietin in tumor cell lines was hypoxia-inducible. Addition of exogenous erythropoietin to tumor cell lines expressing erythropoietin receptor increased nuclear DNA binding activity of nuclear factor kappa B and increased the expression of the antiapoptotic genes bcl-1, bcl-xL, and mcl-1. Additionally, exogenous erythropoietin increased production and secretion of angiogenic growth factors, vascular endothelial growth factor, or placenta growth factor from the tumor cell lines, which promoted endothelial cell proliferation and chemotaxis. Erythropoietin receptor expression that promotes tumor cell survival and releases angiogenic growth factors in pediatric tumors has not been previously described. Therefore, a careful evaluation of the impact of erythropoietin is warranted in vivo, in xenograft models of pediatric tumors, followed by evaluation in pediatric patients with cancer.