Hardee Matthew E, Arcasoy Murat O, Blackwell Kimberly L, Kirkpatrick John P, Dewhirst Mark W
Department of Pathology, Duke University Medical Center, Durham, NC 22710, USA.
Clin Cancer Res. 2006 Jan 15;12(2):332-9. doi: 10.1158/1078-0432.CCR-05-1771.
Erythropoietin (Epo) has long been known to be the principal hematopoietic growth factor that regulates cellular proliferation and differentiation along the erythroid lineage. Recent studies have shown that Epo is a pleiotropic cytokine that is proangiogenic and exerts broad tissue-protective effects in diverse nonhematopoietic organs. Recombinant Epo (rEpo) has been widely used in the clinic to prevent or treat malignancy-associated anemia. A series of clinical trials have documented the efficacy of rEpo in reducing RBC transfusion requirements and improving quality of life in cancer patients, and a recent meta-analysis suggested a positive effect on survival. However, two randomized trials reported negative outcomes with rEpo, as patients in the rEpo arm fared worse than their placebo-treated counterparts with respect to progression-free survival. The expression of Epo receptor (EpoR) in cancer cells has raised the possibility that exogenous rEpo may exert direct effects on tumor cells associated with the potential for stimulation of proliferation, inhibition of apoptosis, or modulation of sensitivity to chemoradiation therapy. The presence of an autocrine-paracrine Epo-EpoR system in tumors and potential effects of Epo on tumor microenvironment and angiogenesis are consistent with a complex biology for Epo-EpoR signaling in cancer that requires further research. This review describes Epo and EpoR biology, focusing on the pleiotropic effects of Epo on nonhematopoietic tissues as well as the expression and function of EpoR in cancer cells.
长期以来，人们一直认为促红细胞生成素（Epo）是调节红系细胞增殖和分化的主要造血生长因子。最近的研究表明，Epo是一种多效细胞因子，具有促血管生成作用，并在多种非造血器官中发挥广泛的组织保护作用。重组促红细胞生成素（rEpo）已在临床上广泛用于预防或治疗恶性肿瘤相关性贫血。一系列临床试验记录了rEpo在减少红细胞输注需求和改善癌症患者生活质量方面的疗效，最近的一项荟萃分析表明其对生存有积极影响。然而，两项随机试验报告了rEpo的负面结果，因为在无进展生存期方面，接受rEpo治疗的患者比接受安慰剂治疗的患者情况更差。癌细胞中促红细胞生成素受体（EpoR）的表达增加了外源性rEpo可能对肿瘤细胞产生直接影响的可能性，这种影响可能与刺激增殖、抑制凋亡或调节对放化疗的敏感性有关。肿瘤中自分泌-旁分泌Epo-EpoR系统的存在以及Epo对肿瘤微环境和血管生成的潜在影响，与癌症中Epo-EpoR信号传导复杂的生物学特性相符，这需要进一步研究。本综述描述了Epo和EpoR的生物学特性，重点关注Epo对非造血组织的多效性作用以及EpoR在癌细胞中的表达和功能。
