Phillips Tiffany M, Kim Kwanghee, Vlashi Erina, McBride William H, Pajonk Frank
Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, 10833 LeConte Ave, Los Angeles, CA 90095-1714, USA.
Neoplasia. 2007 Dec;9(12):1122-9. doi: 10.1593/neo.07694.
Cancer anemia causes fatigue and correlates with poor treatment outcome. Erythropoietin has been introduced in an attempt to correct these defects. However, five recent clinical trials reported a negative impact of erythropoietin on survival and/or tumor control, indicating that experimental evaluation of a possible direct effect of erythropoietin on cancer cells is required. Cancer recurrence is thought to rely on the proliferation of cancer initiating cells (CICs). In breast cancer, CICs can be identified by phenotypic markers and their fate is controlled by the Notch pathway.
In this study, we investigated the effect of erythropoietin on CICs in breast cancer cell lines. Levels of erythropoietin receptor (EpoR), CD24, CD44, Jagged-1 expression, and activation of Notch-1 were assessed by flow cytometry. Self-renewing capacity of CICs was investigated in sphere formation assays.
EpoR expression was found on the surface of CICs. Recombinant human Epo (rhEpo) increased the numbers of CICs and self-renewing capacity in a Notch-dependent fashion by induction of Jagged-1. Inhibitors of the Notch pathway and PI3-kinase blocked both effects.
Erythropoietin functionally affects CICs directly. Our observation may explain the negative impact of recombinant Epo on local control and survival of cancer patients with EpoR-positive tumors.
癌症贫血会导致疲劳,且与治疗效果不佳相关。已引入促红细胞生成素以试图纠正这些缺陷。然而,最近的五项临床试验报告了促红细胞生成素对生存率和/或肿瘤控制的负面影响,这表明需要对促红细胞生成素对癌细胞可能的直接作用进行实验评估。癌症复发被认为依赖于癌症起始细胞(CIC)的增殖。在乳腺癌中,CIC可通过表型标志物来识别,其命运由Notch信号通路控制。
在本研究中,我们调查了促红细胞生成素对乳腺癌细胞系中CIC的影响。通过流式细胞术评估促红细胞生成素受体(EpoR)、CD24、CD44、Jagged-1的表达水平以及Notch-1的激活情况。在成球试验中研究CIC的自我更新能力。
在CIC表面发现了EpoR表达。重组人促红细胞生成素(rhEpo)通过诱导Jagged-1以Notch依赖的方式增加了CIC的数量和自我更新能力。Notch信号通路抑制剂和PI3激酶阻断了这两种作用。
促红细胞生成素直接在功能上影响CIC。我们的观察结果可能解释了重组促红细胞生成素对EpoR阳性肿瘤癌症患者的局部控制和生存率产生负面影响的原因。