Department of Radiation Oncology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA, 90095-1714, USA.
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Breast Cancer Res. 2019 Jan 30;21(1):17. doi: 10.1186/s13058-019-1100-9.
Cancer is frequently associated with tumor-related anemia, and many chemotherapeutic agents impair hematopoiesis, leading to impaired quality of life for affected patients. The use of erythropoiesis-stimulating agents has come under scrutiny after prospective clinical trials using recombinant erythropoietin to correct anemia reported increased incidence of thromboembolic events and cancer-related deaths. Furthermore, previous preclinical reports indicated expansion of the pool of breast cancer-initiating cells when erythropoietin was combined with ionizing radiation.
Using four established breast cancer cell lines, we test the effects of recombinant human erythropoietin and the number of breast cancer-initiating cells in vitro and in vivo and study if recombinant human erythropoietin promotes the phenotype conversion of non-tumorigenic breast cancer cells into breast cancer-initiating cells. In a prospective study, we evaluate whether elevated endogenous serum erythropoietin levels correlate with increased numbers of tumor-initiating cells in a cohort of breast cancer patients who were scheduled to undergo radiation treatment.
Our results indicate that recombinant erythropoietin increased the number of tumor-initiating cells in established breast cancer lines in vitro. Irradiation of breast cancer xenografts caused a phenotype conversion of non-stem breast cancer cells into induced breast cancer-initiating cells. This effect coincided with re-expression of the pluripotency factors c-Myc, Sox2, and Oct4 and was enhanced by recombinant erythropoietin. Hemoglobin levels were inversely correlated with serum erythropoietin levels, and the latter were correlated with disease stage. However, tumor sections revealed a negative correlation between serum erythropoietin levels and the number of ALDH1A3-positive cells, a marker for breast cancer-initiating cells.
We conclude that physiologically slow-rising serum erythropoietin levels in response to tumor-related or chemotherapy-induced anemia, as opposed to large doses of recombinant erythropoietin, do not increase the pool of breast cancer-initiating cells.
癌症常与肿瘤相关性贫血相关，许多化疗药物会损害造血功能，导致受影响患者的生活质量下降。使用促红细胞生成素刺激剂受到了审查，因为使用重组促红细胞生成素纠正贫血的前瞻性临床试验报告称，血栓栓塞事件和癌症相关死亡的发生率增加。此外，以前的临床前报告表明，当促红细胞生成素与电离辐射联合使用时，乳腺癌起始细胞池会扩大。
我们使用四个已建立的乳腺癌细胞系，在体外和体内测试重组人促红细胞生成素和乳腺癌起始细胞数量的影响，并研究重组人促红细胞生成素是否促进非致瘤性乳腺癌细胞向乳腺癌起始细胞的表型转化。在一项前瞻性研究中，我们评估了在计划接受放射治疗的乳腺癌患者队列中，升高的内源性血清促红细胞生成素水平是否与肿瘤起始细胞数量的增加相关。
我们的结果表明，重组促红细胞生成素在体外增加了已建立的乳腺癌系中的肿瘤起始细胞数量。乳腺癌异种移植的照射导致非干细胞乳腺癌细胞向诱导的乳腺癌起始细胞的表型转化。这种效应与多能因子 c-Myc、Sox2 和 Oct4 的重新表达同时发生，并且受到重组促红细胞生成素的增强。血红蛋白水平与血清促红细胞生成素水平呈负相关，后者与疾病分期相关。然而，肿瘤切片显示血清促红细胞生成素水平与 ALDH1A3 阳性细胞（乳腺癌起始细胞的标志物）的数量之间呈负相关。
我们得出结论，与大剂量重组促红细胞生成素相比，肿瘤相关或化疗诱导性贫血引起的血清促红细胞生成素水平缓慢升高不会增加乳腺癌起始细胞池。
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