Erythropoietin and Breast Cancer Stem Cells

描述（由申请人提供）：本研究探讨放射和促红细胞生成素（Epo）是否协同改变乳腺癌干细胞（BCSCs）的自我更新，并将分化的乳腺癌（BC）细胞重编程为诱导的乳腺癌干细胞（iBCSCs）。利用已建立的细胞系和独特的乳腺癌干细胞成像系统、患者来源的肿瘤样本和接受放射治疗（RT）的BC患者的临床预处理血液样本，研究Epo是否直接作用于受照射的BCSCs，是否改变BCSC的生态系统，以及在Epo存在的情况下，辐射诱导的分化BC细胞重编程过程中参与了哪些途径。在一项前瞻性临床研究中，我们将测试高血清Epo水平是否与保乳手术（BCS）和放疗后的高BCSC负担、淋巴结状态和局部控制相关。我们假设，电离辐射将乳腺癌细胞重编程为放射耐药的iBCSCs，内源性Epo与辐射协同增加BCSCs池，从而损害放射治疗结果。有限期乳腺癌通常通过乳房切除术或BCS和RT进行治疗。对于RT，低血红蛋白（Hb）水平预示着早期治疗失败。试图使用Epo增加Hb水平导致BC患者预后较差，表明通过Epo受体的信号传导促进肿瘤生长。最近的研究表明，bscs是由一小群bscs分层组织的，能够再生肿瘤，而它们的后代缺乏这种特征。根据癌症干细胞（CSC）假说，只有清除所有的CSC才有可能治愈，这表明Epo的有害作用是通过Epo对BCSCs的作用介导的。由于骨髓间充质干细胞的罕见性，Epo对这些细胞的作用尚未被研究。bscs具有相对的抗辐射能力。此外，EpoR在肿瘤细胞上的表达与预后呈负相关，rhEpo和RT可能通过RT诱导分化的BC细胞重编程为iBCSCs而增加体外BCSCs的数量。该假设将通过1)研究Epo和RT对BCSCs的影响，2)探索重编程过程中激活的途径，以及3)测试内源性Epo是否对BCSCs有临床影响来验证。癌症相关性贫血是癌症患者中一种高发的疾病。本提案将对此进行研究

DESCRIPTION (provided by applicant): This study explores if radiation and erythropoietin (Epo) synergize to alter the self-renewal of breast cancer stem cells (BCSCs) and to reprogram differentiated breast cancer (BC) cells into induced breast cancer stem cells (iBCSCs). Using established cell lines and a unique imaging system for breast cancer stem cells, patient-derived tumor samples and clinical pretreatment blood samples of BC patients undergoing radiation treatment (RT) it will explore if Epo acts on irradiated BCSCs directly, if it alters the BCSC nich, and which pathways are engaged during radiation-induced reprogramming of differentiated BC cells in the presence of Epo. In a prospective clinical study we will test, if high serum Epo level correlate with high BCSC burden, nodal status and local control after breast-conserving surgery (BCS) and RT. We hypothesize, that ionizing radiation reprograms differentiated breast cancer cells into radioresistant iBCSCs and that endogenous Epo synergizes with radiation to increase the BCSCs pool, thereby impairing radiation therapy outcome. Limited stage BC is usually treated with mastectomy or BCS and RT. For RT, low hemoglobin (Hb) levels predict early treatment failure. Attempts to increase Hb levels using Epo led to inferior outcome of BC patients, suggesting that signaling through the Epo receptor promotes tumor growth. Recent studies indicate that BCs are organized hierarchically with a small population of BCSCs, capable of re-growing a tumor while their progeny lack this feature. According to the cancer stem cell (CSC) hypothesis, cure is only possible if all CSCs are eliminated, suggesting that the deleterious effects of Epo were mediated by effects of Epo on BCSCs. Because of the rare nature of BCSCs, the effects of Epo on these cells have not been investigated. BCSCs are relatively radioresistant. Furthermore, EpoR expression on tumor cells is inversely correlated with prognosis and rhEpo and RT increases the number of BCSCs in vitro possibly through RT-induced reprogramming of differentiated BC cells into iBCSCs. The hypothesis will be tested by 1) investigating the effects of Epo and RT on BCSCs, 2) exploring the pathways activated during reprogramming, and 3) testing if endogenous Epo affects BCSCs clinically. Cancer-related anemia is a condition with a high incidence in cancer patients. This proposal will study if erythropoietin activates pathways that synergize with radiation to increase the pool of therapy-resistant BCSCs and evaluate if endogenous Epo level correlate with BCSC burden and clinical outcome. The long-term goals of this proposal are to study under which circumstances Epo interferes with BCSC numbers and treatment outcome. Understanding the pathways may lead to novel combined treatments that will improve BC treatment outcome.