Erythropoietin and Breast Cancer Stem Cells

促红细胞生成素和乳腺癌干细胞

• 批准号: 8507626
• 负责人: Frank Pajonk
• 金额: $ 30.04万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507626
• 关键词: Address; Adjuvant; Affect; Anemia; Basic Science; Biopsy; Blood specimen; Breast Cancer Cell; Breast Cancer Treatment; Breast-Conserving Surgery; Cancer Patient; Cell Count; Cells; Clinical; Clinical Research; Collagen Type II; Combined Modality Therapy; Data; Deltex Homolog 1; Early treatment; Ensure; Erythropoietin; Erythropoietin Receptor; Excision; Experimental Models; Frequencies; Funding; Gene Expression; Generations; Genes; Goals; Hemoglobin concentration result; Image; In Vitro; Incidence; Inferior; Ionizing radiation; Lead; Limited Stage; Malignant Neoplasms; Mastectomy; Mediating; Metabolic; Molecular Profiling; Nature; Neoadjuvant Therapy; Nodal; Oncologist; Outcome; Pathway interactions; Patient Recruitments; Patients; Polyploidy; Population; Primary Neoplasm; Process; Publishing; Radiation; Radiation therapy; Recurrence; Recurrent tumor; Research Personnel; Role; S100 Calcium Binding Protein; Sampling; Serum; Signal Transduction; Sorting - Cell Movement; Stem cells; Suspension substance; Suspensions; System; Testing; Time; Treatment Failure; Treatment outcome; Tumor-Derived; Validation; cancer stem cell; established cell line; genetically modified cells; high risk; human PARD6A protein; improved; in vivo; malignant breast neoplasm; multicatalytic endopeptidase complex; neoplastic cell; novel; outcome forecast; patient population; prevent; prospective; protein B; radiation effect; research study; self-renewal; stem cell population; therapy outcome; therapy resistant; tool; transcription factor; tumor; tumor growth

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.

描述（由申请人提供）：本研究探讨辐射和促红细胞生成素 (Epo) 是否协同作用以改变乳腺癌干细胞 (BCSC) 的自我更新并将分化的乳腺癌 (BC) 细胞重新编程为诱导乳腺癌干细胞 (iBCSC) ）。使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，将探索 Epo 是否直接作用于受辐射的 BCSC，是否会改变 BCSC在 Epo 存在的情况下，辐射诱导分化 BC 细胞重编程过程中涉及哪些途径。在一项前瞻性临床研究中，我们将测试高血清 Epo 水平是否与高 BCSC 负荷、淋巴结状态和保乳手术 (BCS) 和 RT 后的局部控制相关。我们假设，电离辐射将分化的乳腺癌细胞重新编程为抗辐射的 iBCSC，并且内源性 Epo 与辐射协同作用以增加 BCSC 池，从而损害放射治疗结果。 有限期 BC 通常采用乳房切除术或 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。使用 Epo 增加 Hb 水平的尝试导致 BC 患者的预后较差，这表明通过 Epo 受体的信号传导促进肿瘤生长。最近的研究表明，BCs 是分层组织的，其中有一小部分 BCSCs 能够重新生长肿瘤，而它们的后代则缺乏这种功能。根据癌症干细胞 (CSC) 假说，只有消除所有 CSC，才有可能治愈，这表明 Epo 的有害作用是由 Epo 对 BCSC 的作用介导的。由于 BCSC 的稀有性，Epo 对这些细胞的影响尚未得到研究。 BCSC 具有相对抗辐射性。此外，肿瘤细胞上的 EpoR 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 iBCSC 来增加体外 BCSC 的数量。该假设将通过以下方式进行检验：1) 研究 Epo 和 RT 对 BCSC 的影响，2) 探索重编程过程中激活的途径，3) 测试内源性 Epo 是否在临床上影响 BCSC。癌症相关性贫血是癌症患者中发病率较高的疾病。该提案将研究是否 促红细胞生成素激活与放射协同作用的途径，以增加治疗耐药 BCSC 的数量，并评估内源性 Epo 水平是否与 BCSC 负荷和临床结果相关。该提案的长期目标是研究在什么情况下 Epo 会干扰 BCSC 数量和治疗结果。了解这些途径可能会导致新的联合治疗，从而改善 BC 的治疗结果。