Erythropoietin and Breast Cancer Stem Cells

促红细胞生成素和乳腺癌干细胞

• 批准号: 9056545
• 负责人: Frank Pajonk
• 金额: $ 31.96万
• 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 2017-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056545
• 关键词: Address; Adjuvant; Affect; Anemia; Basic Science; Biopsy; Blood specimen; Breast Cancer Cell; Breast Cancer Patient; 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; Homologous Gene; In Vitro; Incidence; Inferior; Ionizing radiation; Lead; Limited Stage; Malignant Neoplasms; Mammospheres; Mastectomy; Mediating; Molecular Profiling; Nature; Neoadjuvant Therapy; Nodal; Oncologist; Outcome; Pathway interactions; Patients; Population; Primary Neoplasm; Process; Publishing; Radiation; Radiation therapy; Recurrence; Recurrent tumor; Research Personnel; S100 Calcium Binding Protein; Sampling; Serum; Signal Transduction; Sorting - Cell Movement; Stem cells; Suspension substance; Suspensions; Testing; Treatment Failure; Treatment outcome; Tumor-Derived; Validation; cancer stem cell; established cell line; genetic signature; genetically modified cells; high risk; imaging system; improved; malignant breast neoplasm; multicatalytic endopeptidase complex; neoplastic cell; novel; outcome forecast; patient population; prevent; prospective; protein B; radiation effect; radioresistant; 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）：本研究探讨了辐射和红细胞生成素（EPO）是否协同改变乳腺癌干细胞（BCSC）的自我更新并重新编程分化分化的乳腺癌（BC）细胞为诱导的乳腺癌干细胞（IBCSC）。使用已建立的细胞系和用于乳腺癌干细胞的独特成像系统，患者衍生的肿瘤样本和接受放射治疗（RT）的BC患者的临床预处理血样（RT），如果EPO直接在辐射的BCSC上作用，是否会改变BCSC NICH，以及哪些途径在辐射诱导的bcsed诱导的BCS中的BCC中，EPO的BCC在BCSC中进行了互动。在一项前瞻性临床研究中，我们将测试，如果高血清EPO水平与乳腺癌手术（BCS）和RT后的高BCSC负担，淋巴结状态和局部控制相关。我们假设，电离辐射将分化的乳腺癌细胞分化为放射性IBCSC，并且内源性EPO随辐射协同以增加BCSCS池，从而损害了放射治疗结果。 有限的BC阶段通常用乳房切除术或BC和RT处理。对于RT，低血红蛋白（HB）水平预测早期治疗失败。尝试使用EPO提高HB水平的尝试导致卑诗省患者的下降，这表明通过EPO受体的信号促进了肿瘤的生长。最近的研究表明，BC在层次上以少量BCSC的形式组织，能够重新生长肿瘤，而其后代缺乏此特征。根据癌症干细胞（CSC）假设，只有在消除所有CSC的情况下才有可能治愈，这表明EPO的有害作用是通过EPO对BCSC的影响介导的。由于BCSC的罕见性质，尚未研究EPO对这些细胞的影响。 BCSC相对放射耐药。此外，肿瘤细胞上的EPOR表达与预后成反比，RHEPO和RT在体外可能通过RT诱导的分化BC细胞重编程到IBCSC中增加了BCSC的数量。该假设将通过1）研究EPO和RT对BCSC的影响，2）探索在重编程过程中激活的途径，以及3）测试是否内源性EPO在临床上影响BCSC。与癌症有关的贫血是癌症患者发病率高的疾病。该建议将研究是否 红细胞生成素激活与辐射协同的途径，以增加耐药BCSC的库，并评估内源性EPO水平是否与BCSC负担和临床结果相关。该提案的长期目标是在哪些情况下研究EPO会干扰BCSC数字和治疗结果。了解这些途径可能会导致新的综合治疗方法，从而改善BC治疗结果。

项目成果

Radiation-induced Notch signaling in breast cancer stem cells.

• DOI: 10.1016/j.ijrobp.2013.06.2064
• 发表时间: 2013-11-01
• 期刊: INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
• 影响因子: 7
• 作者: Lagadec, Chann;Vlashi, Erina;Alhiyari, Yazeed;Phillips, Tiffany M.;Dratver, Milana Bochkur;Pajonk, Frank
• 通讯作者: Pajonk, Frank

Radiation-induced reprogramming of breast cancer cells.

• DOI: 10.1002/stem.1058
• 发表时间: 2012-05
• 期刊: STEM CELLS
• 影响因子: 5.2
• 作者: Lagadec, Chann;Vlashi, Erina;Della Donna, Lorenza;Dekmezian, Carmen;Pajonk, Frank
• 通讯作者: Pajonk, Frank

The metabolic state of cancer stem cells-a valid target for cancer therapy?

癌症干细胞的代谢状态——癌症治疗的有效靶点？

• DOI: 10.1016/j.freeradbiomed.2014.10.732
• 发表时间: 2015
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Vlashi,Erina;Pajonk,Frank
• 通讯作者: Pajonk,Frank

Cancer stem cells, cancer cell plasticity and radiation therapy.

• DOI: 10.1016/j.semcancer.2014.07.001
• 发表时间: 2015-04
• 期刊: Seminars in cancer biology
• 影响因子: 14.5
• 作者: Vlashi E;Pajonk F
• 通讯作者: Pajonk F

Mebendazole Potentiates Radiation Therapy in Triple-Negative Breast Cancer.

• DOI: 10.1016/j.ijrobp.2018.08.046
• 发表时间: 2019-01-01
• 期刊: International journal of radiation oncology, biology, physics
• 作者: Zhang L;Bochkur Dratver M;Yazal T;Dong K;Nguyen A;Yu G;Dao A;Bochkur Dratver M;Duhachek-Muggy S;Bhat K;Alli C;Pajonk F;Vlashi E
• 通讯作者: Vlashi E