Ceramide glycosylation determines the stemness of cancer stem cells

神经酰胺糖基化决定癌症干细胞的干性

• 批准号: 8497011
• 负责人: Yong-Yu Liu
• 金额: $ 41.34万
• 依托单位: UNIVERSITY OF LOUISIANA AT MONROE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8497011
• 关键词: Adverse effects; Affect; American; Antineoplastic Agents; Antisense Oligonucleotides; Apoptosis; Apoptotic; Behavior; Bone Marrow Neoplasms; Bone Marrow Stem Cell; Cancer Etiology; Cell Count; Cell Fraction; Ceramide glucosyltransferase; Ceramides; Cessation of life; Chemotherapy-Oncologic Procedure; Data; Diagnostic Neoplasm Staging; Disseminated Malignant Neoplasm; Doxorubicin; Drug resistance; Education; Embryonic Development; Epithelial; Failure; Gene Silencing; Glucosylceramides; Glycosphingolipids; Goals; Growth Factor Oncogenes; In Vitro; Institution; Knockout Mice; Lead; Lipid Biochemistry; Louisiana; Mammary gland; Mediating; Names; Neoplasm Metastasis; Outcome; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Plant Roots; Play; Prevalence; Preventive; Preventive Intervention; Process; Proliferating; Property; Publishing; Reporting; Research; Risk Factors; Role; Sampling; Series; Signal Pathway; Source; Stem cells; Students; Technology; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; Universities; Unresectable; Woman; Work; adult stem cell; base; cancer cell; cancer stem cell; cancer therapy; chemotherapy; design; drug discovery; embryonic antigen; embryonic stem cell; glycosylation; human embryonic stem cell; improved; in vivo; inhibitor/antagonist; killings; malignant breast neoplasm; outcome forecast; overexpression; pluripotency; preclinical study; prevent; public health relevance; response; science education; small molecule; stem; stem cell biology; stem cell population; stemness; success; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Ceramide glycosylation determines the stemness of cancer stem cells Drug resistance with disseminated metastases is a cause of cancer death; in breast cancer, it ultimately claims approximately 40,500 American women per year. Tumors often progress rapidly once treatments fail, and enrichment of these tumors with cancer stem cells generally correlates with poor patient prognosis. Thus, cancer stem cells that initiate tumorigenesis and drive tumor progression might be a root cause of chemotherapy failure. Cancer stem cells are distinguished from normal adult stem cells by their tumorous behaviors. It is well known that anticancer drugs can kill normal stem cells, such as bone marrow stem cells-a source of severe side-effects; in contrast, however, some evidence suggests that anticancer drugs might act to expand cancer stem cell fractions or numbers. Our long-term goal is to understand how cancer stem cells can be specifically manipulated for preventive and therapeutic purposes. The objective of the research proposed herein is to determine how selected anticancer drugs affect breast cancer stem cell (BCSC) populations during the course of chemotherapy. It has been reported that glucosylceramide synthase (GCS) is overexpressed in metastatic breast cancers, and is a risk factor predicting poor chemotherapy response. Embryonic stem cells crucially require ceramide glycosylation catalyzed by GCS in order to retain their pluripotency. Little is known, though, concerning the possible involvement of GCS in regulating cancer stem cells. Our hypothesis is that ceramide glycosylation by GCS is a key step enabling tumor enrichment with BCSCs, and that enrichment with cancer stem cells drives rapid tumor progression and metastasis once chemotherapy fails. This application is formulated from our own preliminary data and previously published work, in which it was found that GCS is over-expressed in metastatic breast cancer, and that silencing of GCS was able to reverse drug resistance as well as prevent BCSC enrichment. We will: (1) identify the effects of anticancer drugs on enrichment of BCSCs and apoptosis of normal stem cells; (2) determine GCS-catalyzed ceramide glycosylation is a key process governing the accumulation of BCSCs and apoptosis of normal stem cells; and if so, (3) determine the signaling pathway(s) by which ceramide glycosylation promotes BCSC formation. Findings from in-vitro studies will be further explored in vivo, in orthotopic tumors exposed to anticancer drugs, employing gene silencing and overexpression strategies, and focusing on proposed role(s) of GCS in increasing the formation of BCSCs vs. contrasting apoptotic effects on bone marrow stem cells and normal mammary epithelial stem cells. Results will be further corroborated via studies of tumor and bone marrow samples from patients undergoing chemotherapy. Lastly, the therapeutic efficacy of disrupting ceramide glycosylation by an antisense oligonucleotide or a small molecule in order to effect reductions in BCSCs in orthotopic tumors will be examined, wherein success will lend validity to this unique approach for selectively eliminating cancer stem cells via deletion of key glycosphingolipids. Completion of the proposed studies will introduce new concepts and advanced technologies in cancer stem cells and drug discovery to students who participate, thus greatly enhancing their biomedical sciences education.

描述（由申请人提供）：神经酰胺糖基化确定癌症干细胞用传播转移抗药性的耐药性是癌症死亡的原因。在乳腺癌中，它最终每年声称约40,500名美国女性。一旦治疗失败，肿瘤通常会迅速进展，而这些肿瘤与癌细胞的富集通常与患者预后不良相关。因此，启动肿瘤发生并驱动肿瘤进展的癌症干细胞可能是化学疗法衰竭的根本原因。癌症干细胞与正常成年干细胞通过其肿瘤行为区分开。众所周知，抗癌药可以杀死正常的干细胞，例如骨髓干细胞 - 严重副作用的来源。但是，相比之下，一些证据表明抗癌药物可能会扩大癌症干细胞部分或数量。我们的长期目标是了解如何为预防和治疗目的而专门操纵癌症干细胞。本文提出的研究的目的是确定在化学疗法过程中选定的抗癌药物如何影响乳腺癌干细胞（BCSC）种群。据报道，转移性乳腺癌中的葡萄糖基酶合酶（GCS）过表达，并且是预测化学疗法反应不佳的危险因素。胚胎干细胞至关重要地需要由GC催化的神经酰胺糖基化，以保留其多能性。但是，关于GC可能参与调节癌症干细胞的可能参与的知之甚少。我们的假设是，通过GCS的神经酰胺糖基化是使BCSC富集肿瘤的关键步骤，并且一旦化学疗法失败，癌症干细胞的富集就可以促进肿瘤的快速进展和转移。该应用是根据我们自己的初步数据和先前发表的工作制定的，其中发现GCS在转移性乳腺癌中过表达，并且GC的沉默能够逆转耐药性并防止BCSC富集。我们将：（1）确定抗癌药对BCSC富集和正常干细胞凋亡的影响； （2）确定GCS催化的神经酰胺糖基化是管理BCSC的积累和正常干细胞凋亡的关键过程；如果是这样，（3）确定神经酰胺糖基化促进BCSC形成的信号通路。体内研究的结果将在体内进一步探索，在暴露于抗癌药物的正常肿瘤中，采用基因沉默和过表达策略，并专注于GCS在增加BCSC的形成中GC的作用，从而增加BCSC的形成BCSCS对比型对比对骨骼骨髓干细胞和正常的乳mim毛毛质毛质毛质毛质乳细胞和正常的乳脂细胞。通过研究接受化学疗法的患者的肿瘤和骨髓样品的研究，将进一步证实结果。最后，通过反义寡核苷酸或小分子破坏神经酰胺糖基化的治疗功效，以实现原位肿瘤中BCSC的降低，其中成功将在这种独特的方法中通过选择性地消除癌症干细胞的有效性，从而借助有效性来消除癌症干细胞。 关键糖磷脂。拟议研究的完成将在癌症干细胞中引入新的概念和高级技术，并向参加的学生介绍药物发现，从而大大增强其生物医学教育。