Microenvironmental regulation of the cancer stem cell phenotype by integrin a6

整合素a6对癌症干细胞表型的微环境调节

• 批准号: 8520262
• 负责人: Justin D. Lathia
• 金额: $ 23.41万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-22 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520262
• 关键词: Adult; Area; Behavior; Binding; Biological Assay; Biopsy Specimen; Blocking Antibodies; Blood Vessels; Breast; Cell Communication; Cell Fraction; Cell Nucleus; Cells; Cellular Structures; Cilengitide; Clinical; Clinical Trials; Colon; Communication; Data; Dose; ECM receptor; Evaluation; Excision; Extracellular Matrix; Extracellular Matrix Proteins; Failure; Family; Glioblastoma; Glioma; Heterogeneity; Human; Image; Imaging Techniques; Immunohistochemistry; Integrin alpha6; Integrins; Laminin; Ligands; Location; Maintenance; Malignant - descriptor; Malignant Glioma; Mediating; Modeling; Mus; Operative Surgical Procedures; Outcome; Patients; Phenotype; Play; Primary Brain Neoplasms; Process; Property; Published Comment; RGD (sequence); RNA Interference; Radiation; Radiosurgery; Recurrence; Regulation; Research; Resistance; Resolution; Role; Signal Transduction; Specimen; Study models; Subfamily lentivirinae; System; Therapeutic; Treatment Efficacy; Work; base; cancer stem cell; cell type; chemotherapy; clinically relevant; conventional therapy; design; in vivo; innovation; intravital imaging; laminin-6; neoplastic cell; nerve stem cell; neurodevelopment; novel; pre-clinical; protein aminoacid sequence; receptor; research study; response; self-renewal; small hairpin RNA; stem cell niche; therapeutic development; therapeutic target; tumor; tumor growth; tumor initiation

PROJECT SUMMARY Current treatments for malignant gliomas, the most common being Glioblastoma Multiforme (GBM), include surgical resection, radiation, and chemotherapy but remain ineffective due to recurrence and therapeutic resistance. The inability to adequately treat these tumors may be due in part to a subset of tumor cells, cancer stem cells, that are resistant to many conventional therapies. Cancer stem cells within GBMs are localized to several areas, among them the perivascular compartment, which is a known cancer stem cell microenvironment or niche and has been shown to play a role in therapeutic resistance. Understanding how the cancer stem cells communicate with the perivascular niche to promote the cancer stem cell phenotype and promote therapeutic resistance is of immediate importance and has implications in the design of more effective glioma therapies. Recently, integrin alpha 6 has been identified in the perivascular niche of human GBMs and high expression correlates to cells with a cancer stem cell phenotype. Additionally, targeting of integrin alpha 6 resulted in compromised growth and tumor formation, demonstrating integrin alpha 6 could be a promising therapeutic target. The hypothesis of this proposal is that integrin alpha 6 is a unifying signal that promotes the cancer stem cell phenotype and will be evaluated by: 1) interrogating how integrin alpha 6 interacts with the perivascular microenvironment to maintain the cancer stem cell phenotype and 2) determining the role of integrin alpha 6 in promoting resistance to radiation and chemotherapy. The proposal also aims to develop an intravital imaging model of study the in vivo communication between cancer stem cells and the niche. Experimental studies will utilize human GBM specimens to evaluate extracellular matrix ligands present in the niche and utilize clinically relevant doses of radiation and chemotherapy to assess the impact of integrin alpha 6 targeting by RNA interference or blocking antibody administration. The cancer stem cell phenotype will be evaluated by self-renewal and tumor initiation assays. The long term objective of this proposal is to develop GBM therapies with increased therapeutic efficacy that target the cancer stem cells in combination with conventional therapies. These studies outlined in this proposal will uncover the critical role of cancer stem cell interaction with the niche via integrin ¿6 and evaluate potential therapies to GBM which disrupt niche related communication. Any findings and therapeutic developments may extend to other tumor types with a cancer stem cell component (i.e. colon, breast).

目前恶性胶质瘤的治疗方法，最常见的是胶质母细胞瘤 多形性（GBM），包括手术切除，放射和化疗，但由于 复发和治疗抗性。无法充分治疗这些肿瘤可能部分是由于 肿瘤细胞的亚群，癌症干细胞，对许多常规疗法具有抗性。癌症干细胞 在GBM内定位于几个区域，其中包括血管周围室，这是已知的 癌症干细胞微环境或生态位，并已显示在治疗抗性中发挥作用。 了解癌症干细胞如何与血管周围小生境沟通以促进癌症干细胞 细胞表型和促进治疗耐药性是直接重要的，并在 设计更有效的神经胶质瘤疗法。最近，整合素α 6已被确定在血管周围 人GBM的小生境和高表达与具有癌症干细胞表型的细胞相关。此外，本发明还 整合素α 6的靶向作用导致生长和肿瘤形成受损，表明整合素α 6可能是一个很有前途的治疗靶点。该建议的假设是，整合素α 6是一个统一的 通过以下方式评估促进癌症干细胞表型的整合素信号：1）询问整合素 α 6与血管周围微环境相互作用以维持癌症干细胞表型，以及2） 确定整合素α 6在促进对放疗和化疗的抵抗中的作用。该提案 也旨在开发一种研究肿瘤干细胞之间体内通讯的活体成像模型 还有壁龛实验研究将利用人类GBM标本来评估细胞外基质配体 目前在利基，并利用临床相关剂量的放射和化疗，以评估的影响， 通过RNA干扰或阻断抗体施用靶向整合素α 6。癌症干细胞 表型将通过自我更新和肿瘤起始测定来评估。这一长期目标 一项提案是开发具有更高治疗功效的GBM疗法，靶向癌症干细胞， 与常规治疗相结合。本提案中概述的这些研究将揭示 癌症干细胞通过整合素6与小生境相互作用，并评估GBM的潜在治疗方法， 破坏利基相关的通信。任何发现和治疗进展都可能扩展到其他肿瘤 具有癌症干细胞成分的类型（即结肠，乳腺）。