Characterization of the Multiple Myeloma Cancer Stem Cell and its Niche

多发性骨髓瘤癌症干细胞的特征及其生态位

• 批准号: 8296505
• 负责人: Ruben Claudio Aguilar
• 金额: $ 18.95万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-06 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296505
• 关键词: 3-Dimensional; Affect; Architecture; Aspirate substance; Biological Assay; Biology; Bone Marrow; Bone Marrow Cells; Cell surface; Cells; Characteristics; Clonality; DIF factor; Data; Drug resistance; Equilibrium; Excision; Future; Growth; Hematologic Neoplasms; Hematopoietic; Human; Immunocompromised Host; Investigation; Knowledge; Label; Malignant - descriptor; Malignant Neoplasms; Modeling; Multiple Myeloma; Mus; N-Cadherin; Nature; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Phenotype; Prevention strategy; Proliferating; Relapse; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Solid; Solid Neoplasm; Stem cells; Stromal Cells; System; Testing; Therapeutic Agents; Time; Transplantation; Work; Xenograft procedure; cancer stem cell; cell stroma; design; improved; insight; knock-down; mouse model; novel; novel therapeutics; prevent; programs; self-renewal; small hairpin RNA; stem cell biology; stem cell niche; stem cell population; theories; tissue culture; tumor; tumor growth; tumor initiation; tumorigenic

DESCRIPTION (provided by applicant): The broad objectives of this R21 Stem Cells and Cancer proposal are to 1) to establish the identity and characterize the tumorigenic potential of the MM-CSC and 2) to determine whether N-cadherin interaction between MM-CSC and stroma is required to maintain the proliferative quiescence of the MM-CSC. This work will open a gateway to study the signaling pathways governing the proliferation and differentiation of the MM-CSC, and once those are identified, new drugs can be designed to prevent the interaction between the differentiation-inducing factors and the MM-CSC, thus creating a first MM-CSC targeted therapeutic agent capable of preventing tumor initiation and relapse. Rationale: Strong evidence in support of the cancer stem cell (CSC) theory has been steadily accumulating over the last decade. In addition to tumorigenic potential, a CSC possesses characteristics of normal stem cells including quiescence and self-renewal potential. Upon receiving proliferation signal(s) from the microenvironment, a CSC switches its program from quiescence to differentiation and proliferation, initiating tumor growth. While patients with solid tumors may benefit from the surgical removal of their malignant outgrowth, hopefully along with drug-resistant tumor-initiating CSC, the surgical option is not available for the patients suffering from hematological malignancies. Such patients have a high rate of relapse due to inability of the currently used therapies to target successfully CSC. Thus, determining which characteristics of the CSC can be therapeutically exploited is of utmost importance. Multiple myeloma (MM) is an incurable malignancy of the bone marrow (BM). Nearly all MM patients relapse indicating that the drug-resistant MM cancer stem cell (MM-CSC), the identity of which is currently a subject of investigation, escapes these therapies. Hypothesis: MM-CSCs are found in a specialized microenvironment niche which maintains these cells in a non-proliferative state. Altering the microenvironment in favor of differentiation leads to tumor growth. Specific Aims: Aim 1: To define the phenotype of the MM-CSC. Aim 2: To determine whether N-cadherin interactions between stroma and MM-CSC are required to maintain the MM-CSC niche. Overall approach: We have recently developed a three-dimensional (3-D) ex vivo tissue culture model recapitulating the architecture and composition of the human BM. This model makes proliferating and non-proliferating compartments of the MM BM accessible for further analysis where the identity, clonality, self-renewal, and generative and tumorigenic potential of MM stem cells can be established. To establish the identity of the MM-CSC and to define its niche this proposal will combine the use of the 3-D tissue culture system with xenograft mouse models.

描述（由申请人提供）：该 R21 干细胞和癌症提案的广泛目标是 1) 确定 MM-CSC 的身份并表征其致瘤潜力，2) 确定 MM-CSC 之间是否存在 N-钙粘蛋白相互作用基质需要维持 MM-CSC 的增殖静止。 这项工作将为研究控制MM-CSC增殖和分化的信号通路打开大门，一旦确定了这些信号通路，就可以设计新药物来阻止分化诱导因子与MM-CSC之间的相互作用，从而创造第一种能够预防肿瘤发生和复发的 MM-CSC 靶向治疗剂。 理由：过去十年来，支持癌症干细胞 (CSC) 理论的有力证据不断积累。 除了致瘤潜力外，CSC 还具有正常干细胞的特征，包括静止和自我更新潜力。 在接收到来自微环境的增殖信号后，CSC 将其程序从静止切换到分化和增殖，从而启动肿瘤生长。 虽然实体瘤患者可能会受益于手术切除其恶性增生，并有望与耐药肿瘤起始 CSC 一起切除，但对于患有血液恶性肿瘤的患者来说，手术选择并不适用。 由于目前使用的疗法无法成功靶向 CSC，此类患者的复发率很高。 因此，确定 CSC 的哪些特征可以用于治疗是至关重要的。 多发性骨髓瘤（MM）是一种无法治愈的骨髓（BM）恶性肿瘤。 几乎所有 MM 患者都会复发，这表明耐药 MM 癌症干细胞 (MM-CSC)（其身份目前正在研究中）逃脱了这些治疗。 假设：MM-CSC 存在于一个特殊的微环境中，该微环境使这些细胞保持在非增殖状态。 改变有利于分化的微环境会导致肿瘤生长。 具体目标： 目标 1：定义 MM-CSC 的表型。 目标 2：确定基质和 MM-CSC 之间是否需要 N-钙粘蛋白相互作用来维持 MM-CSC 生态位。 总体方法：我们最近开发了一种三维（3-D）离体组织培养模型，概括了人类骨髓的结构和组成。 该模型使 MM BM 的增殖和非增殖区室可用于进一步分析，从而确定 MM 干细胞的身份、克隆性、自我更新以及生成和致瘤潜力。 为了确定 MM-CSC 的身份并定义其利基，该提案将结合使用 3D 组织培养系统和异种移植小鼠模型。