Perivascular niche for salivary gland cancer stem cells and resistance to therapy

唾液腺癌干细胞的血管周围生态位和治疗耐药性

基本信息

批准号：
8603155
负责人：
Jacques Eduardo Nor
金额：
$ 38.88万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-10 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8603155
关键词：
AP20187 Ablation Address Angiogenesis Inhibitors Animal Model Area Behavior Blood Vessels Brain Neoplasms CD44 gene Cancer Patient Caring Cell Line Cells Cessation of life Cisplatin Clinical Data Development Disease Endothelial Cells Experimental Models Goals Human Implant In Vitro Interleukin-6 Lead Malignant - descriptor Malignant Neoplasms Malignant neoplasm of salivary gland Modality Modeling Molecular Molecular Target Morbidity - disease rate Mucoepidermoid Carcinoma Mus National Institute of Dental and Craniofacial Research Normal tissue morphology Operative Surgical Procedures Outcome Paclitaxel Patients Pharmaceutical Preparations Phenotype Pilot Projects Population Public Health Quality of life Radiation therapy Reporting Research Role SCID Mice STAT3 gene Salivary Gland Neoplasms Salivary Glands Signal Transduction Sorting - Cell Movement Stem cells Testing Therapeutic Tissue Microarray Transplantation United States National Institutes of Health Work Xenograft Model Xenograft procedure aldehyde dehydrogenases base bevacizumab cancer stem cell caspase-9 chemotherapy drug testing effective therapy enhancing factor human disease implantation improved in vitro Assay malignant breast neoplasm mouse model neoplastic neoplastic cell prevent public health relevance receptor research study response scaffold self-renewal small hairpin RNA stem stemness therapy resistant tumor tumor growth tumor microenvironment tumor xenograft tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The Problem: Approximately 3,300 new cases of salivary gland tumors are reported each year in the USA. Surgery is still the primary treatment modality because chemotherapy and radiotherapy are largely ineffective. As a consequence, the morbidity related to the standard-of-care is high and the 5-year survival for patients with advanced salivary gland cancer is low. Notably, the scarcity of animal models has been recently identified by the NIH/NIDCR as a major impediment for the development of effective therapies for salivary gland cancer. Hypothesis: Cancer stem cells are defined by their ability to self-renew and to generate a phenotypically diverse progeny that recapitulates the tumor of origin. The fact that cancer stem cells can drive tumorigenesis and are resistant to therapy suggests that they may influence the outcome of salivary gland cancer patients. However, little is known about the role of cancer stem cells in the pathobiology of these tumors. In preliminary studies, we identified a sub-population of cells that express high levels of ALDH and CD44 (putative cancer stem cell markers) in human salivary gland tumors. ALDH/CD44 sorting distinguished a sub-population of highly tumorigenic cells from a primary human mucoepidermoid carcinoma and from a neoplastic salivary gland cell line (HSG). Preliminary evidence suggest that endothelial cell-secreted factors enhance the survival and self-renewal of salivary gland cancer stem cells (SGCSC) and that blockade of IL-6 prevent endothelial cell-induced activation of STAT3 (a known regulator of stemness). Notably, the expression of IL-6 and its receptors (IL-6R, gp130) is significantly higher in human salivary gland tumors than in controls. Collectively, these data led to the hypothesis that endothelial cell-initiated signaling is critical for the survival of SGCSC and for response to chemotherapy. To address this hypothesis, we propose the following specific aims: Specific Aim #1: To characterize a xenograft model of salivary gland cancer that is generated by human salivary gland cancer stem cells and is vascularized with functional human blood vessels. Specific Aim #2: To define the effect of endothelial cell-derived IL-6 on the survival and self-renewal of salivary gland cancer stem cells. Specific Aim #3: To study the contribution of the crosstalk between endothelial cells and stem cells on the response of salivary gland tumors to chemotherapy. Significance and Impact: More effective therapies are urgently needed to improve the outcomes of patients with malignant salivary gland cancer. Such therapies are likely to come from studies that enhance the understanding of mechanisms underlying the pathobiology of this disease. Here, we will develop a mouse model of human salivary gland cancer with humanized vasculature and use it to study the role of salivary gland cancer stem cells on response to therapy. Our ultimate goal is to discover new, mechanism-based, therapeutic strategies that improve the survival and quality of life of patients with salivary gland cancer.

描述（由申请人提供）：问题：美国每年在美国报告约3,300例唾液腺肿瘤。手术仍然是主要治疗方式，因为化学疗法和放射疗法在很大程度上无效。结果，与护理标准有关的发病率很高，晚期唾液腺癌患者的5年生存率很低。值得注意的是，NIH/NIDCR最近已将动物模型的稀缺性确定为开发有效唾液腺癌疗法的主要障碍。假设：癌症干细胞的定义是它们的自我更新能力和产生表型多样的后代，从而概括了起源肿瘤。癌症干细胞可以促进肿瘤发生并对治疗具有抗性的事实表明，它们可能会影响唾液腺癌患者的结果。但是，对于癌症干细胞在这些肿瘤病理生物学中的作用知之甚少。在初步研究中，我们确定了人类唾液腺肿瘤中表达高水平ALDH和CD44（假定的癌症干细胞标记）的细胞的亚群。 ALDH/CD44分类区分了高度肿瘤细胞的亚构型与原发性粘膜外皮样癌和肿瘤唾液腺细胞系（HSG）。初步证据表明，内皮细胞分泌的因子增强了唾液腺癌干细胞（SGCSC）的生存和自我更新，并阻断IL-6的阻断，可防止内皮细胞诱导的STAT3激活（已知的STEMNNESS的调节剂）。值得注意的是，人类唾液腺肿瘤中IL-6及其受体（IL-6R，GP130）的表达显着高于对照组。总的来说，这些数据导致了一个假说，即内皮细胞发射的信号传导对于SGCSC的存活和对化学疗法的反应至关重要。为了解决这一假设，我们提出了以下特定目的：特定目的＃1：表征由人类唾液腺癌干细胞产生的唾液腺癌的异种移植模型，并用功能性人体血管血管化。具体目的＃2：定义内皮细胞衍生的IL-6对唾液腺癌干细胞生存和自我更新的影响。具体目的3：研究内皮细胞和干细胞之间串扰对唾液腺肿瘤对化学疗法的反应的贡献。意义和影响：迫切需要更有效的疗法来改善恶性唾液腺癌患者的结局。这种疗法可能来自研究，从而增强对这种疾病病理生物学基础机制的理解。在这里，我们将开发一种具有人源性脉管系统的人类唾液腺癌的小鼠模型，并利用它来研究唾液腺癌干细胞对治疗反应的作用。我们的最终目标是发现新的，基于机制的治疗策略，以改善唾液腺癌患者的生存和生活质量。