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：美国每年报告大约 3,300 例新的唾液腺肿瘤病例。手术仍然是主要的治疗方式，因为化疗和放疗基本上无效。因此，与护理标准相关的发病率很高，晚期唾液腺癌患者的 5 年生存率很低。值得注意的是，NIH/NIDCR 最近发现动物模型的稀缺是开发唾液腺癌有效疗法的主要障碍。假设：癌症干细胞的定义是其自我更新和产生表型多样的后代（再现肿瘤起源）的能力。癌症干细胞可以驱动肿瘤发生并对治疗产生抗药性，这一事实表明它们可能会影响唾液腺癌患者的预后。然而，人们对癌症干细胞在这些肿瘤病理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物）的细胞亚群。 ALDH/CD44 分选将高致瘤性细胞亚群与原发性人粘液表皮样癌和肿瘤性唾液腺细胞系 (HSG) 区分开来。初步证据表明，内皮细胞分泌因子可增强唾液腺癌干细胞 (SGCSC) 的存活和自我更新，并且阻断 IL-6 可防止内皮细胞诱导的 STAT3（一种已知的干性调节因子）激活。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，这些数据得出这样的假设：内皮细胞发起的信号传导对于 SGCSC 的存活和化疗反应至关重要。为了解决这一假设，我们提出以下具体目标：具体目标#1：表征唾液腺癌异种移植模型，该模型由人类唾液腺癌干细胞产生，并具有功能性人类血管。具体目标#2：确定内皮细胞来源的 IL-6 对唾液腺癌干细胞存活和自我更新的影响。具体目标#3：研究内皮细胞和干细胞之间的串扰对唾液腺肿瘤化疗反应的影响。意义和影响：迫切需要更有效的治疗方法来改善恶性唾液腺癌患者的预后。此类疗法可能来自于增强对该疾病病理学机制的理解的研究。在这里，我们将开发具有人源化脉管系统的人类唾液腺癌小鼠模型，并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，以提高唾液腺癌患者的生存率和生活质量。