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

• 批准号: 8402545
• 负责人: Jacques Eduardo Nor
• 金额: $ 37.32万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/8402545
• 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

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：在美国，每年大约有3,300例新的唾液腺肿瘤病例报告。手术仍然是主要的治疗方式，因为化疗和放射治疗在很大程度上无效。因此，与护理标准相关的发病率很高，晚期涎腺癌患者的5年生存率很低。值得注意的是，动物模型的缺乏最近被NIH/NIDCR确定为开发有效的涎腺癌治疗方法的主要障碍。假设：癌症干细胞的定义是其自我更新的能力，并产生表型不同的后代，以重塑起源的肿瘤。癌症干细胞可以推动肿瘤的形成并对治疗产生抵抗力，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的病理生物学中的作用知之甚少。在初步研究中，我们确定了在人类唾液腺肿瘤中高水平表达ALDH和CD44(假定的癌症干细胞标记物)的细胞亚群。ALDH/CD44分类将高致瘤性细胞亚群与原发人粘液表皮样癌和肿瘤性涎腺细胞系(HSG)区分开来。初步证据表明，内皮细胞分泌的因子促进唾液腺癌细胞(SGCSC)的存活和自我更新，阻断IL-6可以阻止内皮细胞诱导的STAT3(已知的干性调节因子)的激活。值得注意的是，IL-6及其受体(IL-6R、gp130)在涎腺肿瘤中的表达显著高于对照组。总而言之，这些数据导致了一种假设，即内皮细胞启动的信号对SGCSC的生存和对化疗的反应至关重要。为了解决这一假设，我们提出了以下具体目标：具体目标#1：描述由人涎腺癌细胞生成的、带有功能性血管的涎腺癌异种移植模型。具体目的#2：明确内皮细胞来源的IL-6对涎腺癌细胞存活和自我更新的影响。具体目的#3：研究内皮细胞和干细胞之间的串扰在涎腺肿瘤化疗反应中的作用。意义和影响：迫切需要更有效的治疗方法来改善恶性涎腺癌患者的预后。这种疗法很可能来自于加强对这种疾病病理生物学基础机制的理解的研究。在这里，我们将利用人源化的血管系统建立人类涎腺癌的小鼠模型，并利用它来研究唾液腺肿瘤干细胞在治疗反应中的作用。我们的最终目标是发现新的、基于机制的治疗策略，以提高涎腺癌患者的生存和生活质量。