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

描述（由申请人提供）：问题：美国每年报告约3，300例新的唾液腺肿瘤病例。手术仍然是主要的治疗方式，因为化疗和放疗在很大程度上无效。因此，与标准治疗相关的发病率较高，晚期涎腺癌患者的5年生存率较低。值得注意的是，NIH/NIDCR最近已将动物模型的稀缺性确定为唾液腺癌有效疗法开发的主要障碍。假设：癌症干细胞的定义是它们自我更新的能力和产生重现肿瘤起源的表型多样性后代的能力。癌症干细胞可以驱动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。然而，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，我们确定了一个亚群的细胞，表达高水平的ALDH和CD 44（推定的癌症干细胞标志物）在人类唾液腺肿瘤。ALDH/CD 44分选区分高度致瘤性细胞的亚群从原发性人类粘液表皮样癌和从肿瘤性唾液腺细胞系（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）的存活和自我更新，并且IL-6的阻断阻止了内皮细胞诱导的STAT 3（一种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-6 R，gp 130）的表达在人唾液腺肿瘤中显著高于对照。总的来说，这些数据导致了这样的假设，即内皮细胞启动的信号传导对于SGCSC的存活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：表征由人唾液腺癌干细胞产生并用功能性人血管血管化的唾液腺癌异种移植模型。具体目标#2：确定内皮细胞衍生的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：探讨内皮细胞和干细胞之间的相互作用对涎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涎腺癌患者的预后。这种疗法可能来自于加强对这种疾病病理生物学机制的理解的研究。在这里，我们将建立一个具有人源化血管系统的人涎腺癌小鼠模型，并使用它来研究涎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。

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.