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

描述（由申请人提供）：问题：美国每年报告大约3300例唾液腺肿瘤新病例。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很高，晚期唾液腺癌患者的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确定为唾液腺癌有效疗法发展的主要障碍。假设：癌症干细胞是由它们自我更新的能力和产生表型多样化的后代来定义的，这些后代概括了肿瘤的起源。事实上，癌症干细胞可以驱动肿瘤发生，并且对治疗有抵抗力，这表明它们可能影响唾液腺癌患者的预后。然而，我们对肿瘤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，我们确定了在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从原发性人黏液表皮样癌和肿瘤性唾液腺细胞系（HSG）中区分出来。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，而IL-6的阻断可阻止内皮细胞诱导的STAT3（一种已知的干细胞调节因子）的激活。值得注意的是，IL-6及其受体（IL-6R, gp130）在人唾液腺肿瘤中的表达明显高于对照组。总的来说，这些数据导致了内皮细胞启动的信号传导对SGCSC的生存和对化疗的反应至关重要的假设。为了解决这一假设，我们提出以下具体目标：具体目标#1：表征由人类唾液腺癌干细胞产生的唾液腺癌异种移植模型，并将其与功能性人类血管相结合。特异性目标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。特异性目的#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贡献。意义与影响：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。这种疗法可能来自于加强对这种疾病的病理生物学机制的理解的研究。在此，我们将建立人源化血管的人唾液腺癌小鼠模型，并利用该模型研究唾液腺癌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.