The Contribution of Chronic Inflammation to Pulmonary Adenocarcinoma

慢性炎症对肺腺癌的影响

• 批准号: 7405739
• 负责人: Michael Lawrence Dougan
• 金额: $ 4.57万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-10-01 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405739
• 关键词: Address; Adenocarcinoma; Adenocarcinoma Cell; Age; Biological Response Modifiers; Cancer Etiology; Carcinogen exposure; Cell Line; Cells; Cessation of life; Chronic; Colony-Stimulating Factors; Development; Disease; Generations; Genes; Genetic; Granulocyte-Macrophage Colony-Stimulating Factor; Human; Immune; In Vitro; Inbred BALB C Mice; Inflammation; Inflammatory; Interferon Type II; Interferons; Interleukin-3; Invasive; Life; Lung; Lung Neoplasms; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediator of activation protein; Metastatic Lesion; Modeling; Mus; Mutation; Neoplasm Metastasis; Neoplasm Transplantation; Older Population; Pathology; Pneumonia; Prevention; Primary Neoplasm; Production; Resistance; Role; Sampling; Serum; Site; Surveys; System; Therapeutic; Tissues; Transplantation; Tumor Cell Line; aged; base; chemotherapy; cigarette smoking; cytokine; human disease; in vivo; insight; juvenile animal; lung injury; mouse model; novel; novel therapeutics; tumor

DESCRIPTION (provided by applicant): Relevance: Lung cancer is the major cause of cancer-related death, and current treatments are often ineffective. Understanding the role of inflammation in lung cancer may provide insights into its treatment and prevention. Project Summary: Most lung cancer (LC) arises in older populations as the result of chronic lung damage and carcinogen exposure from cigarette smoke; current therapies are largely ineffective due to frequent LC spread and resistance to chemotherapy. BALB/c mice deficient in the cytokines granulocyte- macrophage colony stimulating factor, interleukin-3, and interferon-gamma (TKO mice) develop chronic pulmonary inflammation and, as the mice age, lung tumors resembling human LC. Many mouse models of LC make use of pre-established genetic alterations in known tumor-associated genes, leading to multiple primary tumors in young animals. In contrast to current models and similar to human LC, aged TKO mice develop tumors subsequent to chronic lung injury. Transplanted TKO tumors grow in secondary hosts and recapitulate many of the inflammatory features of present at the site of initial tumor formation. These findings indicate that TKO mice are a novel system for studying the role of inflammation in LC with particular relevance to the disease as it occurs in older populations. Based upon this initial assessment, the aims of this project are as follows: 1) to identify the inflammatory mediators secreted by transplantable TKO tumors and evaluate their role in tumor maintenance; 2) to determine composition and function of tumor associated immune cells in the transplant setting; 3) to characterize pathology samples from TKO mice for evidence that the immune effectors identified in Aims 1 and 2 are present in the context of primary adenocarcinoma development. To address aim 1, inflammatory cytokine secretion will be measured in cultured tumor cell lines. Inhibition of cytokine production or blockade of cytokine function will then be used to assess the importance of these mediators to tumor survival in vitro and in vivo. Aim 2 will be addressed by isolating immune cells associated with transplanted tumors and evaluating their composition and cytokine secretion profile. The role of these immune effectors in tumor maintenance will then be evaluated through genetic deletion of immune components or by neutralizing cytokines; these finding may have therapeutic implications. In aim 3, previously collected serum and tissue from aged TKO mice will be surveyed for the specific inflammatory cells and cytokines identified through aims 1and 2. A detailed examination of the relationship between inflammation and LC promises to further our understanding of the relationship between chronic inflammation and the generation of LC later in life, and may prove useful in evaluating therapeutics.

描述（由申请人提供）：相关性：肺癌是与癌症相关死亡的主要原因，当前治疗通常无效。了解炎症在肺癌中的作用可能会提供有关其治疗和预防的见解。项目摘要：大多数肺癌（LC）是由于慢性肺损伤和香烟烟雾暴露的致癌物而导致较老的人群。由于LC的频繁扩散和对化疗的耐药性，目前的疗法在很大程度上无效。 BALB/C小鼠缺乏细胞因子粒细胞 - 巨噬细胞刺激因子，白介素-3和干扰素 - γ（TKO小鼠）会出现慢性肺部炎症，并且随着小鼠的年龄，肺tum tum them肿瘤类似于人类液晶。许多LC的小鼠模型都利用了已知肿瘤相关基因的预先建立的遗传改变，从而导致年轻动物的多个原发性肿瘤。与当前的模型相比，与人类LC相似，老化的TKO小鼠会在慢性肺损伤之后发展出肿瘤。移植的TKO肿瘤在次生宿主中生长，并概括了初始肿瘤形成部位的许多炎症特征。这些发现表明，TKO小鼠是研究炎症在LC中的作用的新型系统，与疾病在较老的人群中的作用特别相关。基于此初步评估，该项目的目的如下：1）确定由可移植TKO肿瘤分泌的炎症介质并评估其在肿瘤维持中的作用； 2）确定在移植设置中肿瘤相关免疫细胞的组成和功能； 3）表征来自TKO小鼠的病理样本，以证明AIM 1和2中鉴定出的免疫效应子在原发性腺癌发育的背景下存在。为了解决目标1，将在培养的肿瘤细胞系中测量炎性细胞因子分泌。然后，将使用抑制细胞因子产生或细胞因子功能的阻断来评估这些介体在体外和体内肿瘤存活的重要性。 AIM 2将通过分离与移植肿瘤相关的免疫细胞并评估其组成和细胞因子分泌谱。然后，这些免疫效应子在肿瘤维持中的作用将通过免疫成分的遗传缺失或中和细胞因子来评估。这些发现可能具有治疗意义。在AIM 3中，将对先前收集的老年TKO小鼠的血清和组织进行调查，以通过AIM 1和2鉴定的特定炎症细胞和细胞因子2和2。对炎症与LC之间的关系的详细检查有望进一步了解我们对慢性炎症与后来的LC生成之间的关系的理解，并证明了对治疗方法的有用，并且可以评估有用。