The Contribution of Chronic Inflammation to Pulmonary Adenocarcinoma

描述(申请人提供)：相关性：肺癌是癌症相关死亡的主要原因，目前的治疗方法往往无效。了解炎症在肺癌中的作用可能会为肺癌的治疗和预防提供见解。项目概述：大多数肺癌(LC)发生在老年人群中，是慢性肺损伤和香烟烟雾致癌物质暴露的结果；目前的治疗方法大多无效，因为LC扩散频繁，对化疗耐药。缺乏细胞因子粒-巨噬细胞集落刺激因子、白细胞介素3和干扰素-γ的BALB/c小鼠(TKO小鼠)发生慢性肺部炎症，随着小鼠年龄的增长，出现类似于人类LC的肺部肿瘤。许多LC小鼠模型利用已知的肿瘤相关基因的预先建立的遗传改变，导致年轻动物的多原发肿瘤。与目前的模型不同，与人类LC相似，老年TKO小鼠在慢性肺损伤后发生肿瘤。移植的TKO肿瘤生长在继发性宿主中，并概括了许多目前存在的肿瘤形成部位的炎症特征。这些发现表明，TKO小鼠是一种研究炎症在LC中的作用的新系统，尤其与老年人群中发生的疾病相关。基于这一初步评估，该项目的目标如下：1)确定可移植的TKO肿瘤分泌的炎症介质，并评估它们在肿瘤维持中的作用；2)确定移植环境中肿瘤相关免疫细胞的组成和功能；3)鉴定TKO小鼠的病理标本，以证明AIMS 1和2中确认的免疫效应分子存在于原发腺癌的发生中。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的分泌。抑制细胞因子的产生或阻断细胞因子的功能将被用来评估这些介质在体外和体内对肿瘤存活的重要性。目标2将通过分离与移植肿瘤相关的免疫细胞并评估它们的组成和细胞因子分泌谱来解决。然后，将通过基因缺失免疫成分或中和细胞因子来评估这些免疫效应器在肿瘤维持中的作用；这些发现可能具有治疗意义。在目标3中，将调查先前从老年TKO小鼠收集的血清和组织中通过目标1和2确定的特定炎症细胞和细胞因子。详细检查炎症和LC之间的关系有望加深我们对慢性炎症和LC在以后生活中产生的关系的理解，并可能被证明对评估治疗方法有用。

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.