The Contribution of Chronic Inflammation to Pulmonary Adenocarcinoma

描述（由申请人提供）：相关性：肺癌是癌症相关死亡的主要原因，目前的治疗通常无效。了解炎症在肺癌中的作用可能为其治疗和预防提供见解。项目摘要：大多数肺癌（LC）发生在老年人群中，是由于慢性肺损伤和吸烟致癌物暴露的结果;由于频繁的LC扩散和对化疗的耐药性，目前的治疗在很大程度上是无效的。缺乏细胞因子粒细胞-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）发展为慢性肺部炎症，并且随着小鼠年龄的增长，发展为类似于人LC的肺肿瘤。许多LC小鼠模型利用已知肿瘤相关基因中预先建立的遗传改变，导致年幼动物中的多个原发性肿瘤。与目前的模型相反，与人LC相似，老年TKO小鼠在慢性肺损伤后发生肿瘤。移植的TKO肿瘤在第二宿主中生长，并重现了初始肿瘤形成部位的许多炎症特征。这些发现表明，TKO小鼠是一种研究炎症在LC中作用的新系统，与老年人群中发生的疾病特别相关。基于这一初步评估，本项目的目的如下：1）鉴定可移植TKO肿瘤分泌的炎症介质并评估其在肿瘤维持中的作用; 2）确定移植环境中肿瘤相关免疫细胞的组成和功能; 3）表征来自TKO小鼠的病理学样品，以证明目的1和2中鉴定的免疫效应物存在于原发性腺癌发展的背景下。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。然后将使用细胞因子产生的抑制或细胞因子功能的阻断来评估这些介质对体外和体内肿瘤存活的重要性。目的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来解决。这些免疫效应物在肿瘤维持中的作用将通过免疫组分的遗传缺失或通过中和细胞因子来评估;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鉴定的特异性炎症细胞和细胞因子。炎症和LC之间的关系的详细检查有望进一步了解慢性炎症和LC的产生之间的关系，在以后的生活中，并可能被证明是有用的，在评估治疗。

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.