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.
|Dougan, Michael; Li, Danan; Neuberg, Donna et al. (2011) A dual role for the immune response in a mouse model of inflammation-associated lung cancer. J Clin Invest 121:2436-46|
|Dougan, Michael; Dougan, Stephanie; Slisz, Joanna et al. (2010) IAP inhibitors enhance co-stimulation to promote tumor immunity. J Exp Med 207:2195-206|