Our research team is interested in airway inflammation and its role in lung carcinogenesis. Tumor-induced inflammation is now a cancer hallmark, and it is considered an enabling characteristic due to its contributions to the acquisition of core hallmark capabilities. Tumor cells produce various cytokines and chemokines that attract leukocytes. Leukocytes can amplify parenchymal innate immune responses, and have been shown to contribute to tumor promotion (intrinsic inflammation).
On the other hand, many environmental causes and risk factors for cancer are associated with chronic inflammation. According to epidemiological studies, up to 20% of cancers are linked to chronic infections and inflammation. Several studies have found that smokers with chronic obstructive pulmonary disease (COPD) have an increased risk of lung cancer compared to smokers without COPD. Histopathologic studies have clearly demonstrated lung inflammation in COPD. Importantly, among smokers with COPD, even following withdrawal of cigarette smoke, inflammation persists and lung function continues to deteriorate as does the increased risk of lung cancer. These facts suggest a link between airway inflammation due to COPD and lung cancer, and suggest that just as inflammation in the colon due to ulcerative colitis leads to colon cancer, so inflammation in the lung due to COPD may also impact the risk of lung cancer. This is being studied and mechanistically dissected in our laboratory.
We have previously developed a COPD-like mouse model of airway inflammation, and shown that this type of airway inflammation, but not asthma-like airway inflammation, promotes lung cancer in a K-ras mutant mouse model of lung cancer. This seems to be mediated by activation of epithelial cell inflammatory pathways and amplified by inflammatory leukocytes. Therefore, we suggest that activation of epithelial cell signaling pathways and release of inflammatory mediators provide a microenvironment with activation of pro-survival, anti-apoptotic, and pro-angiogenic signals that favors lung tumorigenesis. Importantly, these inflammatory mediators are released by both immune (leukocytes) and non-immune cells (e.g. the epithelial/tumor cells).
Accordingly, we study the role of epithelial innate immune signaling pathways and inflammatory cells recruited by these signals to mechanistically dissect the promoting role of airway inflammation in lung carcinogenesis. To study these, we have generated/obtained knockout mice for each pathway, and cells, and we have also developed techniques to transgenically overexpress them. Students and fellows working in my laboratory will have the opportunity to study lung biology, airway inflammation, molecular aspects of lung cancer, and tumor microenvironment while applying different techniques in these genetically engineered mice.
Since cigarette smoking is the principal cause of both COPD and lung cancer, a successful, straightforward, preventive strategy to reduce the incidence of both diseases is sustained prevention of tobacco consumption. However, not all individuals respond to behavioral intervention. Furthermore, because of the persistent risk among former smokers, and increased diagnosis of early stage lung cancer with the recommended screening method (low dose CT scan), and current failure in directly targeting the most common mutated gene, K-ras, in lung cancer patients, preventive strategies targeting pathways, e.g., inflammation, which stop the progression from COPD to lung cancer and from early stage to to late stage lung cancer are additionally required.
Our research projects, by having the potential to detect and target important microenvironments and pro-carcinogenic pathways in the lungs, would have a major impact on preventing the leading cause of cancer death by providing the basis for rationally directed therapy in patients at high risk for lung cancer development, and patients with early stage tumors.