Overview
Lung cancer is the leading cause of cancer-related deaths in men and women in the United States. It has a high morbidity because it is difficult to detect early and is frequently resistant to available chemotherapy and radiotherapy. We believe that identification of genes regulating the process of lung tumorigenesis will provide novel therapeutic targets for prevention, diagnosis and treatment of human lung cancer.
Lung cancers consist of genetically altered epithelial tumor cells and a diverse array of mesenchyme-derived stromal and inflammatory cells that are activated in and/or recruited to the neoplastic microenvironment, including macrophages, endothelial cells, fibroblasts, lymphocytes and some others. During lung cancer initiation and progression, the microenvironment of the tumor lesions changes dynamically in architecture, gene expression, synthesis of soluble mediators, and extracellular matrix deposition. The result of these changes is the activation of non-tumor cells in tumor lesions. Persistent activation of innate immune cells, especially macrophages, causes local chronic inflammation that promotes lung tumorigenesis. Increased macrophage infiltration is strongly associated with poor prognosis in human lung cancer patients. Moreover, activation of endothelial cells in the tumors leads to release of growth factors that further support the proliferation of tumor cells. The tumor reciprocates by providing endothelial growth signals, resulting in tumor angiogenesis. In addition, tumor-associated non-neoplastic cells may provide a support system that enables tumor cells to survive traditional cytotoxic therapies.
FoxM1 is a member of the Forkhead box (Fox) transcription factor family, which is a master regulator of the cell cycle. It is expressed in all proliferating cells, including epithelial cells, macrophages and endothelial cells, where it regulates genes essential for DNA replication and mitosis. Foxm1 is over-expressed in a variety of different human tumors, including non-small cell lung cancers (NSCLC). Increased Foxm1 expression in NSCLC is associated with increased proliferation of tumor cells. My laboratory recently demonstrated that ubiquitous over-expression of Foxm1 in all cell types in Rosa26-Foxm1 transgenic mice significantly increased the growth of lung tumors induced by 3-methylcholanthrene (MCA)/ butylated hydroxytoluene (BHT) [Wang, 2008, Oncogene]. Foxm1 over-expression induced lung inflammation and increased macrophage infiltration in the lung.
Although these studies demonstrated a critical role of Foxm1 in lung tumorigenesis, specific requirements for the Foxm1 transcription factor in different populations of respiratory cells remain unknown.
