Cancers consist of mutated tumor cells and a diverse array of 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 cancer initiation and progression, the microenvironment changes dynamically in architecture, gene expression, synthesis of soluble mediators and extracellular matrix deposition. Increased macrophage infiltration is strongly associated with poor prognosis in human lung cancer patients. Activation of endothelial cells in the tumors leads to release of growth factors that further support the proliferation of tumor cells and tumor angiogenesis.
Macrophage-mediated inflammation that promotes pulmonary carcinogenesis.
Macrophages are important in supporting inflammation that helps tumor cells to grow, and their infiltration is associated with an unfavorable clinical prognosis in patients. Our results suggest that expression of Foxm1 transcription factor increases inflammation. We study the direct role of Foxm1 in macrophages during lung and prostate cancer formation using mice with macrophage-specific Foxm1 deletion.
Regulation of endothelial cells during tumor-mediated angiogenesis.
In most tumors, vascularization starts with the activation of endothelial cells by specific growth factors, followed by endothelial cell proliferation and / or migration. Since it was shown that Foxm1 regulates both cell proliferation and migration, we hypothesize that deletion of Foxm1 from endothelial cells will disrupt endothelial cells ability to proliferate and / or migrate, preventing tumor angiogenesis in lung cancers. Our laboratory is working to determine whether specific deletion of Foxm1 or Foxf1 genes in endothelial cells inhibits formation of lung cancer by decreasing tumor-associated angiogenesis. Mice with endothelial-specific Foxm1 or Foxf1 deletion are utilized for these studies.
Role of fibroblasts in carcinogenesis.
Mice with fibroblast-specific Foxm1 or Foxf1 deletion utilized in these studies.