Lung cancers consist of genetically altered epithelial tumor cells and a diverse array of stromal and inflammatory cells, including macrophages, endothelial cells, fibroblasts, lymphocytes and some others. During lung cancer initiation and progression, the microenvironment of the tumors changes dynamically. The result of the changes is the activation of non-tumor cells in tumor lesions. Persistent activation of macrophages causes local chronic inflammation that promotes lung tumorigenesis. Activation of endothelial cells in the tumors results in tumor angiogenesis. The FoxM1 transcription factor is expressed in all proliferating cells, including epithelial cells, macrophages and endothelial cells. The Foxm1 protein is induced in a variety of human cancers, including non-small cell lung cancers. Although previous studies from our laboratory demonstrated a critical role of Foxm1 in lung tumorigenesis, specific requirements for the Foxm1 transcription factor in different populations of respiratory cells in vivo remain unknown. In this grant proposal, we provide preliminary data demonstrating that conditional deletion of Foxm1 in lung epithelial cells, the precursors of tumor cells, causes striking delay in initiation and progression of lung tumors. However, lung cancer lesions contain not only tumor cells, but also diverse stromal and inflammatory cells of tumor promoting microenvironment. To study the cell autonomous role of Foxm1 in the tumor microenvironment, we propose to utilize new mouse models with endothelial cell-specific or macrophage-specific Foxm1 deletion. The goal of this proposal is to use both genetic and pharmacological approaches to test the hypothesis that inactivation of Foxm1 transcription factor in specific cells of tumor microenvironment decreases lung tumorigenesis.
Three specific aims are proposed.
In Aim 1 we will use mice with endothelial-specific Foxm1 deletion to determine whether Foxm1-deficiency in endothelial cells inhibits formation of lung cancer by decreasing tumor angiogenesis. Number and sizes of lung tumors, tumor cell proliferation and angiogenesis will be compared in endothelial-specific Foxm1 knockout mice versus control mice.
In Aim 2 we will establish whether specific deletion of Foxm1 gene in macrophages diminishes lung inflammation and decrease lung tumor formation induced by three well-characterized carcinogenesis protocols: urethane, MCA/BHT and inducible K-ras.
In Aim 3 we will develop the therapeutic treatment for lung tumor bearing mice using pharmacological inhibition of Foxm1 transcriptional activity with ARF 26-44 peptide, a known Foxm1 inhibitor. Our preliminary data show that nasal administration of a mixture of InfaSurf (Surfactant) and fluorescently tagged ARF 26-44 peptide is effectively delivered to all cell types of the lung. The lung tumor-bearing mice will be treated with ARF peptide to determine whether this ARF peptide diminishes proliferation of tumor cell, decreases tumor angiogenesis and decreases inflammation in mouse lung tumors. Completion of the proposed studies will enable us to determine whether Foxm1 plays critical role in tumor microenvironment and whether Foxm1 is an important target for lung cancer treatment.
The present study seeks to identify the direct role of Foxm1 in macrophages and endothelial cells during initiation and progression of lung cancer and to develop the therapeutic treatment for lung tumor bearing mice using pharmacological inhibition of Foxm1 transcriptional activity with ARF 26-44 peptide, a known Foxm1 inhibitor. The novel signaling pathways in lung cancer initiation and progression will be studied, which will allow us to better understand the molecular mechanisms responsible for this disease. Completion of the proposed studies will enable us to determine whether the cell specific inhibition of Foxm1 will offer new strategies to prevent chronic lung inflammation and angiogenesis and to determine whether pharmacological inhibition of Foxm1 will provide information regarding potential novel targets for drug design to treat lung cancer.
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