Role of Foxm1 in Lung Cancer Microenvironment

Foxm1在肺癌微环境中的作用

• 批准号: 8295951
• 负责人: Tanya Kalin
• 金额: $ 30.8万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-20 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295951
• 关键词: 3-Methylcholanthrene; Accounting; Apoptosis; Applications Grants; Architecture; Boxing; Breeding; Butylated Hydroxytoluene; Cancer Biology; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chronic; Cytotoxic Chemotherapy; Data; Deposition; Disease; Drug Design; Drug resistance; Elastases; Employee Strikes; Endothelial Cells; Epithelial; Epithelial Cells; Extracellular Matrix; Family; Fibroblasts; Foxes; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Growth; Growth Factor; Human; Immune; In Vitro; Infasurf; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Knockout Mice; Laboratories; Lesion; Lung; Lung Adenoma; Lung Inflammation; Lung Neoplasms; Lymphocyte; Macrophage Activation; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Membrane; Mesenchyme; Microscopy; Molecular; Mus; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Nose; Patients; Peptides; Play; Population; Primary carcinoma of the liver cells; Proliferating; Proteins; Protocols documentation; Publishing; Recruitment Activity; Role; Signal Pathway; Signal Transduction; Support System; Tamoxifen; Testing; Therapeutic; Transgenic Mice; Tumor Angiogenesis; Tumor Expansion; Urethane; angiogenesis; cancer initiation; cancer therapy; carcinogenesis; cell type; clinically relevant; cyclooxygenase 2; fibromodulin; in vivo; inhibitor/antagonist; knock-down; lung carcinogenesis; lung tumorigenesis; macrophage; member; mouse model; neoplastic; neoplastic cell; novel; novel therapeutic intervention; outcome forecast; prevent; public health relevance; recombinase; research study; respiratory; surfactant; transcription factor; treatment strategy; tumor; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（申请人提供）：肺癌由基因改变的上皮肿瘤细胞和多种基质和炎症细胞组成，包括巨噬细胞、内皮细胞、成纤维细胞、淋巴细胞和其他一些细胞。在肺癌的发生和发展过程中，肿瘤的微环境是动态变化的。这种变化的结果是激活肿瘤病变中的非肿瘤细胞。巨噬细胞的持续激活引起局部慢性炎症，促进肺肿瘤的发生。肿瘤中内皮细胞的活化导致肿瘤血管生成。FoxM1转录因子在所有增殖细胞中均有表达，包括上皮细胞、巨噬细胞和内皮细胞。Foxm1蛋白在多种人类癌症中被诱导，包括非小细胞肺癌。虽然我们实验室之前的研究证明了Foxm1在肺肿瘤发生中的关键作用，但体内不同呼吸细胞群体对Foxm1转录因子的具体需求仍然未知。在这项拨款申请中，我们提供了初步数据，证明肺上皮细胞（肿瘤细胞的前体）中Foxm1的条件缺失导致肺肿瘤的发生和进展显著延迟。然而，肺癌病变中不仅含有肿瘤细胞，还含有多种促瘤微环境的间质细胞和炎症细胞。为了研究Foxm1在肿瘤微环境中的细胞自主作用，我们建议利用内皮细胞特异性或巨噬细胞特异性Foxm1缺失的新小鼠模型。本研究的目的是利用遗传学和药理学两种方法来验证肿瘤微环境中特定细胞Foxm1转录因子失活可降低肺肿瘤发生的假设。提出了三个具体目标。在Aim 1中，我们将使用内皮特异性Foxm1缺失的小鼠来确定内皮细胞中Foxm1缺失是否通过减少肿瘤血管生成来抑制肺癌的形成。将比较内皮特异性Foxm1敲除小鼠与对照小鼠肺肿瘤的数量和大小、肿瘤细胞增殖和血管生成。在Aim 2中，我们将确定巨噬细胞中Foxm1基因的特异性缺失是否会减少肺部炎症并减少三种典型的致癌方案（氨基甲酸乙酯、MCA/BHT和诱导性K-ras）诱导的肺肿瘤形成。在Aim 3中，我们将利用已知的Foxm1抑制剂ARF 26-44肽对Foxm1转录活性的药理抑制，开发肺癌荷瘤小鼠的治疗方法。我们的初步数据表明，InfaSurf（表面活性剂）和荧光标记的ARF 26-44肽的混合物经鼻给药可以有效地传递到所有类型的肺细胞。用ARF肽治疗肺荷瘤小鼠，观察该ARF肽是否能抑制小鼠肺肿瘤的肿瘤细胞增殖、抑制肿瘤血管生成、降低炎症反应。本研究的完成将使我们能够确定Foxm1是否在肿瘤微环境中起关键作用，Foxm1是否是肺癌治疗的重要靶点。