Eicosanoids in Lung Cancer: Progression and Metastasis

类二十烷酸在肺癌中的作用：进展和转移

• 批准号: 8598081
• 负责人: RAPHAEL A. NEMENOFF
• 金额: $ 31.1万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598081
• 关键词: Address; Affect; Animal Model; Animals; Apoptosis; Arachidonic Acids; Biological; Biology; Bone Marrow; Brain; Cancer Etiology; Cancer cell line; Cell Communication; Cells; Cessation of life; Clinical; Clinical Data; Coculture Techniques; Complex; Cytochrome P450; Cytosolic Phospholipase A2; Data; Development; Diagnosis; Dinoprostone; Distant; Eicosanoid Production; Eicosanoids; Epithelial; Epithelial Cells; Epoprostenol; Exhibits; Family; Growth; Human; Immune; In Vitro; Knock-out; Knockout Mice; Laboratories; Leukotriene C4; Lipoxygenase; Liver; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Mediastinal lymph node group; Mediating; Membrane; Modeling; Molecular; Molecular Mechanisms of Action; Mus; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Nude Mice; Oncogenic; Organ; Outcome; Pathway interactions; Patients; Pattern; Phenotype; Phospholipids; Play; Primary Neoplasm; Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Prostaglandins I; Proteins; Role; Sampling; Site; Somatic Mutation; Staging; Stromal Cells; Structure of parenchyma of lung; Survival Rate; System; Time; Tissue Banking; Tissue Banks; Transplantation; Tumor Angiogenesis; Wild Type Mouse; Work; Xenograft procedure; base; cancer cell; cancer type; cell type; cytokine; defined contribution; in vivo; in vivo Model; leukotriene-C4 synthase; liquid chromatography mass spectrometry; lung lobe; lung tumorigenesis; macrophage; migration; neoplastic cell; novel; public health relevance; research study; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths, largely due to the presence of metastasis at the time of diagnosis. During the past 25 years, studies in epithelial cancers have defined genetic changes in the tumor cells themselves. However, cancer progression and metastasis requires complex interactions between tumor cells and the surrounding stroma. Our laboratory has studied the role of cytosolic phospholipase A2-? (cPLA2) in the development of lung cancer. cPLA2 represents the rate-limiting step in production of a family of eicosanoids with diverse affects in cancer progression. We have demonstrated that cPLA2 knockout (KO) mice are protected against chemically-induced lung tumorigenesis. However, these studies do not discriminate between the action of cPLA2 in the tumor cells versus the surrounding tumor microenvironment (TME). To address this question, we developed a model in which mouse tumor cells are directly injected into the lungs of syngeneic, immune-competent mice. These cells form well-defined primary tumors which metastasize to other lobes of the lungs, the mediastinal lymph nodes and to distant organs including the liver and brain. Importantly, when identical cells are injected into cPLA2-KO mice, primary tumor growth is not significantly altered, but there is a profound inhibition of metastasis. Tumors growing in cPLA2-KO mice exhibit alterations in the pattern of macrophages surrounding the tumor, supporting a role for cPLA2 in macrophage recruitment/function. Transplantation of cPLA2 KO bone marrow into wild-type mice was sufficient to inhibit tumor metastasis and promote survival. These data demonstrate that cPLA2 has distinct effects both in tumor cells and cells of the TME. We therefore hypothesize these effects are mediated through distinct eicosanoids which are produced in a cell-specific and time dependent fashion. While previous work by many laboratories including our own has focused on the effects of specific eicosanoids, there has not been a systematic examination of the spectrum of products produced through cPLA2 and the role these molecules play in cancer progression. The advent of mass spectrometric approaches allows us to define these molecules in an unbiased way, and determine their biological effects. This project will use this approach to define the role of cPLA2 and eicosanoids in distinct cell types using both in vivo and in vitro approaches. Four Specific Aims are proposed. Aim 1 will define the eicosanoid spectrum during tumor progression in tumors, surrounding stroma, uninvolved lung and distant organs. The effects of deleting cPLA2 in specific compartments will be correlated with changes in tumor progression and alterations in the TME. Aim 2 will use in vitro studies to examine the role of cPLA2 in cancer cells and macrophages, as well as in cross-talk between these cells. Mechanistic studies will define the role of specific eicosanoids and their downstream effectors. Aim 3 will use mice deficient in production of PGE2 or LTC4 to define the role of these products in tumor progression. Finally Aim 4 will examine eicosanoid profiles in human lung cancers and correlate this with clinical data and mutational status.

描述（由申请人提供）：肺癌是癌症死亡的主要原因，很大程度上是由于诊断时存在转移。在过去的 25 年里，上皮癌的研究已经确定了肿瘤细胞本身的遗传变化。然而，癌症进展和转移需要肿瘤细胞与周围基质之间复杂的相互作用。我们实验室研究了胞浆磷脂酶A2-？ (cPLA2) 在肺癌发展中的作用。 cPLA2 代表类二十烷酸家族产生的限速步骤，对癌症进展具有多种影响。我们已经证明 cPLA2 敲除 (KO) 小鼠可以免受化学诱导的肺部肿瘤发生。然而，这些研究并没有区分 cPLA2 在肿瘤细胞中的作用与周围肿瘤微环境 (TME) 的作用。为了解决这个问题，我们开发了一种模型，将小鼠肿瘤细胞直接注射到同基因、具有免疫能力的小鼠的肺部。这些细胞形成边界明确的原发性肿瘤，转移到肺的其他叶、纵隔淋巴结以及包括肝脏和大脑在内的远处器官。重要的是，当将相同的细胞注射到 cPLA2-KO 小鼠体内时，原发肿瘤的生长没有显着改变，但对转移有深刻的抑制。 cPLA2-KO 小鼠中生长的肿瘤表现出肿瘤周围巨噬细胞模式的改变，支持 cPLA2 在巨噬细胞招募/功能中的作用。将cPLA2 KO骨髓移植到野生型小鼠体内足以抑制肿瘤转移并促进存活。这些数据表明 cPLA2 在肿瘤细胞和 TME 细胞中具有独特的作用。因此，我们假设这些作用是通过不同的类花生酸介导的，这些类花生酸以细胞特异性和时间依赖性的方式产生。虽然许多实验室（包括我们自己的实验室）之前的工作都集中在特定类二十烷酸的作用上，但尚未对 cPLA2 产生的产品谱以及这些分子在癌症进展中发挥的作用进行系统检查。质谱方法的出现使我们能够以公正的方式定义这些分子，并确定它们的生物效应。该项目将使用这种方法通过体内和体外方法来定义 cPLA2 和类二十烷酸在不同细胞类型中的作用。提出了四个具体目标。目标 1 将定义肿瘤进展过程中的类二十烷酸谱、周围基质、未受累的肺和远处器官。在特定区室中删除 cPLA2 的影响将与肿瘤进展的变化和 TME 的改变相关。目标 2 将利用体外研究来检查 cPLA2 在癌细胞和巨噬细胞中的作用，以及在这些细胞之间的串扰中的作用。机理研究将确定特定类二十烷酸及其下游效应器的作用。目标 3 将使用缺乏 PGE2 或 LTC4 产生的小鼠来确定这些产品在肿瘤进展中的作用。最后，目标 4 将检查人类肺癌中的类二十烷酸谱，并将其与临床数据和突变状态相关联。