Cell Motility in the Pathogenesis of Lung Cancer

肺癌发病机制中的细胞运动

• 批准号: 8734940
• 负责人: Steven M. Dubinett
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734940
• 关键词: Address; Attention; Automobile Driving; Behavior; Biological Markers; Biological Models; Cancer Etiology; Candidate Disease Gene; Carcinogens; Cell Separation; Cells; Cessation of life; Chemoprevention; Clinical; Coupling; Detection; Development; Disease; Disease Progression; Disease-Free Survival; Early Diagnosis; Ensure; Epithelial; Epithelial Cells; Evaluation; Event; Excision; Future; Gene Expression Profile; Gene Proteins; Genes; Genetic Programming; Goals; Growth; Heterogeneity; Human; Image; In Situ; In Vitro; Investigation; Laboratories; Lead; Lesion; Lung; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Mesenchymal; Microarray Analysis; Modeling; Molecular; Monitor; Mus; Mutation; Neoplasm Circulating Cells; Non-Small-Cell Lung Carcinoma; Onset of illness; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Premalignant; Prevalence; Property; Reporting; Research; Research Support; Resources; Risk; Role; Services; Snails; Staging; Stem cells; System; Techniques; Testing; Therapeutic; Time; Transcription Repressor/Corepressor; Veterans; Xenograft procedure; angiogenesis; base; cancer cell; carcinogenesis; cell motility; cigarette smoking; clinically relevant; effective therapy; high risk; in vivo; in vivo Model; innovation; lung carcinogenesis; malignant phenotype; metastatic process; novel; outcome forecast; programs; prototype; public health relevance; trait; tumor

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death among US Veterans. The most effective therapy is surgical resection, but lung cancer recurs in approximately 50% of patients, most commonly as metastatic disease. This suggests that micrometastatic disease is often already present at the time of surgery, but below the level of detection of our current imaging studies. This is consistent with reports of circulating tumor cells in patients with stage I non-small cell lung cancer (NSCLC). Although metastatic behavior is often considered a late event, these clinical findings suggest that the metastatic process is also operative early in the pathogenesis of the disease. These clinical observations are consistent with recent laboratory-based investigations indicating that dissemination may occur during early tumor development. Furthermore, recent studies implicate the genetic program associated with epithelial-mesenchymal transition (EMT), not only in driving metastatic behavior, but also in transforma-tion and stem cell expansion. Our preliminary studies indicate that key genes in the EMT program are responsible for both transformation and enhanced motility of human bronchial epithelial cells (HBECs). In addition, we find that HBECs expressing genes associated with EMT or common NSCLC driver mutations show marked heterogeneity in their capacity for cell motility. We hypothesize that enhanced epithelial cell motility is operative during premalignancy and is a driver of early metastatic dissemination. The proposed research will elucidate the fundamental mechanisms involved in epithelial cell motility and their potential impact on disease onset and progression by coupling novel in vitro and in vivo models of human lung carcinogenesis and an innovative motility-based cell isolation technique. We anticipate that the proposed investigations will yield a more complete understanding of the molecular determinants of lung cancer pathogenesis, which will stimulate development of more effective chemopre-vention and early detection. Here, we have focused attention on the transcriptional repressor prototype SNAI1 (Snail) as a molecular driver of the high velocity phenotype, because we find that it: 1) is up-regulated in human NSCLC and pulmonary premalignancy in situ; 2) portends a poor prognosis when elevated in early stage NSCLC and mediates tumor-promoting phenotypes in lung cancer, including angiogenesis; 3) is a driver of the stem cell expansion, transformation, and metastatic behavior of HBECs in vitro and in vivo; and 4) is a mediator of the enhanced motility and deformability of HBECs in vitro. As these properties are important for metastatic behavior, we hypothesize that motility may also facilitate lung carcinogenesis and early dissemination via both Snail/EMT-dependent and -independent expression of motility-related genes. The studies proposed in Aims 1 and 2 will identify the motility-based pathway intermediaries that play a role in early metastatic behavior and carcinogenesis in in vitro human models. By determining the prevalence of the leading motility gene candidates in human premalignant lung lesions, subAim 2B will also ensure that our subsequent detailed mechanistic studies are focused on novel drivers of motility that are relevant to the clinical situation they ae intended to investigate (pulmonary premalignancy). Finally, Aim 3 seeks to determine the contribution of the clinically-relevant motility-candidates identified in Aims 1 and 2 to growth an early metastatic seeding in vivo. By coupling 1) innovative approaches to single-cell motility and deformability analysis with 2) a novel model of premalignancy (that includes the capacity to induce transformation to cancer in a human system in mice) and 3) a rare bank of pulmonary premalignant lesions (that ensures the clinical relevance of all findings), we are uniquely poised to identify the mechanisms underlying motility that are critical for early metastatic behavior in situ. This research is a prerequisite for future studies that focus on new biomarkers of disease onset and new targets for early detection, disease monitoring, and chemoprevention for lung cancer.

描述（由申请人提供）： 肺癌是美国退伍军人癌症死亡的主要原因。最有效的治疗方法是手术切除，但大约50%的患者会复发肺癌，最常见的是转移性疾病。这表明微转移性疾病通常在手术时就已经存在，但低于我们目前成像研究的检测水平。这与I期非小细胞肺癌（NSCLC）患者中循环肿瘤细胞的报告一致。虽然转移行为通常被认为是一个晚期事件，这些临床研究结果表明，转移过程也是早期的疾病发病机制。这些临床观察结果与最近基于实验室的研究一致，表明在早期肿瘤发展期间可能发生播散。此外，最近的研究表明，与上皮-间质转化（EMT）相关的遗传程序不仅在驱动转移行为中，而且在转化和干细胞扩增中。我们的初步研究表明，EMT程序中的关键基因负责人支气管上皮细胞（HBEC）的转化和增强运动。此外，我们发现表达与EMT或常见NSCLC驱动突变相关基因的HBEC在细胞运动能力方面显示出显著的异质性。我们假设增强的上皮细胞运动性在癌前病变期间是有效的，并且是早期转移性播散的驱动因素。拟议的研究将阐明参与上皮细胞运动的基本机制及其对疾病发作和进展的潜在影响，通过耦合新的体外和体内人类肺癌发生模型和创新的基于运动的细胞分离技术。我们预期，这些研究将对肺癌发病机制的分子决定因素有更全面的了解，这将促进更有效的化学预防和早期检测的发展。在此，我们将注意力集中在转录抑制因子原型SNAI 1（Snail）作为高速表型的分子驱动因子，因为我们发现：1）在人NSCLC和肺癌前病变中原位上调; 2）当在早期NSCLC中升高时预示不良预后，并介导肺癌中的肿瘤促进表型，包括血管生成; 3）是体外和体内HBEC的干细胞扩增、转化和转移行为的驱动者;和4）是体外HBEC的增强的运动性和变形性的介导者。由于这些属性是重要的转移行为，我们假设，运动也可能促进肺癌的发生和早期传播通过蜗牛/EMT依赖和独立的运动相关基因的表达。目的1和2中提出的研究将确定在体外人类模型中早期转移行为和致癌作用中发挥作用的基于运动的途径中介。通过确定人类癌前病变中主要运动基因候选者的患病率，subAim 2B还将确保我们随后的详细机制研究集中在与他们打算研究的临床情况（肺癌前病变）相关的运动性新驱动因素上。最后，目的3试图确定目的1和2中鉴定的临床相关运动候选物对体内早期转移性播种生长的贡献。通过将1）单细胞运动性和变形性分析的创新方法与2）癌前病变的新模型相结合，（包括在小鼠中诱导人类系统转化为癌症的能力）和3）一种罕见的肺癌前病变库（确保所有发现的临床相关性），我们正处于独特的准备，以确定潜在的机制，运动是至关重要的早期转移行为在原位。这项研究是未来研究的先决条件，未来的研究重点是疾病发作的新生物标志物和肺癌早期检测、疾病监测和化学预防的新靶点。