Targeting lymph node metastases to prevent cancer progression

针对淋巴结转移预防癌症进展

• 批准号: 9286149
• 负责人: TIMOTHY P PADERA
• 金额: $ 39.5万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-02 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9286149
• 关键词: Address; Adoptive Transfer; Animal Model; Antigens; Arginine; B-Lymphocytes; Biological; Biology; Blood; Blood Vessels; Cancer Patient; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Chronic; Clinical; Complex; Data; Disease; Disease Progression; Disseminated Malignant Neoplasm; Distant; Distant Metastasis; Elements; Enzymes; Equipment; Essential Amino Acids; Event; Exclusion; Goals; Growth; Growth Factor; Hepatocyte; High Endothelial Venule; Home environment; Immune; Immune response; Immune system; Immunologist; Immunology procedure; Immunosuppression; Immunosuppressive Agents; In Vitro; Infiltration; Interdisciplinary Study; Interleukin-10; Invaded; Knowledge; Label; Laboratories; Lesion; Liquid substance; Lung; Lymph; Lymphatic Metastasis; Lymphatic System; Lymphocyte; Lymphocyte Activation; Malignant Lymph Node Neoplasm; Malignant Neoplasms; Measures; Mediating; Metastatic Melanoma; Metastatic Neoplasm to Lymph Nodes; Microscopy; Modeling; Molecular; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Patients; Play; Positioning Attribute; Primary Neoplasm; Process; Production; Prognostic Marker; Radiation; Recommendation; Regimen; Reticular Cell; Risk; Role; Seeds; Signal Transduction; Site; Survival Rate; System; Systemic Therapy; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; Transgenic Animals; Translating; Travel; Tryptophan; Tryptophan 2,3 Dioxygenase; Tumor Cell Migration; Tumor Immunity; Work; adaptive immunity; angiogenesis; arginase; cancer cell; cell motility; cell type; chemokine; experience; image processing; immune function; improved; improved outcome; in vivo; innovation; intravital imaging; intravital microscopy; lymph nodes; macrophage; member; migration; mouse model; neoplastic cell; neutrophil; novel; novel therapeutic intervention; novel therapeutics; outcome forecast; prevent; response; time use; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT Breakthroughs in our knowledge of the molecular and cellular mechanisms regulating metastasis have yet to be broadly translated into improved survival rates for patients with metastatic disease. Lymph node metastasis in a cancer patient brings with it a poorer prognosis and the recommendation for systemic therapy. However, it is unclear whether lymphatic metastases are only predictive or whether they play a role in cancer progression and the emergence of distant metastases. Evidence shows that treating lymph node metastases improves survival in some patients. The work proposed here aims to build a biological understanding of lymph node metastases in order to define their role in disease progression and identify new therapeutic interventions to improve patient survival. Recently, we have shown that lymph node metastases do not require angiogenesis to grow and do not respond to anti-angiogenic therapy. We will build upon our unique expertise by addressing why lymph node metastasis are such strong prognostic indicators and explore how lymph node metastasis drive cancer progression. Specifically, we will test the hypotheses that lymph node metastases disseminate to distant sites (Aim 1) and inhibit the ability of the immune system to develop and maintain anti-tumor immunity (Aim 2). We will accomplish our goals using innovative animal models that allow state-of-the-art intravital microscopy of spontaneous lymph node metastasis. In Aim 1, we will determine whether cancer cells utilize the fibroblastic reticular cell-lined conduit system in lymph nodes to home to blood vessels and spread to distant sites. We will attempt to block this process. In Aim 2, we will determine whether metastatic lymph nodes retain the ability to initiate immune responses to new antigens. Further, we will determine the mechanism of immune suppression in metastatic lymph nodes. We will attempt to increase immune effector function in lymph node metastases to eradicate lymph node disease and stimulate systemic anti-tumor immunity. In completing these aims, we will have better lymph node focused therapeutic options to limit the growth and spread of cancer from lymph nodes and thus provide better outcomes for patients. Critical elements to achieving these goals are intravital imaging equipment, complex animal models and functional immunological assays, all available in the PI’s laboratory. In addition, the assembled team has complementary expertise that will enable them to overcome any problems that occur during the project. Dr. Padera is an expert in intravital microscopy of the lymphatic system and mechanisms of lymph node metastasis. Dr. Carroll is an immunologist with deep knowledge of fluid and cellular transport in lymph nodes as well as adaptive immunity. Dr. Munn has expertise in image processing and quantitative biology with experience in measuring directed cell migration. Each team member, along with our collaborators, will play a critical role in this interdisciplinary research, uniquely positioning us to address these clinically driven questions. With the completion of our studies we will be able to better contain and eradicate lymph node metastasis to extend survival for patients with metastatic cancer.

项目摘要/摘要 我们在调控转移的分子和细胞机制方面的知识尚未取得突破 广泛地转化为转移性疾病患者存活率的提高。淋巴转移 癌症患者的预后较差，并建议进行系统治疗。然而，它 目前尚不清楚淋巴转移是仅仅是预测性的，还是在癌症进展中起作用。 以及远处转移的出现。有证据表明，治疗淋巴转移可以改善 一些患者的存活率。这里提出的工作旨在建立对淋巴结的生物学理解 转移，以确定它们在疾病进展中的作用，并确定新的治疗干预措施 提高患者存活率。最近，我们已经表明，淋巴结转移不需要血管生成来 生长，并且对抗血管生成治疗没有反应。我们将以我们独特的专业知识为基础，通过解决 为什么淋巴结转移是如此强大的预后指标，并探讨淋巴转移是如何 推动癌症的发展。具体地说，我们将测试淋巴转移扩散到 远距离位点(目标1)和抑制免疫系统发展和维持抗肿瘤免疫的能力 (目标2)。我们将使用创新的动物模型来实现我们的目标，这些模型允许最先进的体内 自发性淋巴结转移的显微镜检查。在目标1中，我们将确定癌细胞是否利用 淋巴结内成纤维细胞网状细胞管道系统通向血管并向远处扩散 网站。我们将尝试阻止此过程。在目标2中，我们将确定转移性淋巴结是否保留 启动对新抗原的免疫反应的能力。进一步，我们将确定免疫的机制。 转移性淋巴结中的抑制。我们将尝试增加淋巴结的免疫效应功能 转移，以根除淋巴疾病，并刺激全身抗肿瘤免疫。在完成这些工作时 旨在，我们将有更好的以淋巴结为重点的治疗选择，以限制癌症的生长和扩散。 这种方法可以减少淋巴结转移，从而为患者提供更好的结果。实现这些目标的关键要素是 活体成像设备、复杂动物模型和功能免疫分析，所有这些都可以在 派的实验室。此外，组建的团队拥有互补的专业知识，使他们能够 克服项目过程中出现的任何问题。帕德拉博士是活体显微镜方面的专家 淋巴系统和淋巴转移的机制。卡罗尔博士是一位免疫学家，他对 有关淋巴结液和细胞转运以及获得性免疫的知识。芒恩博士有专业知识 在图像处理和定量生物学方面有测量细胞定向迁移的经验。每支队伍 成员和我们的合作者将在这项跨学科研究中发挥关键作用， 使我们能够解决这些临床驱动的问题。随着我们学习的完成，我们将能够 更好地遏制和根除淋巴转移，以延长转移性癌症患者的生存期。