Mechanisms and therapeutic targets of cancer metastasis

癌症转移的机制和治疗靶点

• 批准号: 10307085
• 负责人: Gregory L Beatty
• 金额: $ 36.43万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307085
• 关键词: Acute-Phase Proteins; Address; Agonist; Amyloid Proteins; Biology; CD47 gene; Cancer Model; Cell Proliferation; Cells; Clinical; Cytotoxic Chemotherapy; Deposition; Development; Disease; Elements; Environment; Equilibrium; Extracellular Matrix; Extracellular Matrix Proteins; Genetic; Goals; Growth; Hepatic Stellate Cell; Hepatocyte; Immunologics; Interleukin-6; KPC model; KRASG12D; Kupffer Cells; Liver; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mechanics; Metabolic; Metastatic Neoplasm to the Liver; Modeling; Molecular; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Nature; Neoplasm Circulating Cells; Neoplasm Metastasis; Neutrophil Infiltration; Non-Malignant; Outcome; Pancreas; Pliability; Primary Neoplasm; Process; Property; Risk; Role; STAT3 gene; Serum; Shapes; Signal Pathway; Signal Transduction; Soil; TNFRSF5 gene; Testing; Therapeutic; Treatment Efficacy; Tropism; Variant; Work; cancer cell; cancer site; carcinogenesis; chemotherapy; clinically relevant; design; human disease; improved; macrophage; mortality; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; pancreatic ductal adenocarcinoma model; prevent; standard of care; therapeutic target; therapy design/development; tool; tumor

Project Summary Metastasis is the primary cause of morbidity and mortality in cancer with little improvement in outcomes over the past decade. This is particularly evident in gastrointestinal cancers where metastasis to the liver is the most common site of cancer cell spread. We hypothesize that the spread and growth of cancer cells in the liver is dependent on formation of a reversible niche environment that is directed by hepatocytes, the chief functional cells of the liver. In support of this hypothesis, we have found that primary tumors release soluble factors that activate hepatocytes in the liver. This process begins during the earliest stages of cancer development. Activated hepatocytes respond by releasing acute phase reactants which orchestrate a niche environment in the liver that is underpinned by the recruitment of neutrophils and myeloid cells and the deposition of extracellular matrix proteins. This environment supports cancer cell seeding and colonization. In the absence of this pro-metastatic niche, disseminated cancer cells enter a state of cell dormancy in the liver. Although macrophages are a first- line of defense against metastasis to the liver, their biology is also altered during formation of the niche environment in the liver. Thus, our findings identify an intercellular network within the liver underpinned by hepatocytes that responds to cancer development by preparing the “soil” that supports cancer cell “seeding”. Our ultimate goal is to devise novel therapies that will resolve the pro-metastatic niche and redirect the liver environment from pro- to anti-metastatic for treating and preventing cancer metastasis. However, this will require an understanding of the signals by which hepatocytes direct formation of the niche and identification of strategies capable of reversing the pro-metastatic potential of the niche. Therefore, in Aim 1, we will define the downstream signals by which hepatocytes coordinate formation of a pro-metastatic niche in the liver. In Aim 2, we will identify strategies to shift the niche environment in the liver from pro- to anti-metastatic. In Aim 3, we will investigate the impact of hepatocytes on cancer cell dormancy in the liver and the efficacy of cytotoxic chemotherapy. Together, these complementary aims will inform the development of therapies designed to condition the liver for anti- metastatic potential as a strategy to prevent and treat cancer metastasis.

项目摘要 转移是癌症发病率和死亡率的主要原因，而与 过去十年。这是胃肠道癌的尤其证据，其中转移到肝脏是最多的 癌细胞扩散的常见部位。我们假设癌细胞在肝脏中的扩散和生长是 取决于由肝细胞指导的可逆利基环境的形成，这是主要功能 肝细胞。为了支持这一假设，我们发现原发性肿瘤释放了固体因素 激活肝脏中的肝细胞。这个过程始于癌症发展的最早阶段。活性 肝细胞的反应是释放急性相应反应物，这些反应物在肝脏中精心策划了一个小众环境 受嗜中性粒细胞和髓样细胞的募集以及细胞外基质的沉积为基础 蛋白质。该环境支持癌细胞播种和定植。在没有这个亲解的情况下 利基，传播的癌细胞进入肝脏中的细胞休眠状态。虽然巨噬细胞是首先 防御转移向肝脏的防御线，其生物学在成立时也发生了变化 肝脏中的环境。这，我们的发现确定了由肝脏内部的细胞间网络。 通过准备支持癌细胞“播种”的“土壤”来对癌症发展做出反应的肝细胞。 我们的最终目标是设计新的疗法，这些疗法将解决亲戚的利基市场并重定向肝脏 从促进到抗中转移的环境，用于治疗和预防癌症转移。但是，这需要 了解肝细胞直接形成利基的信号和策略的识别 能够逆转利基市场的促进潜力。因此，在AIM 1中，我们将定义下游 肝细胞坐标形成肝脏中的丙蜜人属裂市场的信号。在AIM 2中，我们将确定 将肝脏中的利基环境转移到抗过程中的策略。在AIM 3中，我们将调查 肝细胞对肝脏癌细胞休眠的影响和细胞毒性化学疗法的效率。一起， 这些完整的目标将告知旨在调节肝脏抗肝脏的疗法的发展 转移性潜力作为预防和治疗癌症转移的策略。