The Metastatic Cascade: Macrophages Lead the Way

转移级联：巨噬细胞引领潮流

• 批准号: 8601300
• 负责人: JEFFREY W. POLLARD
• 金额: $ 42.62万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 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/8601300
• 关键词: Ablation; Accounting; Affect; Applications Grants; Biological Products; Blood; Blood Vessels; Bone Marrow; Breast; Breast Diseases; CCL2 gene; Cancer Biology; Cancer Etiology; Cell Survival; Cell physiology; Cells; Cessation of life; Clinical Data; Cytotoxic agent; Data; Depressed mood; Development; Disease; Distant; Epigenetic Process; Extravasation; Genetic; Growth; Growth Factor; Hematopoietic; Hematopoietic stem cells; Human; Immune response; In Situ; Inflammatory; Lead; Left; Ligands; LoxP-flanked allele; Lung; Lymph; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Mammary Neoplasms; Metastatic Neoplasm to the Bone; Modeling; Mononuclear; Mutation; Myeloid Cells; Neoplasm Circulating Cells; Neoplasm Metastasis; Osteoclasts; Pathway interactions; Phagocytes; Play; Population; Primary Neoplasm; Process; Receptor Signaling; Recruitment Activity; Resistance; Role; Signal Pathway; Signal Transduction; Site; Staging; Testing; Therapeutic; Tissues; Travel; Tumor Angiogenesis; Tumor Cell Invasion; Vascular Endothelial Growth Factor Receptor-1; Woman; angiogenesis; base; bone; cell type; chemotherapeutic agent; conventional therapy; density; innovation; macrophage; malignant breast neoplasm; malignant phenotype; migration; monocyte; mortality; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutics; outcome forecast; public health relevance; receptor; statistics; stem cell niche; tumor; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): Breast Cancer is the most common malignancy in women, accounting for approximately 28% of all cancers affecting US women. Approximately 230,480 new cases of invasive breast cancer along with 54,010 new cases of non-invasive (in situ) breast cancer and 39,520 breast cancer deaths are expected to occur among US women in 2011. Recent clinical data indicated significant improvement in overall survival in women with local disease but no change in this parameter when women have metastatic disease. This depressing statistic shows that the current armamentarium of therapeutics is inadequate and indicates the metastatic tumor cells are resistant to cytotoxic drugs as well as targeted biologics This indicates the need for new approaches to the treatment of metastatic disease and it is this aspect of breast cancer biology that the current application is focused upon. The metastatic cascade has many steps. Firstly the tumor cells need to leave the primary site and travel through the lymph to the blood or to directly enter the blood. Data shows that there can be large numbers of circulating tumor cells in humans but despite this load only one or a few metastases occur. Thus the steps of extravasation, survival and establishment at distant sites are thought to be major barriers to the formation of metastases. Clearly the genetic/epigenetic changes in the tumor cells define their ability to be metastatic and their trophism to particular tissues. However, the microenvironment of the target site also plays a significant role in this process and determines the fate of the tumor cells. These data strongly suggest that targeting the microenvironment could be of significant value in therapy. Our preliminary studies have shown that macrophages promote tumor cell extravasation, survival and persistent growth in bone and lung, the primary sites of breast cancer metastasis. In addition the PI has recently defined several macrophage-tumor cell-signaling pathways that result in the enhancement of metastasis. These pathways involve the ligands, CCL2, vascular endothelial derived growth factor (VEGF) and colony stimulating factor-1 (CSF-1) and their respective receptors. It is the intent of this application to define the mechanisms behind these pro-metastatic functions of macrophages in the two metastatic sites bone and lung. To do this there are three specific aims: Aim 1: The mechanistic basis for macrophage enhancement of metastatic seeding in the lung. Aim 2: Mechanistic Basis of CSF-1R Promotion of Persistent Growth Aim 3: Define the role of mononuclear phagocytes in bone marrow metastasis. Our strategies are innovative and novel because we are defining important microenvironmental controls of metastatic seeding and subsequent growth. Our focus upon macrophages is because they have been shown to have important roles in this process. Definition of these mechanism behind these actions will potentially allow novel therapeutics to be devised that pull away the microenvironmental support for metastatic cells and which should enhance the chemotherapeutic and biological agents currently in use.

描述(申请人提供)：乳腺癌是女性最常见的恶性肿瘤，约占所有影响美国女性的癌症的28%。2011年，美国女性中预计将出现大约230,480例浸润性乳腺癌新病例、54,010例非浸润性(原位)乳腺癌新病例和39,520例乳腺癌死亡病例。最近的临床数据表明，患有局部疾病的女性的总体存活率显著提高，但当女性患有转移性疾病时，这一参数没有变化。这一令人沮丧的统计数据表明，目前的治疗手段是不够的，并表明转移的肿瘤细胞对细胞毒药物和靶向生物制剂具有耐药性，这表明需要新的方法来治疗转移疾病，而目前的应用正是集中在乳腺癌生物学的这一方面。 转移的级联有许多步骤。首先，肿瘤细胞需要离开原发部位，通过淋巴进入血液或直接进入血液。数据显示，在人类体内可以有大量的循环肿瘤细胞，但尽管有这样的负载，只有一个或几个转移发生。因此，外渗、存活和在远处建立的步骤被认为是形成转移的主要障碍。显然，肿瘤细胞的遗传/表观遗传变化决定了它们的转移能力以及它们对特定组织的滋养能力。然而，靶点的微环境在这一过程中也起着重要的作用，并决定着肿瘤细胞的命运。这些数据强烈表明，以微环境为靶点在治疗中可能具有重要价值。 我们的初步研究表明，巨噬细胞促进肿瘤细胞在骨和肺内的外渗、存活和持续生长，而骨和肺是乳腺癌转移的主要部位。此外，PI最近定义了几个巨噬细胞-肿瘤细胞-信号通路，这些信号通路导致了转移的增强。这些通路涉及配体、CCL2、血管内皮细胞衍生生长因子(VEGF)和集落刺激因子-1(CSF-1)及其各自的受体。这项应用的目的是确定巨噬细胞在骨和肺两个转移部位的这些促转移功能背后的机制。要做到这一点，有三个具体目标： 目的1：巨噬细胞增强肺转移种植的机制。 目的2：CSF-1R促进持续生长的机制基础 目的3：明确单核巨噬细胞在骨髓转移中的作用。 我们的策略是创新和新颖的，因为我们正在定义转移性播种和随后生长的重要微环境控制。我们对巨噬细胞的关注是因为它们已被证明在这一过程中发挥着重要作用。对这些作用背后的机制的定义将可能使人们能够设计出新的治疗方法，从而消除对转移细胞的微环境支持，并应加强目前使用的化疗和生物制剂。