The Metastatic Cascade: Macrophages Lead the Way

转移级联：巨噬细胞引领潮流

• 批准号: 8422479
• 负责人: JEFFREY W. POLLARD
• 金额: $ 45.05万
• 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/8422479
• 关键词: Ablation; Accounting; Affect; Alleles; 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; 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（由申请人提供）：乳腺癌是女性最常见的恶性肿瘤，约占影响美国女性的所有癌症的28%。预计2011年美国女性中将发生约230，480例浸润性乳腺癌新发病例沿着54，010例非浸润性（原位）乳腺癌新发病例和39，520例乳腺癌死亡。最近的临床数据表明，局部疾病的女性总生存率显着改善，但当女性有转移性疾病时，该参数无变化。这一令人沮丧的统计数据表明，目前的治疗手段是不够的，并表明转移性肿瘤细胞对细胞毒性药物以及靶向生物制剂具有抗性。这表明需要新的方法来治疗转移性疾病，目前的应用集中在乳腺癌生物学的这一方面。 转移级联有许多步骤。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，人体内可能存在大量循环肿瘤细胞，但尽管存在这种负荷，仅发生一种或几种转移。因此，外渗、存活和在远处部位建立的步骤被认为是形成转移的主要障碍。显然，肿瘤细胞中的遗传/表观遗传变化决定了它们转移的能力和它们对特定组织的营养作用。然而，靶部位的微环境在这一过程中也发挥着重要作用，并决定了肿瘤细胞的命运。这些数据强烈表明，靶向微环境可能在治疗中具有重要价值。 我们的初步研究表明，巨噬细胞促进肿瘤细胞外渗，存活和持续生长的骨和肺，乳腺癌转移的主要网站。此外，PI最近定义了几个巨噬细胞肿瘤细胞信号传导途径，导致转移的增强。这些途径涉及配体、CCL 2、血管内皮衍生生长因子（VEGF）和集落刺激因子-1（CSF-1）及其各自的受体。本申请的目的是定义巨噬细胞在骨和肺两个转移部位中的这些促转移功能背后的机制。为此，有三个具体目标： 目的1：探讨巨噬细胞增强肺转移瘤种植的机制. 目的2：CSF-1 R促进持续生长的机制基础 目的3：明确单核吞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重要作用。这些作用背后的这些机制的定义将可能允许设计新的治疗方法，这些治疗方法可以消除转移细胞的微环境支持，并且应该增强目前使用的化学治疗剂和生物制剂。