Tumor Progression and Metastasis

项目负责人和其他人在小鼠癌症模型中的研究以及越来越多的临床研究， 研究已经达成共识，即肿瘤相关巨噬细胞（TAMs）在促进肿瘤生长中起主要作用。 在很多种癌症中都是恶性的。在上一次拨款期间，我们设立了多个 由巨噬细胞执行的促进肿瘤进展和转移的功能。这些是通过 炎症、基质重塑、肿瘤细胞侵袭、内渗、血管生成和外渗。在 特别是，我们发现巨噬细胞被显著地募集到良性病变中， 恶性转化所需的血管生成开关。此外，与其他成员一起， PPG，我们发现巨噬细胞和肿瘤细胞处于一种专性旁分泌关系， 在肿瘤迁移、侵袭和内渗中的作用。我们还发现了一种独特的巨噬细胞群 是转移瘤的播种和持续生长所必需的。重要的是，我们证明， 该群体的消融导致已建立的转移性病变的生长受到抑制。它的目的是 目前的建议，以测试两个既定的和新确定的途径的要求， 我们在巨噬细胞亚群中定义的，以及在 最后一个授予期，以确定巨噬细胞诱导的性状的机械基础， 恶性程度增强 具体目标是： 1.为巨噬细胞亚群在肿瘤中的作用提供机制依据 微环境 2.明确巨噬细胞调节血管生成的分子基础。 3.确定巨噬细胞介导的机制，促进转移播种和持续增长。 乳腺癌是全世界妇女癌症死亡的最常见原因之一。这是 通常由转移性疾病引起。我们使用小鼠癌症模型进行的基础生物学研究表明， TAM在促进乳腺癌的进展和转移中起主要作用。因此 鉴定本申请中提出的巨噬细胞作用的分子基础将允许新的 针对这些细胞的治疗方法。这样的治疗剂比旨在治疗癌症的常规治疗剂具有优势。 肿瘤细胞，因为这些支持细胞不表现出肿瘤细胞的遗传不稳定性， 可能会产生抗药性。

The Project leader's and others studies in mouse models of cancer together with a growing body of clinical studies has led to a consensus that tumors associated macrophages (TAMs) play a major role in promoting malignancy in a wide variety of cancers. During the last granting period we have established a number of functions performed by macrophages that promote tumor progression and metastasis. These are through inflammation, matrix remodeling, tumor cell invasion, intravasation, angiogenesis and extravasation. In particular, we showed that macrophages were dramatically recruited to benign lesions and thereafter control the angiogenic switch that is required for the malignant transition. In addition, together with other members of the PPG, we showed that macrophages and tumor cells are in an obligate paracrine relationship that results in tumor migration, invasion and intravasation. We have also identified a unique population of macrophages that are required for seeding and persistent growth of metastases. Importantly we demonstrated that ablation of this population resulted in an inhibition of growth of established metastatic lesions. It is the aim of the current proposal to test out the requirement for both well-established and the newly identified pathways that we have defined in macrophage sub-populations, as well as unique mouse models developed during the last granting period, to identify the mechanistic basis of the macrophage-induced traits that lead to enhanced malignancy. The specific aims are: 1. To provide the mechanistic basis for the functions of macrophage sub-populations in the tumor microenvironment 2. Define the molecular basis of macrophage regulation of angiogenesis. 3. Identify macrophage mediated mechanisms that promote metastatic seeding and persistent growth. Breast cancer is one of the most common causes of cancer death in women throughout the world. This is usually caused by metastatic disease. Our basic biology research using mouse models of cancer implicate TAMs as playing a major role in promoting the progression and metastasis of mammary cancer. Thus identifying the molecular basis for the macrophage actions proposed in this application will allow novel therapeutics targeted to these cells. Such therapeutics have an advantage over conventional ones aimed at tumor cells since these support cells do not exhibit the genetic instability of tumor cells and thus they are less likely to develop resistance.