Tumor Progression and Metastasis

项目负责人和其他人在小鼠癌症模型上的研究以及越来越多的临床 研究已达成共识，即肿瘤相关巨噬细胞(TAM)在促进 多种癌症中的恶性肿瘤。在上一次授权期内，我们建立了一些 巨噬细胞执行的促进肿瘤进展和转移的功能。这些都是通过的 炎症、基质重塑、肿瘤细胞侵袭、血管内、血管生成和外渗。在……里面 具体地说，我们发现巨噬细胞被戏剧性地聚集到良性病变中，然后对照。 恶性转化所需的血管生成开关。此外，与其他成员一起 PPG，我们表明巨噬细胞和肿瘤细胞处于专有的旁分泌关系，从而导致 在肿瘤的迁移、侵袭和侵袭中起重要作用。我们还鉴定了一组独特的巨噬细胞 这是播种和持续生长转移瘤所必需的。重要的是，我们证明了 该人群的消融导致已建立的转移灶的生长受到抑制。它的目标是 目前关于测试已建立的和新确定的路径的要求的建议 我们已经在巨噬细胞亚群中定义了，以及在 最后一个授权期，以确定导致以下疾病的巨噬细胞诱导特征的机制基础 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基础 微环境 2.明确巨噬细胞调控血管生成的分子基础。 3.确定巨噬细胞介导的促进转移种植和持续生长的机制。 乳腺癌是全世界女性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 TAMs在促进乳腺癌的进展和转移中起着重要作用。因此， 确定本申请中提出的巨噬细胞作用的分子基础将使新的 针对这些细胞的治疗。与传统疗法相比，这种疗法具有优势，旨在 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，因此它们较少 可能会产生抵抗力。

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.