Macrophages and Tumor Angiogenesis

描述(申请人提供)：越来越多的证据表明，肿瘤相关巨噬细胞()在乳腺癌从良性向恶性发展的过程中发挥关键作用。在人类中，流行病学研究表明，高密度的TAMS与预后不良有关。在小鼠中，巨噬细胞的消融抑制了乳腺肿瘤的进展和转移，而过量的供应则加速了这些过程。TAMs对肿瘤进展的影响机制至今仍不明确。然而，我们最近在乳腺癌小鼠模型上的研究表明，随着肿瘤的恶性进展，TAMS调节血管生成开关。这一发现与临床数据一致，表明TAMs与乳腺癌微血管密度增加有关。解释效应的一个可能机制是通过它们产生血管内皮生长因子A，因为我们已经证明它们表达这种强大的血管生成因子。最近，也有研究表明，巨噬细胞在发育过程中表达Wnt配体，这些因素可以刺激血管内皮细胞(VECs)的增殖。TAMs也表达Wnt配体。因此，TAMS产生的血管生成调节因子可能解释了它们增强血管生成的能力，从而促进肿瘤进展。在这项提案中，我们将使用成熟的小鼠遗传学在乳腺癌小鼠模型中评估TAMS产生的VEGFA和WNT配体在肿瘤血管生成和进展中的作用。其具体目的是：1.确定巨噬细胞VEGFA是否在肿瘤血管生成中起关键作用，以及VEGFA是否像培养时一样在肿瘤组织中被CSF1上调。2.探讨口服液对肿瘤血管生成和进展的影响。3.确定肿瘤血管内皮细胞是否对WNT有反应，以及VEGFA是否调节WNT的表达。预计在这三个特定目标中提出的实验将阐明TAMs促进血管生成的机制。血管生成是肿瘤形成的关键步骤，也是肿瘤恶变的必要条件。鉴于TAMS与人类乳腺癌微血管密度和不良预后的关系，所提出的研究将阐明调节这一过程的新机制，这将具有临床意义，并建议新的抗血管生成疗法。 项目简介：临床和实验证据表明，巨噬细胞在乳腺癌的发展过程中发挥了作用。在一定程度上，这是通过调节血管形成(血管生成)来实现的，而血管生成是肿瘤生存所必需的。这一建议将定义巨噬细胞的作用机制，这将表明新的治疗策略。

DESCRIPTION (provided by applicant): There is a growing body of evidence that suggest that tumor associated macrophages (TAM) play a critical role in the progression of breast cancer from the benign to malignant state. In humans, epidemiological studies show that a high density of TAMs is associated with poor prognosis. In mice, ablation of macrophages inhibits the progression and metastasis of mammary tumors while over-supply accelerates these processes. The mechanisms by which TAMs exert their influence on tumor progression are as yet still ill defined. However, our recent studies in mouse models of breast cancer have shown that TAMs regulate the angiogenic switch as tumors progress to malignancy. This finding is consistent with clinical data that shows the association of TAMs with increased micro-vessel density in breast cancer. One possible mechanism to explain the TAM effect is through their production of Vascular Endothelial Growth Factor (VEGF) A as we have shown that they express this potent angiogenic factor. Recently, it has also been shown that macrophages, during development, express Wnt ligands and that these factors stimulate proliferation of vascular endothelial cells (VECs). TAMs also express Wnt ligands. Thus, this production of angiogenic regulatory factors by TAMs may explain their ability to potentiate angiogenesis and, thereby, enhance tumor progression. In this proposal we will assess the role of VEGFA and Wnt ligands produced by TAMs in tumor angiogenesis and progression, using sophisticated mouse genetics in a well-established mouse-model of breast cancer. The specific aims are: 1. To determine whether macrophage VEGFA is critical for tumor angiogenesis and whether TAM VEGFA is up-regulated by CSF1 in the tumor as it is in culture. 2. To determine whether TAM Wnts regulate tumor angiogenesis and progression. 3. To determine whether tumor VECs are TAM Wnt responsive and whether VEGFA regulates Wnt TAM expression. It is expected that the experiments proposed in the three specific aims will elucidate mechanisms by which TAMs enhance angiogenesis. Angiogenesis is a critical step in the establishment of tumors and a requirement for them to become malignant. Given the association of TAMs with microvessel density and poor prognosis in human breast cancers, the studies proposed should elucidate novel mechanisms in the regulation of this process that will have clinical relevance and suggest novel anti-angiogenic therapies. Project Narrative: Clinical and experimental evidence indicates that macrophages play a role in the progression of breast cancer. In part, this is through the regulation of blood vessel formation (angiogenesis), essential for tumor survival. This proposal will define the mechanism of macrophage action that should indicate novel therapeutic strategies.