Macrophages and Tumor Angiogenesis

描述（由申请人提供）：越来越多的证据表明，肿瘤相关巨噬细胞（TAM）在乳腺癌从良性发展为恶性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TAM与不良预后相关。 在小鼠中，巨噬细胞的消融抑制了乳腺肿瘤的进展和转移，而过度供应加速了这些过程。 TAM对肿瘤进展产生影响的机制仍然不清楚。 然而，我们最近在小鼠乳腺癌模型中的研究表明，随着肿瘤进展为恶性肿瘤，TAM调节血管生成开关。 这一发现与临床数据一致，临床数据显示TAM与乳腺癌微血管密度增加相关。 解释TAM效应的一个可能机制是通过它们产生血管内皮生长因子（VEGF）A，因为我们已经表明它们表达这种有效的血管生成因子。 最近，还显示巨噬细胞在发育期间表达Wnt配体，并且这些因子刺激血管内皮细胞（VEC）的增殖。 TAM还表达Wnt配体。 因此，这种由TAM产生的血管生成调节因子可以解释它们增强血管生成的能力，从而增强肿瘤进展。 在这项提案中，我们将评估VEGFA和Wnt配体产生的TAM在肿瘤血管生成和进展中的作用，使用复杂的小鼠遗传学在一个完善的小鼠乳腺癌模型。 具体目标是：1.确定巨噬细胞VEGFA是否对肿瘤血管生成至关重要，以及TAM VEGFA是否在培养的肿瘤中被CSF 1上调。 2.确定TAM Wnt是否调节肿瘤血管生成和进展。 3.为了确定肿瘤VEC是否是TAM Wnt应答性的以及VEGFA是否调节Wnt TAM表达。 预计在三个具体目标中提出的实验将阐明TAM增强血管生成的机制。 血管生成是肿瘤形成的关键步骤，也是肿瘤恶性化的必要条件。 鉴于TAM与人类乳腺癌中微血管密度和预后不良的相关性，所提出的研究应阐明调节该过程的新机制，这将具有临床意义，并提出新的抗血管生成疗法。 项目叙述：临床和实验证据表明，巨噬细胞在乳腺癌的进展中发挥作用。 在某种程度上，这是通过调节血管形成（血管生成），这对肿瘤生存至关重要。 该建议将定义巨噬细胞作用的机制，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.