The Role of NF-kappaB in Stromal Macrophage Influence on Breast Cancer Tumorigene

描述（由申请人提供）：巨噬细胞是免疫系统的重要组成部分，从血流中招募到肿瘤，在那里它们有助于肿瘤基质并促进致癌表型。在某些癌症中，如乳腺癌，肿瘤相关巨噬细胞（tam）占肿瘤总质量的很大一部分，这与患者预后不良有关。tam通常被癌细胞激活为M2免疫抑制表型，导致抗炎因子的产生，促进血管生成和组织重塑活性，并使其成为不良的抗原呈递物。目前尚不清楚肿瘤如何激活基质巨噬细胞，以及这些不同表型如何促进肿瘤发生，但NF-:B转录因子途径已被涉及。在巨噬细胞释放生长因子/细胞因子的作用下，癌细胞内NF-:B通路可能被激活，促进肿瘤细胞上皮-间质转化（epithelial-mesenchymal transition， EMT），从而导致肿瘤起始细胞（tumor initiation cell， TIC）产生和转移。由于NF-:B通路具有靶向治疗的潜力，了解NF-:B活化如何影响TAM表型是很重要的。我们的假设是肿瘤通过NF-:B激活间质巨噬细胞，通常是M2免疫抑制表型，这反过来增加了肿瘤细胞中NF-:B的激活。这影响EMT，并最终增加tic的产生以促进肿瘤发生。癌细胞和巨噬细胞之间的这种NF-:B反馈回路的破坏可能导致EMT减少，tic减少，因此，肿瘤大小和转移减少，化疗敏感性增强。为了验证我们的假设，我们将分析三个具体目标，解决以下问题：(i)乳腺癌巨噬细胞的激活是否具有增强EMT和乳腺癌表型的功能？（ii） NF-:B通路是否参与基质巨噬细胞促进乳腺癌肿瘤发生？（iii） NF-:B抑制是否可能通过影响巨噬细胞来减少基底样和人低claudin乳腺肿瘤模型的肿瘤发生？为了回答这些问题，我们将利用基于细胞的检测和基底样和低claudin乳腺癌的小鼠模型，以及骨髓细胞中NF-:B和IKK被敲除的小鼠模型。重要的是，这些模型将使我们能够确定NF-:B途径的药理学抑制剂是否可能通过靶向巨噬细胞导致肿瘤发生减少。该应用首次提出了利用体内模型对肿瘤相关巨噬细胞和乳腺癌进行深入研究。该项目与公共卫生直接相关，因为它将确定肿瘤相关巨噬细胞中导致免疫和肿瘤促进活性失调的途径。抑制肿瘤相关巨噬细胞的促癌活性可能对包括乳腺癌在内的化疗耐药癌症具有重要的治疗益处。

DESCRIPTION (provided by applicant): Macrophages are essential components of the immune system and are recruited from the blood stream to tumors where they contribute to the tumor stroma and promote oncogenic phenotypes. In certain cancers, like those of the breast, tumor-associated macrophages (TAMs) comprise a significant portion of total tumor mass, which correlates with poor patient prognosis. TAMs are often activated by cancer cells to an M2 immunosuppressive phenotype, which results in the production of anti-inflammatory factors, promotion of angiogenesis and tissue remodeling activity, and makes them poor antigen presenters. It is still unclear how tumors alternatively activate stromal macrophages and how these different phenotypes promote tumorigenesis, but the NF-:B transcription factor pathway has been implicated. In response to macrophage release of growth factors/cytokines, the NF-:B pathway might be activated in cancer cells to promote epithelial-mesenchymal transition (EMT) in tumor cells, which can lead to tumor initiating cell (TIC) generation and metastasis. Because the NF-:B pathway has the potential to be targeted therapeutically, understanding how NF-:B activation influences TAM phenotype is important. Our hypothesis is that tumors activate stromal macrophages via NF-:B, typically to an M2 immunosuppressive phenotype, which reciprocally increases NF-:B activation in the tumor cells. This influences EMT, and ultimately, increases generation of TICs to enhance tumorigenesis. Disruption of this NF-:B feedback loop between cancer cells and macrophages may lead to decreased EMT, fewer TICs, and therefore, decreased tumor size and metastases, and enhanced chemotherapy sensitivity. To test our hypothesis, we will analyze three specific aims addressing the following questions: (i) Does breast cancer activation of macrophages function to enhance EMT and breast cancer phenotypes? (ii) Is the NF-:B pathway involved in stromal macrophage promotion of breast cancer tumorigenesis? (iii) Does NF-:B inhibition, potentially by affecting macrophages, decrease tumorigenesis in basal-like and human claudin-low breast tumor models? To answer these questions we will utilize cell-based assays and mouse models of basal-like and claudin-low breast cancer and mouse models that have NF-:B and IKK knocked out in myeloid cells. Importantly, these models will allow us to determine if pharmacological inhibitors against the NF-:B pathway result in decreased tumorigenesis, potentially through targeting macrophages. This application proposes the first in-depth study of tumor-associated macrophages and breast cancer using in vivo models. This project is directly relevant to public health because it will determine pathways in tumor-associated macrophages that lead to dysregulated immunological and tumor promoting activity. Inhibiting the cancer promoting activity of tumor associated macrophages could have major therapeutic benefits for chemoresistant cancers, including breast cancer.