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

描述（由申请方提供）：巨噬细胞是免疫系统的重要组成部分，从血流中募集至肿瘤，在肿瘤中形成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）占总肿瘤质量的很大一部分，这与患者预后不良相关。TAM通常被癌细胞激活为M2免疫抑制表型，这导致抗炎因子的产生，促进血管生成和组织重塑活性，并使它们成为不良的抗原呈递者。目前还不清楚肿瘤如何交替激活基质巨噬细胞以及这些不同的表型如何促进肿瘤发生，但NF-：B转录因子途径已被牵连。在巨噬细胞释放生长因子/细胞因子的反应中，NF-：B途径可能在癌细胞中被激活以促进肿瘤细胞中的上皮-间充质转化（EMT），这可以导致肿瘤起始细胞（TIC）的产生和转移。由于NF-：B通路具有治疗靶向的潜力，因此了解NF-：B活化如何影响TAM表型是重要的。我们的假设是肿瘤通过NF-：B活化间质巨噬细胞，典型地活化为M2免疫抑制表型，其间接增加肿瘤细胞中的NF-：B活化。这影响EMT，并最终增加TIC的产生以增强肿瘤发生。癌细胞和巨噬细胞之间的NF-：B反馈环的破坏可能导致EMT降低、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的目标，解决以下问题：（i）乳腺癌激活巨噬细胞的功能，以提高EMT和乳腺癌表型？(ii)NF-：B通路是否参与乳腺癌肿瘤发生的基质巨噬细胞促进作用？(iii)NF-：B抑制（可能通过影响巨噬细胞）是否降低基底细胞样和人低密蛋白乳腺肿瘤模型中的肿瘤发生？为了回答这些问题，我们将利用基于细胞的测定和基底细胞样和低密蛋白乳腺癌的小鼠模型以及在骨髓细胞中敲除NF-：B和IKK的小鼠模型。重要的是，这些模型将使我们能够确定针对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。 该申请提出了使用体内模型对肿瘤相关巨噬细胞和乳腺癌的第一次深入研究。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癌症促进活性可能对包括乳腺癌在内的化学抗性癌症具有重大治疗益处。 公共卫生相关性：乳腺肿瘤中巨噬细胞的存在可导致癌症侵袭、转移和对化疗的抗性增加。由于美国妇女在其一生中有八分之一的机会患上浸润性乳腺癌，因此该项目与公共卫生直接相关。能够减少巨噬细胞对肿瘤发生的影响将允许更好的治疗选择和增加乳腺癌患者的生存率。

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. PUBLIC HEALTH RELEVANCE: The presence of macrophages in breast tumors can lead to increased cancer aggression, metastasis and resistance to chemotherapy. As women in the United States have a 1 in 8 chance of developing invasive breast cancer during their lifetime, this project is directly relevant to public health. Being able to reduce the influence that macrophages have on tumorigenesis will allow for better treatment options and increased breast cancer patient survival.