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

NF-κB 在基质巨噬细胞对乳腺癌致瘤基因影响中的作用

• 批准号: 8200895
• 负责人: Jennifer Webster Bradford
• 金额: $ 4.84万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8200895
• 关键词: Address; Affect; Aggressive behavior; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Biological Assay; Blood; Bone Marrow; Breast Cancer Cell; Breast Cancer Model; Cancer Patient; Cancer cell line; Cell Count; Cell Line; Cell surface; Cells; Coculture Techniques; Data; Epithelial; Event; Fatty acid glycerol esters; Feedback; Foundations; Generations; Genes; Growth Factor; Human; Immune system; Immunoblotting; Immunosuppressive Agents; Inflammatory; Knock-out; Knockout Mice; Lead; Macrophage Activation; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Matrigel Invasion Assay; Measures; Mediating; Mesenchymal; Modeling; Monitor; Mus; Myeloid Cells; NF-kappa B; Neoplasm Metastasis; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Production; Public Health; Recruitment Activity; Reporting; Resistance; Role; Signal Pathway; Sorting - Cell Movement; Stream; Testing; Therapeutic; Time; Tissues; United States; Woman; angiogenesis; base; cancer cell; chemotherapy; cytokine; human tissue; in vivo Model; inhibitor/antagonist; knock-down; macrophage; malignant breast neoplasm; member; mouse model; neoplastic cell; outcome forecast; p65; research study; response; therapeutic target; transcription factor; tumor; tumor growth; tumorigenesis

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.

描述(申请人提供)：巨噬细胞是免疫系统的基本组成部分，从血流中被招募到肿瘤中，在那里它们有助于肿瘤间质和促进致癌表型。在某些癌症中，如乳腺癌，肿瘤相关巨噬细胞(TAM)在总肿瘤质量中占相当大的比例，这与患者预后不良有关。TAMs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动，使其缺乏抗原提呈。目前还不清楚肿瘤是如何激活间质巨噬细胞的，以及这些不同的表型如何促进肿瘤的发生，但已经牵涉到了核因子：B转录因子途径。作为对巨噬细胞释放生长因子/细胞因子的响应，肿瘤细胞中的核因子：B通路可能被激活，从而促进肿瘤细胞的上皮-间充质转化(EMT)，从而导致肿瘤起始细胞(TIC)的产生和转移。因为核因子-：B通路具有潜在的治疗靶点，了解核因子-：B的激活如何影响的表型是很重要的。我们的假设是，肿瘤通过核因子-B激活间质巨噬细胞，通常表现为M2免疫抑制表型，从而相互促进肿瘤细胞中核因子-：B的激活。这影响了EMT，并最终增加了抽动的产生，从而促进了肿瘤的发生。破坏癌细胞和巨噬细胞之间的这种核因子-B反馈环路可能会导致EMT减少，抽动次数减少，从而减少肿瘤大小和转移，并提高化疗敏感性。为了验证我们的假设，我们将分析解决以下问题的三个具体目标：(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)核因子-B途径是否参与间质巨噬细胞促进乳腺癌的发生？(Iii)抑制核因子：B，潜在地通过影响巨噬细胞，是否减少了基底细胞样和人类克拉丁-低位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分析和小鼠模型的基底样癌和克拉丁低乳腺癌，以及在髓系细胞中敲除了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途径的药物抑制剂是否可能通过靶向巨噬细胞而导致肿瘤发生的减少。这项应用首次提出了使用活体模型深入研究肿瘤相关巨噬细胞和乳腺癌。该项目与公众健康直接相关，因为它将确定肿瘤相关巨噬细胞中导致免疫和促肿瘤活性失调的途径。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有重大的治疗益处。 公共卫生相关性：乳腺肿瘤中巨噬细胞的存在可能导致癌症侵袭性、转移性和化疗耐药性的增加。由于美国女性在有生之年患浸润性乳腺癌的几率为八分之一，该项目与公众健康直接相关。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提高乳腺癌患者的存活率。