SENESCENT STROMA STIMULATES INFLAMMATION TO PROMOTE TUMORIGENESIS

衰老基质刺激炎症促进肿瘤发生

• 批准号: 10310473
• 负责人: Sheila A Stewart
• 金额: $ 35万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310473
• 关键词: Affect; Age; Aging; Animals; Atmosphere; CD8-Positive T-Lymphocytes; Cells; Chronic; Clinical Trials; Complex; Data; Development; Disease; Environment; Enzymes; Extracellular Matrix; Fibroblasts; Foundations; Future; Generations; Growth; Growth Factor; Human; Human papillomavirus 16; Hyperplasia; Immune; Immune response; Immune system; Immunocompetent; Immunocompromised Host; Immunologic Surveillance; Immunosuppression; Incidence; Infiltration; Inflammation; Inflammatory; Interleukin-6; Investigation; Knowledge; Maintenance; Malignant Neoplasms; Mediating; Mesenchymal; Modeling; Mosaicism; Mus; Mutation; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasms; Pathway interactions; Pattern; Penetrance; Phenotype; Phosphotransferases; Play; Process; Property; Proteins; Risk; Risk Factors; Role; Shelter facility; Skin; Squamous cell carcinoma; Stromal Cells; T cell response; Time; Tissues; Tumor-infiltrating immune cells; Work; age related; aged; cell growth; chemokine; immunoregulation; insight; mouse model; neoplastic cell; new therapeutic target; novel therapeutic intervention; pre-clinical; preneoplastic cell; recruit; senescence; skin squamous cell carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis; tumorigenic

Abstract Age is a significant risk factor for the development of cancer. The mechanisms that drive this risk are complex and involve both the accumulation of cell autonomous mutations within incipient tumor cells and pro-tumorigenic changes in the tumor microenvironment. Investigation into the impact of an aging microenvironment on tumorigenesis has revealed that senescent stromal cells can directly stimulate preneoplastic and neoplastic growth. Because senescent cells accumulate with age, these observations raise the possibility that senescent cells are an important contributor to age-related increases in tumorigenesis. To understand how senescent stromal cells contribute to tumorigenesis, we developed the FASST mouse (Fibroblasts Accelerate Stromal- Supported Tumorigenesis) that allows us to control the spatial and temporal activation of senescence in mesenchymal cells. Using this mouse, we found that senescent mouse skin fibroblasts (MSFs) support increased tumorigenesis in immunocompetent mice. Strikingly, we found that MSFs that arise independently of neoplastic cells mediate their pro-tumorigenic properties by modulating the host immune system and creating immunosuppression that limits CD8 T cell activity, thus allowing increased tumor growth. Previous work has focused on the ability of senescent fibroblasts to directly stimulate tumor cell growth. Thus our work is the first to show that senescent MSFs can promote tumor growth by modulating the immune system. Because we find that senescent MSFs in our model cause localized recruitment of immunosuppressive cells, similar to what we find in aging human skin, we propose that they contribute to age-related increases in tumorigenesis by creating regions of local immune suppression that shelter incipient tumor cells and allow their outgrowth. To understand the dynamics of immune modulation in the FASST model, we propose to determine the temporal pattern of immune cell infiltration, the mechanisms that drive immune cell infiltration, and the senescence-specific factors that drive the development and maintenance of the suppressive microenvironment present in the FASST mouse. Further we propose to examine the impact of senescent stromal cells on a spontaneous model of squamous cell carcinoma (SCC, K14-HPV16) where 100% of animals develop hyperplasia yet only 20% convert to SCC. Here we propose that the activation of senescence within the stromal compartment will increase the penetrance in this model by altering the immune landscape. Finally, we will ask how p38MAPK-dependent senescence-associated secretory phenotype (SASP) factors contribute to the immunosuppressive environment created by senescent stromal cells and ask in a preclinical setting if targeting p38MAPK or its downstream kinase MK2 is a valid approach to reducing senescent stromal-supported tumorigenesis. Data from this proposal will provide vital mechanistic insight and novel therapeutic targets that may reduce age-related increases in cancer.

抽象的 年龄是癌症发展的重要危险因素。驱动这种风险的机制很复杂 并涉及初期肿瘤细胞中细胞自主突变的积累和促肿瘤的积累 肿瘤微环境的变化。调查衰老微环境对 肿瘤发生表明衰老基质细胞可以直接刺激肿瘤和肿瘤。 生长。因为衰老细胞随着年龄的增长而积聚，所以这些观察结果提高了衰老的可能性 细胞是与年龄相关的肿瘤发生增加的重要因素。了解如何衰老 基质细胞有助于肿瘤发生，我们开发了FASST小鼠（成纤维细胞加速基质 - 支持的肿瘤发生），使我们能够控制衰老的空间和时间激活 间充质细胞。使用此鼠标，我们发现衰老小鼠皮肤成纤维细胞（MSF）支持增加 免疫能力小鼠的肿瘤发生。令人惊讶的是，我们发现独立于肿瘤的无疑是MSF 细胞通过调节宿主免疫系统来介导其促肿瘤特性并创建 限制CD8 T细胞活性的免疫抑制，从而增加肿瘤生长。以前的工作有 专注于衰老成纤维细胞直接刺激肿瘤细胞生长的能力。因此，我们的工作是第一个 表明衰老无国界医生可以通过调节免疫系统来促进肿瘤生长。因为我们发现 在我们的模型中，衰老的无限无度无限委员会引起免疫抑制细胞的局部募集，类似于我们在 随着人类皮肤的衰老，我们建议它们通过创建区域有助于肿瘤发生的与年龄相关的增加 局部免疫抑制，避免了肿瘤细胞并允许其生长。理解 FASST模型中免疫调制的动力学，我们建议确定免疫的时间模式 细胞浸润，驱动免疫细胞浸润的机制以及驱动衰老特异性因素 FASST小鼠中存在的抑制微环境的发展和维护。更远 我们建议检查衰老基质细胞对鳞状细胞自发模型的影响 癌（SCC，K14-HPV16），其中100％的动物发展增生，但只有20％转化为SCC。这里 我们建议，基质室内衰老的激活将增加此处的渗透率 通过更改免疫景观模型。最后，我们将询问P38MAPK依赖性衰老如何相关 分泌表型（SASP）因素有助于衰老产生的免疫抑制环境 基质细胞并在临床前询问靶向p38mapk或其下游激酶MK2是有效的 减少衰老基质支撑性肿瘤发生的方法。该提案的数据将提供至关重要的 机械洞察力和新型治疗靶标可能会减少癌症与年龄相关的增加。