P53 inactivation on MDSC development and tumor progression

P53 失活对 MDSC 发育和肿瘤进展的影响

• 批准号: 8577716
• 负责人: YAN CUI
• 金额: $ 29.88万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2014-02-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577716
• 关键词: Aging-Related Process; Autoimmunity; Cancer Etiology; Cells; Chronic; Clinical; Colon Carcinoma; Development; Dominant-Negative Mutation; Environment; Fibroblasts; Functional disorder; Growth; Human; Immune; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Inflammation; Inflammatory Response; Laboratories; Link; Lymphoid; Malignant Neoplasms; Mediating; Molecular; Mus; Mutation; Myelogenous; NF-kappa B; Neoplasm Metastasis; Oncogene Activation; Oncogenes; Pathway interactions; Physiological; Play; Protein p53; Role; Sodium Dextran Sulfate; Somatic Mutation; Suppressor-Effector T-Lymphocytes; TP53 gene; Testing; Tumor Suppression; Tumor Suppressor Genes; Virus Diseases; arginase; chemokine; cytokine; human NOS2A protein; insight; melanoma; novel; outcome forecast; progenitor; public health relevance; restoration; tumor; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Increasing evidence has linked chronic inflammation to tumor development, progression, and metastases. Clinical and experimental results suggest that chronic inflammation enhances expression of the tumor suppressor p53 leading to its mutations and inactivation. In fact, p53 mutations are observed in 50% of human cancers and are considered to be one of the leading causes of cancer. Moreover, in tumors that maintain normal p53 gene, p53 mutations sometimes occur in cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME), which correlates with an increased rate of metastases and poor prognosis. Although it is well appreciated that immune dysregulation in the TME plays a crucial role in tumorigenesis, whether p53 inactivation immunomodulates the TME and whether the immunological consequence of p53 inactivation plays an integral role in tumorigenesis are still largely unexplored. Since recent studies by our laboratory and others have shown that the immunological environment in p53null hosts is skewed in favor of inflammation, we hypothesized that p53 inactivation in the cellular compartment constituting the TME favors tumor establishment and progression by promoting inflammation. Indeed, our studies showed that inoculated B16-F1 melanoma progressed more rapidly in p53null mice than that in WT mice, which is associated with a marked expansion of the lymphoid-like stromal network and enhanced accumulation of myeloid-derived suppressor cells (MDSC), both of which are immunosuppressive due to their high expression of proinflammatory cytokines and chemokines. Here, we propose to elucidate mechanistically how p53 inactivation enhances inflammatory responses and promotes the development of MDSCs, thereby tumor progression, through the following specific aims: (1) to determine whether tumor-stroma interaction in the tumor microenvironment lacking functional p53 results in the expansion of the lymphoid-like reticular fibroblastic cell (FRC) network, due to highly activated NF-kB pathway, which creates a cytokine milieu and immunological microenvironment strongly favoring MDSC development; (2) to examine whether the augmented MDSC development and tumor progression in p53null hosts are contributed by p53 inactivation enhanced proliferation of myeloid progenitors and lymphoid-like FRC-mediated enhancement of MDSC accumulation; and (3) to determine whether p53 inactivation in fibroblasts and myeloid precursors synergistically enhances chronic inflammation and tumorigenesis in the dextran sulfate sodium (DSS)-induced colon cancer, whereas targeted restoration of p53 in fibroblast or MDSC delays colon cancer development. By focusing on the mechanisms of p53 dysfunction in promoting MDSC development and tumor progression, this application provides novel insights into the immunological mechanism of p53 dysfunction/inactivation in tumorigenesis and new strategies targeting the p53 pathway in the TME that can be implemented to tumor treatment. .

描述（由申请人提供）：越来越多的证据将慢性炎症与肿瘤发育，进展和转移联系起来。临床和实验结果表明，慢性炎症增强了肿瘤抑制p53的表达，导致其突变和灭活。实际上，在50％的人类癌症中观察到p53突变，被认为是癌症的主要原因之一。此外，在维持正常p53基因的肿瘤中，p53突变有时会发生在肿瘤微环境（TME）内癌症相关的成纤维细胞（CAF）中，这与转移率增加和预后不良相关。尽管人们很好地认为，TME的免疫失调在肿瘤发生中起着至关重要的作用，但p53失活是否可以免疫调节TME以及p53失活的免疫学后果是否在肿瘤发生中具有不可或缺的作用在很大程度上都没有探索。自实验室和其他人最近的研究表明，p53Null宿主中的免疫学环境偏向于炎症，我们假设p53在构成TME构成TME构成肿瘤的细胞隔室中的p53失活通过促进炎症而促进肿瘤的建立和进展。实际上，我们的研究表明，在p53Null小鼠中接种的B16-F1黑色素瘤的进展比在WT小鼠中的进展速度更快，WT小鼠与淋巴样基质网络的显着膨胀以及髓样衍生的抑制细胞（MDSC），（MDSC）的积累增强有关。这两者都是由于促炎细胞因子和趋化因子的高表达而进行免疫抑制作用。在这里，我们建议从机械上阐明p53灭活方式如何增强炎症反应并促进MDSC的发展，从而通过以下具体目的通过以下具体目的进行肿瘤进展：（1）确定缺乏功能性p53的肿瘤微环境中的肿瘤 - 损伤相互作用是否导致功能性p53导致。由于高度激活的NF-KB途径，淋巴样网络（FRC）网络的扩展，该途径产生了细胞因子环境和免疫学微环境，非常有利于MDSC发展。 （2）检查p53Null宿主的增强MDSC发育和肿瘤进展是否通过p53失活增强，从而增强了髓样祖细胞的增殖和淋巴样FRC介导的MDSC积累的增强； （3）确定成纤维细胞和髓样前体中的p53是否会增强硫酸葡萄酸钠（DSS）诱导的结肠癌的慢性炎症和肿瘤发生，而成纤维细胞ORMDSC DELASE DELAES CORON CORON CORON CORON CORON CORON CORON CORON CORON CORON CALER CALEN CALEN CORNARE CORON CORON CORNARE CORNARE CORNATION p53的靶向恢复。通过关注p53功能障碍在促进MDSC发育和肿瘤进展中的机制，该应用为p53功能障碍/失活的免疫学机制提供了新的见解，在肿瘤发生和针对TME中p53途径的新策略中可以实现TME治疗的p53途径。 。