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)：越来越多的证据表明慢性炎症与肿瘤的发展、进展和转移有关。临床和实验结果表明，慢性炎症增强了抑癌基因P53的表达，导致其突变和失活。事实上，在50%的人类癌症中观察到P53突变，并被认为是癌症的主要原因之一。此外，在保持正常p53基因的肿瘤中，肿瘤微环境(TME)内的肿瘤相关成纤维细胞(CAF)有时会发生p53突变，这与转移率增加和预后不良有关。虽然已经认识到TME中的免疫失调在肿瘤的发生中起着至关重要的作用，但P53失活是否对TME具有免疫调节作用，以及P53失活的免疫学后果是否在肿瘤发生中起着不可或缺的作用，仍在很大程度上尚不清楚。由于我们实验室和其他人最近的研究表明，p53nul宿主的免疫环境偏向于炎症，我们假设构成TME的细胞室中的p53失活通过促进炎症而有利于肿瘤的建立和发展。事实上，我们的研究表明，接种B16-F1黑色素瘤的小鼠比WT小鼠进展得更快，这与淋巴样基质网络显著扩张和髓系抑制细胞(MDSC)的聚集有关，这两种细胞都是免疫抑制的，因为它们高表达促炎细胞因子和趋化因子。在这里，我们建议通过以下特定目的从机制上阐明p53失活是如何增强炎症反应并促进MDSC的发展，从而促进肿瘤进展的：(1)确定在缺乏功能性p53的肿瘤微环境中，肿瘤与间质的相互作用是否导致淋巴样网状成纤维细胞(FRC)网络的扩张，这是由于高激活的NF-kB途径，从而创造了强烈有利于MDSC发展的细胞因子和免疫微环境；(2)检测P53失活是否促进了髓系祖细胞的增殖和淋巴样FRC介导的MDSC聚集；以及(3)确定成纤维细胞和髓系前体细胞中的P53失活是否协同增强了葡聚糖硫酸钠(DSS)诱导的结肠癌的慢性炎症和肿瘤发生，而靶向修复成纤维细胞或MDSC中的P53则延缓了结肠癌的发展。通过关注P53功能障碍促进MDSC发展和肿瘤进展的机制，这一应用为肿瘤发生中P53功能障碍/失活的免疫学机制提供了新的见解，并提供了针对TME中P53通路的新策略，可用于肿瘤治疗。。