Regulation of tumor recurrence by stress activated neutrophils

应激激活中性粒细胞调节肿瘤复发

• 批准号: 10416030
• 负责人: Rugang Zhang
• 金额: $ 32.53万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10416030
• 关键词: Address; Adjuvant; Adrenergic Agents; Adrenergic Receptor; Binding; Cell Cycle; Cells; Cessation of life; Characteristics; Chemotherapy and/or radiation; Clinical; DNA Damage; Data; Development; Distant; Distant Metastasis; Elements; Excision; Felis catus; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Goals; Hormones; Human; In complete remission; Lesion; Leukotriene B4; Lipid Peroxidation; Lipids; Lipopolysaccharides; Lipoxygenase; Lung; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mediating; Modeling; Mus; Myeloid Cells; Neoplasm Metastasis; Neurosecretory Systems; Non-Small-Cell Lung Carcinoma; Norepinephrine; Operative Surgical Procedures; Paracrine Communication; Patients; Peroxidases; Primary Neoplasm; Process; Proteins; Radiation therapy; Receptor Signaling; Recurrence; Regulation; S100A8 gene; Signal Transduction; Site; Stress; System; TLR4 gene; TP53 gene; Testing; Therapeutic Intervention; Tissues; Tumor Suppressor Genes; Up-Regulation; WNT Signaling Pathway; autocrine; base; cancer cell; cancer therapy; cancer type; chemotherapy; clinically significant; lung cancer cell; neoplastic cell; neutrophil; novel; oxidized lipid; prevent; radiation response; receptor; receptor for advanced glycation endproducts; senescence; targeted treatment; therapeutic target; treatment choice; treatment response; tumor

Abstract Complete removal of tumor lesions with surgical resection is the treatment of choice for patients with early stages of non-small cell lung cancer (NSCLC), as well as with many other types of cancer. It often results in cancer cure. However, substantial proportion of patients develops local or distant recurrences within several years. It is widely accepted that small numbers of tumor cells disseminate from primary tumor site early on during tumor development and persist in dormant state until cells re-enter the cell cycle. Cancer cell dormancy can also be the response to radiation and chemotherapy associated with DNA damage, which explains recurrence even after a complete response to therapies. Those dormant cells usually have characteristics of senescent cells, thus this phenomenon is often referred as “therapy-induced senescence” (TIS). Although signaling in dormant and senescent tumor cells is relatively well understood, much less is known about the mechanisms that evade dormancy to form local recurrence or distant metastases years after complete elimination of primary tumor. In this application, we model tumor cell dormancy by using two experimental systems. The first is the induction of dormancy by regulation of the expression of tumor suppressor gene p53 in lung cancer cells. This model allows for the study of tumor dormancy, which is not induced by treatment with chemo- or radiation therapy and may reflect changes in tumor cells after dissemination to tissues. The second is the model of TIS in mouse lung and human ovarian cancer treated with chemotherapy. Our preliminary studies demonstrated that neutrophils were able to induce proliferation of dormant tumor cells. We found that this effect could be caused by neuroendocrine adrenergic hormones as the result of prolonged stress. We suggest a novel concept of regulation of tumor recurrence. We propose that adrenergic hormones cause a rapid release and autocrine/paracrine signaling by S100A8/A9 proteins heterodimer leading to up-regulation of myeloperoxidase (MPO) in neutrophils. MPO and ROS contributed to formation of oxidized lipids by neutrophils, which directly activated dormant tumor cells. The main goal of this study is to identify the mechanism of recurrence in cancer and to determine therapeutic targeting strategy to control this process and ultimately eliminate dormant tumor cells to prevent recurrence. To achieve this goal, we propose the following specific aims. Specific Aim 1. To identify specific mechanisms of neutrophil-mediated reactivation of dormant tumor cells. Specific Aim 2. To determine signaling in dormant tumor cells responsible for their reactivation, to identify clinical significance and therapeutic targeting of reactivation of dormant tumor cells.

抽象的 完全切除手术切除的肿瘤病变是早期患者的选择治疗 非小细胞肺癌（NSCLC）以及许多其他类型的癌症的阶段。它经常导致 癌症治疗。但是，很大一部分患者在内部发展本地或遥远的回报 几年。广泛认为，少量肿瘤细胞从原发性肿瘤部位传播 肿瘤发育期间的早期，一直处于休眠状态，直到细胞重新进入细胞周期。癌症 细胞休眠也可能是对与DNA损伤相关的辐射和化学疗法的反应， 即使在对疗法做出完全反应后，它也解释了复发。那些休眠的细胞通常具有 感觉细胞的特征，因此这种现象通常被称为“治疗诱导的感应” （tis）。 知道避免休眠的机制形成局部复发或远处转移 完全消除原发性肿瘤后。在此应用中，我们使用两个 实验系统。首先是通过调节肿瘤的表达来诱导休眠 肺癌细胞中抑制基因p53。该模型允许研究肿瘤休眠，这不是 通过化学或放射疗法治疗诱导的，可能反映 传播到组织。第二个是治疗的小鼠肺和人卵巢癌中TI的模型 进行化学疗法。我们的初步研究表明，中性粒细胞能够诱导增殖 休眠的肿瘤细胞。我们发现这种效果可能是由神经内分泌肾上腺素骑马引起的 由于延长压力。我们建议对肿瘤复发调节的新概念。我们 提议肾上腺虫会迅速释放，并由S100A8/A9释放自分泌/旁分泌信号传导 蛋白质异二聚体导致嗜中性粒细胞中髓过氧化物酶（MPO）的上调。 MPO和ROS 有助于由中性粒细胞形成氧化脂质，后者直接激活休眠的肿瘤细胞。这 这项研究的主要目标是确定癌症复发的机理并确定治疗 针对控制这一过程的策略并最终消除休眠的肿瘤细胞以防止 复发。为了实现这一目标，我们提出以下特定目标。 具体目的1。确定中性粒细胞介导的休眠肿瘤重新激活的特定机制 细胞。 具体目的2。确定负责重新激活的休眠肿瘤细胞中的信号传导，以识别 休眠肿瘤细胞重新激活的临床意义和治疗靶向。