Regulation of tumor recurrence by stress activated neutrophils

摘要 手术切除肿瘤病灶完全切除是治疗早期 非小细胞肺癌（NSCLC）的分期，以及许多其他类型的癌症。起义的结果经常是 癌症治疗然而，相当大比例的患者会在手术后出现局部或远处复发， 几年人们普遍认为，少量肿瘤细胞从原发肿瘤部位扩散 在肿瘤发展的早期，并持续处于休眠状态，直到细胞重新进入细胞周期。癌 细胞休眠也可能是对与DNA损伤相关的放疗和化疗的反应， 这就解释了即使对治疗完全有反应也会复发。这些休眠细胞通常 衰老细胞的特征，因此这种现象通常被称为“治疗诱导的衰老”。 （TIS）的文件。尽管对休眠和衰老肿瘤细胞中的信号传导的了解相对较好， 了解逃避休眠形成局部复发或远处转移的机制 原发性肿瘤完全消除后。在这个应用中，我们通过使用两个 实验系统第一种是通过调节肿瘤的表达诱导休眠 抑癌基因p53的表达。这个模型允许研究肿瘤休眠，这不是 通过化疗或放疗治疗诱导，并可反映化疗后肿瘤细胞的变化。 扩散到组织。二是TIS模型在小鼠肺癌和人卵巢癌治疗中的应用 化疗。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作用可能是由神经内分泌肾上腺素能激素引起的 因为长期的压力。我们提出了一个新的概念，调节肿瘤复发。我们 提出肾上腺素能激素通过S100 A8/A9引起快速释放和自分泌/旁分泌信号传导 蛋白质异二聚体导致中性粒细胞中髓过氧化物酶（MPO）的上调。MPO和ROS 导致中性粒细胞形成氧化脂质，直接激活休眠的肿瘤细胞。的 本研究的主要目的是确定癌症复发的机制，并确定治疗方法。 靶向策略来控制这一过程，并最终消除休眠的肿瘤细胞， 复发为实现这一目标，我们提出以下具体目标。 具体目标1。确定嗜中性粒细胞介导的休眠肿瘤再激活的具体机制 细胞 具体目标2。为了确定休眠肿瘤细胞中负责其重新激活的信号传导， 休眠肿瘤细胞再激活的临床意义和治疗靶点。

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.