Roles of neutrophils in c-Met mediated breast cancer brain metastases

大多数癌症死亡归因于转移性疾病，而大脑是癌症的主要部位之一 乳腺肿瘤转移。即使采用立体定向放射外科(SRS)等先进治疗手段， 发生脑转移的乳腺癌患者的中位生存期不到一年。不管 尽管临床意义较高，但脑转移瘤的病理机制尚不清楚。我们 最近发现：(1)c-Met信号转导能够诱导一组炎症基因的表达 在脑转移灶中中性粒细胞N_2的产生起关键作用，(II)N_2中性粒细胞促进 肿瘤干细胞的自我更新和抑制T细胞介导的免疫监视和(III)血脑屏障 渗透性天然化合物PTER通过选择性靶向c-Met抑制脑转移。这些 新的发现使我们假设：(I)c-蛋氨酸促进脑转移和对 放射治疗通过产生N_2中性粒细胞，以及(Ii)N_2中性粒细胞反过来促进癌症的自我更新 干细胞样细胞和促进局部免疫抑制。我们还假设，血脑屏障中的一种叫翼二苯乙烯(PTER) 透性天然化合物通过抑制c-选择素抑制放射治疗后脑转移和复发 MET信号转导，从而减少中性粒细胞的数量。为了检验这些假设，我们将(I) 研究c-Met诱导的中性粒细胞调节因子(NRFs)如何调节脑内中性粒细胞的活动 转移灶(Aim1)，(Ii)破译N_2中性粒细胞促进肿瘤进展的机制 和放射抗性(目标2)，以及(Iii)测试PTER在抑制BRM和SRS后复发方面的有效性 体内实验(目标3)。该项目具有很高的创新性。首先，我们建立了最先进的系统生物学 筛查方法，发现c-Met的过度表达与患者发生 脑转移与NRFs的诱导有关，NRFs促进了脑转移的表型变化 转移部位的中性粒细胞。因此，这个项目的结果将揭示出新的病理 肿瘤分泌因子对中性粒细胞的调节作用机制与脑转移的关系。 第二，中性粒细胞促进肿瘤进展和辐射的确切反馈机制。 人们对抵抗知之甚少。我们建议破译肿瘤之间相互作用的途径。 脑微环境中的细胞、中性粒细胞和T细胞，我们相信这将导致发现 靶向氮中性粒细胞的新治疗方法。最后，我们将研究BBB的潜在效用- 透性天然化合物，PTER，作为治疗和放射增敏剂治疗脑部 转移。如果我们的假设得到证实，这项工作有可能成为一种新的范式， 显著提高乳腺癌的治疗和预防水平。

The majority of cancer death is attributed to metastatic disease, and the brain is one of the major sites of breast tumor metastasis. Even with the advanced treatment such as stereotactic radiosurgery (SRS), the median survival of breast cancer patients who developed brain metastases is less than a year. Regardless of high clinical significance, the pathological mechanism of brain metastasis is still poorly understood. We recently found that (i) c-Met signaling is able to induce the expression of a group of inflammatory genes which play critical roles in the generation of N2 neutrophils in the brain metastatic lesions, (ii) N2 neutrophils promote the self-renewal of cancer stem-like cells and suppress T cell mediated immune surveillance and (iii) the BBB permeable natural compound, PTER, suppresses brain metastasis by selectively targeting the c-Met. These novel and discoveries led us to hypothesize that (i) c-Met promotes brain metastasis and resistance to the radiation therapy by generating N2 neutrophils, and (ii) N2 neutrophils in turn enhance self-renewal of cancer stem-like cells and promote local immune suppression. We also hypothesize that pterostilbene (PTER), a BBB permeable natural compound suppresses brain metastasis and relapse after radio-therapy by suppressing c- Met signaling and thereby reducing the amount of N2 neutrophils. To test these hypotheses, we will (i) investigate how c-Met-induced neutrophil regulatory factors (NRFs) modulate neutrophil activities in the brain metastatic lesions (Aim1), (ii) decipher the mechanisms by which N2 neutrophils promote tumor progression and radio-resistance (Aim 2), and (iii) test the efficacy of PTER in suppressing BrM and post-SRS recurrence in vivo (Aim 3). The project is highly innovative. First, we have established a state-of-the-art system biology screening approach and found that overexpression of c-Met is strongly correlated with patients who developed brain metastasis and it is associated with an induction of NRFs which promotes phenotypic changes of neutrophils in metastatic sites. Therefore, the outcome of this project will reveal novel pathological mechanisms of how neutrophil modulation by cancer-secreted factors contributes to the brain metastasis. Secondly, the exact feed-back mechanism by which N2 neutrophils promote tumor progression and radio- resistance is poorly understood. We propose to decipher the pathway of reciprocal interaction between tumor cells, N2 neutrophils and T-cells in the brain microenvironment, which we believe will lead to a discovery of novel therapeutic approaches to target N2 neutrophils. Finally, we will examine the potential utility of the BBB- permeable natural compound, PTER, as a therapeutic agent and a radiosensitizer agent for treating brain metastasis. If our hypotheses are borne out, this work has the potential to be a novel paradigm that could significantly improve the treatment and prevention of breast cancer.