The Endothelin axis in the primary tumour, the tumour microenvironment and the premetastatic niche – Visualization by target-specific imaging

原发肿瘤中的内皮素轴、肿瘤微环境和转移前生态位 â 通过目标特异性成像进行可视化

• 批准号: 431103449
• 负责人: Professor Dr. Michel Eisenblätter
• 金额: --
• 依托单位: Klinik für Radiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/431103449?language=en
• 关键词: Endothelin; axis; primary; tumour; microenvironment

The prognosis of malignant disease is mainly determined by the individual potential of the tumour to spread systemically and form distant metastases. The endothelin (ET) axis, composed of three peptide hormones (ET-1, -2 and -3) and the two receptor subtypes ETAR and ETBR, is a potent regulator of immune cell recruitment and activation, putatively involved in the induction of tumour-associated immune cells and premetastatic tissue priming. In recent years, activation of intrinsic immune defence mechanisms for combatting tumour growth and spread and the inhibition of tumour-supportive immune signalling have been established as a promising therapeutic option. The formation of distant metastases by seeding of tumour cells within a fostered premetastatic niche is also a process putatively dependent on this interaction.To visualize the influence of the endothelin axis on immune response within the tumour and the tumour microenvironment is the aim of this study.For the proposed project, the syngeneic murine 4T1 breast cancer model system will be used. The different tumours are well characterised for development, kinetics and immune interaction; they share the genetic background of a spontaneous Balb/c tumour but differ in malignant potential. For visualisation of ETBR, a new small molecular fluorescent probe with high specificity for ETBR will be developed and combined with a recently established probe for ETAR for simultaneous imaging of both receptors. The use in planar 2D and tomographic optical fluorescence imaging as well as multispectral optoacoustic tomography (MSOT) will provide high resolution images of probe distribution in primary tumour and sites of (future) metastasis. The correlative cellular composition of tumour, tumour microenvironment and possible metastases will be analysed using flow cytometry, enabling the differentiation of pro- and anti-inflammatory macrophages, regulatory T cells and natural killer cells. Using this experimental regimen of imaging and consecutive analysis of the cellular representation, we will assess potential effects of ETA/ETB blockade on tumour development and tumour microenvironment makeup. Moreover, the effects of specific blockade of either receptor on the other one will be analysed and visualized.This project will provide a tool for specific and differentiated analysis of the ETA/ETB signaling system; the experiments will elucidate the effects of specific intervention into the endothelin axis and enable evaluation of the therapeutic potential.

恶性疾病的预后主要取决于肿瘤全身扩散和形成远处转移的个体潜力。内皮素（ET）轴由三种肽激素（ET-1、ET-2和ET-3）和两种受体亚型ETAR和ETBR组成，是免疫细胞募集和激活的有效调节剂，参与诱导肿瘤相关免疫细胞和转移前组织引发。近年来，激活内在免疫防御机制以对抗肿瘤生长和扩散以及抑制肿瘤支持性免疫信号传导已被确立为一种有前景的治疗选择。肿瘤细胞在转移前小生境中的种植形成远处转移也是一个依赖于这种相互作用的过程。本研究的目的是观察内皮素轴对肿瘤内免疫反应和肿瘤微环境的影响。不同的肿瘤在发育、动力学和免疫相互作用方面都有很好的特征;它们具有自发性Balb/c肿瘤的遗传背景，但恶性潜力不同。对于ETBR的可视化，将开发一种对ETBR具有高特异性的新的小分子荧光探针，并与最近建立的ETAR探针结合，用于同时成像两种受体。在平面2D和断层光学荧光成像以及多光谱光声断层扫描（MSOT）中的使用将提供原发肿瘤和（未来）转移部位中探针分布的高分辨率图像。将使用流式细胞术分析肿瘤的相关细胞组成、肿瘤微环境和可能的转移，从而能够区分促炎和抗炎巨噬细胞、调节性T细胞和自然杀伤细胞。使用这种成像和连续分析细胞表现的实验方案，我们将评估ETA/ETB阻断对肿瘤发展和肿瘤微环境构成的潜在影响。此外，还将分析和观察特异性阻断一种受体对另一种受体的影响。该项目将为ETA/ETB信号系统的特异性和差异化分析提供工具;实验将阐明特异性干预内皮素轴的影响，并评估治疗潜力。