Development of the chick embryo as a replacement for rodent models of tumour metastasis.

鸡胚胎的发育作为肿瘤转移啮齿动物模型的替代品。

• 批准号: NC/R001324/1
• 负责人: Anne Herrmann
• 金额: $ 30.53万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FR001324%2F1
• 关键词: Development; chick; embryo; replacement; rodent

The majority of cancer deaths are caused by aggressive cancer cells, which break away from the original (primary) tumour and spread to other parts of the body. This process is called metastasis. While the treatment of primary tumours has advanced greatly in the last decades, there is to date no effective cure for metastasis. Therefore, new therapies are urgently needed to increase patient survival. To understand how, when and why cancer cells spread, mouse or rat models of cancer are used in research. To study tumour formation and metastasis, adult mice or rats often have to undergo invasive procedures. These can cause pain, suffering and distress to the animal, which could be eliminated by using an immature model. Here, I propose to replace mouse and rat experiments with the chick embryo model. This model is cheaper, easier, quicker and enables the non-invasive study of metastasis, which is not possible with mouse or rat models. Cancer cells can be grown on a transparent membrane that is located directly beneath the eggshell, which is rich in blood vessels and located outside of the embryo and tumour formation occurs within days. If the cancer cells are aggressive, as in metastatic cancer, they will break away from the original tumour, travel through the vascular system and form a new tumour in organs of the chick embryo. I aim to study this process by implementing advanced imaging methods, some of which are used clinically, such as magnetic resonance imaging, and some that are only used for small animals. These include special techniques called bioluminescence, photoacoustic and intravital imaging. Because these imaging methods are predominantly used for mammals, I will adapt them for the imaging of tumours and metastasis in the chick embryo. Then, I will use them to study fundamental questions in cancer research, thus demonstrating that the chick embryo model is suitable to study tumour development, metastasis and treatment in a variety of tumour types. I have successfully developed this model during the past 6 years to elucidate the mechanisms of metastasis in the paediatric cancer neuroblastoma. It is now crucial that the wider cancer research community becomes aware of this model as it would accelerate their research and enable the replacement of a large number of animal experiments. I will therefore apply it to other tumour types during my fellowship, where I will test the role of different proteins involved in the metastasis of breast and pancreatic cancers and establish standard protocols and videos to share good practices. I will also explore how this model can be used by pharmaceutical companies to generate pharmacokinetics data; a requirement for clinical testing. Pharmaceutical companies are continuously developing a large number of new drugs against cancer and the most promising ones have to be tested in animals to evaluate their safety and efficacy. By testing novel compounds in the chick-embryo, these companies can quickly screen and eliminate ineffective drugs, testing only the most promising options in rats or mice. I am going to work with a pharmaceutical company, learn about the industrial needs and use the chick embryo model to test newly developed drugs targeting tumour formation and metastasis. If successful, the chick embryo model could not only be used by this company but also by the wider pharmaceutical industry, ultimately leading to a significant reduction in the use of mice and rats in research.

大多数癌症死亡是由侵袭性癌细胞引起的，这些癌细胞从原始（原发性）肿瘤中脱离并扩散到身体的其他部位。这个过程称为转移。虽然原发性肿瘤的治疗在过去几十年中取得了很大进展，但迄今为止还没有有效治愈转移的方法。因此，迫切需要新的治疗方法来提高患者的生存率。为了了解癌细胞如何、何时以及为什么扩散，研究中使用了小鼠或大鼠癌症模型。为了研究肿瘤的形成和转移，成年小鼠或大鼠通常必须接受侵入性手术。这些可能会给动物带来疼痛、痛苦和痛苦，这些都可以通过使用不成熟的模型来消除。在这里，我建议用鸡胚模型代替小鼠和大鼠实验。这种模型更便宜，更容易，更快，并且能够进行转移的非侵入性研究，这在小鼠或大鼠模型中是不可能的。癌细胞可以生长在直接位于蛋壳下方的透明膜上，蛋壳富含血管，位于胚胎外部，肿瘤形成在几天内发生。如果癌细胞是侵袭性的，如转移性癌症，它们将脱离原来的肿瘤，穿过血管系统，在鸡胚的器官中形成新的肿瘤。我的目标是通过实施先进的成像方法来研究这一过程，其中一些方法用于临床，如磁共振成像，还有一些方法仅用于小动物。其中包括称为生物发光、光声和活体成像的特殊技术。由于这些成像方法主要用于哺乳动物，我将调整它们的鸡胚肿瘤和转移的成像。然后，我将用它们来研究癌症研究中的基本问题，从而证明鸡胚模型适合于研究各种肿瘤类型的肿瘤发展、转移和治疗。在过去的6年里，我成功地建立了这个模型，以阐明儿童癌症神经母细胞瘤的转移机制。现在至关重要的是，更广泛的癌症研究界意识到这种模式，因为它将加速他们的研究，并能够取代大量的动物实验。因此，我将在研究期间将其应用于其他肿瘤类型，在那里我将测试参与乳腺癌和胰腺癌转移的不同蛋白质的作用，并建立标准方案和视频以分享良好做法。我还将探讨制药公司如何使用该模型来生成药代动力学数据;这是临床测试的要求。制药公司正在不断开发大量的抗癌新药，最有希望的药物必须在动物身上进行测试，以评估其安全性和有效性。通过在鸡胚中测试新化合物，这些公司可以快速筛选和淘汰无效药物，只在大鼠或小鼠中测试最有希望的选择。我将与一家制药公司合作，了解工业需求，并使用鸡胚模型测试针对肿瘤形成和转移的新开发药物。如果成功，鸡胚胎模型不仅可以被这家公司使用，而且可以被更广泛的制药行业使用，最终导致在研究中使用小鼠和大鼠的显着减少。