Utilising tissue-on-a-chip technology as an ex vivo model of breast cancer metastatic colonisation

在英国，每年有超过11，000名女性死于乳腺癌。几乎所有这些女性的死亡都是因为她们的乳腺癌细胞转移到体内的其他器官，如肝脏、肺、骨骼和大脑，在那里它们生长成新的肿瘤并阻止器官工作。因此，阻止女性死于乳腺癌的一种方法是防止乳腺癌细胞在其他器官中生长。然而，目前我们还不了解乳腺癌细胞是如何转移到其他器官并在其中生长的，因此我们无法用药物来预防。大多数试图了解乳腺癌细胞如何在不同器官中生长的研究都是在小鼠身上进行的。然而，这并不是研究这一过程的理想方法，因为很难观察癌细胞在小鼠体内的生长。为了解决这个问题，每个实验都使用了大量的小鼠，其中一些小鼠在不同的时间点被杀死，然后确定癌细胞是否扩散到其他器官。这使用了大量的小鼠，仍然不能让我们确切地看到当癌细胞在这些器官中生长时会发生什么。在实验室培养皿中复制乳腺癌细胞在其他器官中的生长将是更好地理解这一过程的一种方法，同时也减少了研究中使用的小鼠数量。以前的工作试图做到这一点，但是已经创建的实验室系统缺乏在患者中观察到的癌细胞生长的复杂性，因此研究人员的吸收率很低。我们已经确定了一个已经在使用的模型，该模型有可能用于研究其他器官中的乳腺癌生长。该模型由船体大学开发，被称为“组织芯片”。组织芯片是从老鼠或人类身上取下少量组织，并将其保存在玻璃或聚合物芯片中，不断提供流动的营养物质。这些芯片以前曾被用于研究正常组织和肿瘤组织，在这里，我们建议研究乳腺癌细胞如何在其他器官中生长。来自肝脏的组织，乳腺癌扩散的常见部位，将被放置在芯片内，然后来自乳腺肿瘤的癌细胞将缓慢流过，并允许结合并侵入肝脏。这将使用强大的显微镜进行监测。我们相信，这种模型的成功开发可能对致力于了解癌症如何传播的科学家有很大的帮助。因此，我们设计了这个项目，首先是为了适应研究在其他器官中生长的乳腺癌细胞的技术，其次是为了向其他科学家展示其潜力。为了使组织芯片技术适用于研究癌症扩散，我们将把它转移到曼彻斯特大学，在那里我们可以使用世界一流的设施来观察癌细胞的生长。我们还将展示如何使用这项技术来测试药物，通过添加不同的药物来防止癌细胞在其他器官中生长，看看我们是否可以防止癌细胞生长。随着这项技术的建立，我们将开始与英国各地的其他科学家进行讨论，以确保人们了解这种模型，并将积极宣传其研究的好处，同时大幅减少研究中使用的小鼠数量。

Breast cancer kills over 11,000 women each year in the UK. Virtually all of these women die because their breast cancer cells travel to other organs within the body such as the liver, lungs, bones and brain, where they grow into new tumours and stop the organs from working. Therefore, one way to stop women dying from breast cancer is to prevent breast cancer cells from growing in other organs. Currently, however, we do not understand how breast cancer cells move to and grow in other organs, so we are not able to prevent it with drugs. Most studies trying to understand how breast cancer cells grow in different organs take place in mice. However this is not an ideal way to study the process, as it is very difficult to watch cancer cells growing inside a mouse. To get around this, large numbers of mice are used for each experiment with some being killed at different time points and the cancer cell spread to other organs then determined. This uses a lot of mice, and still does not allow us to see exactly what happens when cancer cells are growing in these organs. Replicating the growth of breast cancer cells in other organs in a laboratory dish would be a way to better understand this process, whilst also reducing the number of mice used in research. Previous work has attempted to do this, however the laboratory systems which have been created lack the complexity of cancer cell growth seen in patients, so uptake amongst researchers has been low. We have identified a model already in use which has the potential to be used to study breast cancer growth in other organs. This model has been developed at the University of Hull, and is called "tissue-on-a-chip". Tissue-on-a-chip involves taking a small amount of tissue from either a mouse or a human, and keeping it alive in a glass or polymer chip constantly supplied with flowing nutrients. These chips have previously been used to study both normal tissue and tumour tissue, and here we propose to study how breast cancer cells grow in other organs. Tissue from liver, a common site for breast cancer spread, will be placed inside the chips, and then cancer cells from breast tumours will be slowly flowed across and allowed to bind to and invade the liver. This will be monitored using powerful microscopes. We believe that the successful development of this model could be of great use to scientists working to understand how cancer spreads. We have therefore designed this project firstly to adapt the technology for study breast cancer cells growing in other organs, and secondly to showcase its potential to other scientists. To adapt the tissue-on-a chip technology to study cancer spread we will transfer it to the University of Manchester, where we can use world-class facilities to watch cancer cells as they grow. We will also demonstrate how this technology can be used to test drugs to prevent cancer cells growing in other organs by adding different drugs, and seeing if we can prevent cancer cells from growing. As this technology is being established, we will begin discussions with other scientists across the UK to ensure that people know about this model, and will actively promote the benefits to their research alongside significantly reducing number of mice used in research.