The human tumour micro-environment modelled in in vitro biomatrices and applied to cancer drug discovery

正在开发新的抗癌药物，以靶向恶性细胞和正常人类细胞（如成纤维细胞）之间的相互作用，这些细胞被招募来支持肿瘤。人类肿瘤细胞可以在啮齿动物中生长，但由啮齿动物成纤维细胞支持。人类和啮齿动物细胞之间的串扰可能不是评估新药的最佳选择，限制了使用异种移植模型进行此类药物筛选的相关性。我们计划在体外模拟这种环境，最初使用来自基质中生长的患者标本的细胞作为支持。我们将关注的肿瘤类型是结肠直肠癌，其中细胞扩散到肝脏。已知肝成纤维细胞产生的生长因子支持这些入侵的结直肠肿瘤细胞的生长，我们将研究这种途径在我们的系统中是否起作用，作为概念验证。将在生物基质系统中观察到的细胞相互作用与来自结直肠癌患者的新鲜分离的肝转移中存在的细胞相互作用进行比较。我们还将研究使用更容易获得的人类成纤维细胞样细胞的可能性，以扩大该技术在不同类型癌症中的应用，并应用我们小组目前正在开发的报告系统，以允许实时监测细胞生长和环境信号，而无需收获细胞。将传播与制药业的广泛合作联系，以传播良好做法，并最大限度地吸收和使用这些做法，从而减少对动物模型的不当使用。

New anti-cancer drugs are being developed to target the interactions between malignant cells and normal human cells, such as fibroblasts, that are recruited to support the tumour. Human tumour cells can be grown in rodents but are supported by rodent fibroblasts. The cross-talk between human and rodent cells may not be optimal to evaluate new drugs, limiting the relevance of using xenograft models for such drug screening. We plan to model this environment in vitro, initially using cells derived from patient specimens grown within a matrix to act as a support. The tumour type we will focus on is colorectal cancer in which cells spread to the liver. Growth factors produced by liver fibroblasts are known to support the growth of these invading colorectal tumour cells and we will investigate whether this pathway is functional in our systems as a proof of concept. The cell interactions observed in the biomatrix system will be compared to those present in freshly isolated liver metastases from patients with colorectal cancer. We will also investigate the possibility of using more readily available human fibroblast-like cells to broaden the applications of the technology to different types of cancer and apply reporter systems which are currently being developed by our group to allow real-time monitoring of cell growth and environmental signals without having to harvest the cells.Once validated the findings/protocols will be published and, through the applicants? extensive collaborative links with the pharmaceutical industry, will be disseminated to spread good practice and maximise their uptake and use, overall resulting in reduced inappropriate use of animal models.