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

在体外生物基质中建模的人类肿瘤微环境并应用于癌症药物发现

• 批准号: G0900765/1
• 负责人: Susan Watson
• 金额: $ 51.89万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0900765%2F1
• 关键词: human; tumour; micro; environment; modelled

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.

新的抗癌药物正在开发，以恶性细胞和正常人类细胞（如成纤维细胞）之间的相互作用为目标，成纤维细胞被招募来支持肿瘤。人类肿瘤细胞可以在啮齿动物体内生长，但需要啮齿动物成纤维细胞的支持。人类和啮齿动物细胞之间的相互作用可能不是评估新药的最佳方法，这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，最初使用从基质中生长的患者标本中提取的细胞作为支持。我们将重点讨论的肿瘤类型是细胞扩散到肝脏的结肠直肠癌。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，我们将研究这一途径是否在我们的系统中起作用，作为概念的证明。在生物基质系统中观察到的细胞相互作用将与来自结直肠癌患者的新分离肝转移瘤中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，以便在不收集细胞的情况下实时监测细胞生长和环境信号。一经验证，研究结果/方案将通过申请人？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它们，从而减少对动物模型的不当使用。