Development of 3D organ-specific models of colorectal cancer metastasis

结直肠癌转移的3D器官特异性模型的开发

• 批准号: 8737824
• 负责人: Andrew Zhuang Wang
• 金额: $ 18.86万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737824
• 关键词: Address; Animals; Architecture; Binding; Biological Assay; Biological Preservation; Biology; Cancer Biology; Cancer Patient; Cancer cell line; Cell Culture Techniques; Cell Line; Cells; Collagen; Colon Carcinoma; Colorectal Cancer; Complex; Data; Development; Disease; Disease model; Disseminated Malignant Neoplasm; Engineering; Extracellular Matrix; Gene Expression; Genetic Models; Growth; Growth Factor; Hepatic; Hepatocyte; Human; In Vitro; Lead; Liver; Lung; Malignant Neoplasms; Metastatic Neoplasm to the Liver; Methods; Modeling; Molecular Profiling; Morbidity - disease rate; Nature; Neoplasm Metastasis; Normal tissue morphology; Organ; Organoids; Phenotype; Plastics; Primary Neoplasm; Process; Radiation therapy; Research; Role; SW480; Stem cells; System; Techniques; Therapeutic; Therapeutic Agents; Tissue Engineering; Tissues; Xenograft procedure; anticancer research; base; cancer care; cancer cell; cancer therapy; chemotherapy; cytokine; improved; in vitro Model; in vivo; innovation; monolayer; mortality; neoplastic cell; novel; public health relevance; response; scaffold; screening; success; three-dimensional modeling; tissue culture; tissue support frame; tool; treatment response; tumor; tumor microenvironment; two-dimensional

DESCRIPTION (provided by applicant): Understanding the biology of cancer metastases is critical to improving the treatment of cancer. A key challenge in these efforts has been the lack of easy-to-use tumor models that can recapitulate the metastatic disease condition or process. Current models are either too difficult to study or unable to replicate the complex microenvironment of tumor metastasis. Our application aims to address the need for models of cancer metastasis by applying recent advances in tissue engineering. A recent breakthrough in tissue engineering has been the development of decellularized tissue. One novel technique for generating decellularized tissue, developed by Dr. Reid, preserves growth factors and cytokines that are matrix-bound in addition to the extracellular matrix. Decellularized tissue generated using this technique has been termed biomatrix scaffolds. The Reid group has shown that biomatrix scaffolds are tissue-specific but not species-specific both chemically and functionally. Using biomatrix scaffolds, we have obtained exciting preliminary data. We have found that colorectal cancer cells, HT29, SW480 and CaCO2, can spontaneously form 3D colonies on tissue culture dishes coated with liver and lung biomatrix scaffolds. More importantly, we have demonstrated that treatment responses to chemotherapy and radiotherapy are different between cells grown on liver and lung biomatrix scaffolds. Such organ-specific responses have not been observed with other 3D culture systems. Lastly, we have shown that human primary tumor cells from hepatic metastases of colorectal cancer form significantly more colonies when grown on liver biomatrix in vitro compared to that on lung biomatrix, collagen or plastic. Based on our preliminary data, we hypothesize that we can use biomatrix scaffolds to generate 3D in vitro and ex vivo models of cancer metastasis. In this application, we plan to use colorectal cancer as a model disease and develop models of colorectal cancer with liver and lung metastases. We theorize that our proposed models can recapitulate the biology of colorectal cancer metastasis to liver and lung as well as predict treatment responses of metastases. Our application has two specific aims. The first aim will focus on the development of in vitro organ-specific 3D models of colorectal cancer metastasis using tissue-specific biomatrix scaffolds only. Our second aim will focus on the development of 3D ex vivo models of colorectal cancer liver metastases using liver organoids prepared by recellularization of liver biomatrix scaffolds. Success with our research can lead to the development of novel in vitro/ex vivo models of cancer metastasis that can better mimic the disease process. These can become powerful tools for studying the biology of metastasis including: mechanisms of metastasis; roles of physical forces on metastasis; and identification of matrix components controlling metastatic potential. Furthermore, models can be useful for in vitro therapeutic screening assays targeted towards cancer metastasis to a specific organ. Our strategy can also be applied to other types of cancers and metastasis to other organs.

描述（由申请人提供）：了解癌症转移的生物学对于改善癌症治疗至关重要。在这些努力中，主要的挑战是缺乏易于使用的肿瘤模型，这些模型可以概括转移性疾病或过程。当前的模型要么很难研究，要么无法复制肿瘤转移的复杂微环境。我们的应用旨在通过应用组织工程的最新进展来满足对癌症转移模型的需求。最近的组织工程突破是脱细胞组织的发展。由Reid博士开发的一种新型技术用于生成脱细胞组织，它保留了生长因子和细胞因子，除细胞外基质外，它们是基质结合的。使用该技术产生的脱细胞组织称为Biomatrix支架。 REID组表明，生物质支架在化学和功能上都是组织特异性但物种特异性的。使用Biomatrix支架，我们获得了令人兴奋的初步数据。我们发现结直肠癌细胞HT29，SW480和CACO2可以自发地在涂有肝脏和肺biomomatrix支架的组织培养皿上形成3D菌落。更重要的是，我们已经证明了对化学疗法和放疗的治疗反应在肝脏和肺biomomatrix支架上生长的细胞之间有所不同。其他3D培养系统尚未观察到这种特定器官的反应。最后，我们已经表明，与肺biomomatrix，胶原蛋白或塑料相比，在体外生长时，结直肠癌肝转移的人类原发性肿瘤细胞形成了更多的菌落。根据我们的初步数据，我们假设我们可以使用Biomatrix支架来生成癌症转移的体外和离体模型。在此应用中，我们计划将大肠癌用作模型疾病，并开发与肝脏和肺转移酶的大肠癌模型。我们认为，我们提出的模型可以概括结直肠癌转移到肝脏和肺的生物学，并预测转移的治疗反应。我们的应用程序有两个具体的目标。第一个目标将仅使用组织特异性生物支架的结直肠癌转移的体外器官特异性3D模型的发展。我们的第二个目标将着重于使用肝脏Biomatrix支架延迟制备的肝癌的结直肠癌转移的3D离体模型。通过我们的研究取得成功可以导致新型的体外/离体离体模型的癌症转移模型，从而更好地模仿疾病过程。这些可以成为研究转移生物学的强大工具，包括：转移机制；物理力在转移中的作用；以及控制转移潜能的基质组件的鉴定。此外，模型对于针对特定器官的癌症转移的体外治疗筛查测定法可能是有用的。我们的策略也可以应用于其他类型的癌症和向其他器官转移。