Abstract
Murine models of intestinal cancer are powerful tools to recapitulate human intestinal cancer, understand its biology and test therapies. With recent developments identifying the importance of the tumour microenvironment and the potential for immunotherapy, autochthonous genetically engineered mouse models (GEMMs) will remain an important part of preclinical studies for the foreseeable future. This review will provide an overview of the current mouse models of intestinal cancer, from the Apc Min/+ mouse, which has been used for over 25 years, to the latest ‘state‐of‐the‐art’ organoid models. We discuss here how these models have been used to define fundamental processes involved in tumour initiation and the attempts to generate metastatic models, which is the ultimate cause of cancer mortality. Together these models will provide key insights to understand this complex disease and hopefully will lead to the discovery of new therapeutic strategies. © 2015 The Authors. Pathological Society of Great Britain and Ireland.
Highlights
In the Western world, colorectal cancer (CRC) is the second-highest cause of cancer mortality [1]
In the early 1990s Fearon and Vogelstein [2] postulated that mutations in CRC occur in a sequential manner, with specific mutations being associated with tumour initiation, eg the adenomatous polyposis coli (APC) gene, and other mutations occurring later that drive progression, eg TP53
The function of Notch signalling in intestinal mouse models is controversial, as over-expression of the intracellular active domain of the Notch-receptor 1 (Nicd1LSL–GFP) in combination with the ApcMin/+ mutation generates higher numbers of adenomas which were higher-differentiated compared to the control [120]
Summary
In the Western world, colorectal cancer (CRC) is the second-highest cause of cancer mortality [1]. Many other stem cell markers have been identified and, using a similar Cre knock-in approach, ISCs have been shown to act as cells of origin for cancer when Apc is deleted or a constitutive-active β-catenin is expressed [63,64,65]. Since Apc mutations alone do not produce invasive tumours, later mutations in the adenoma–carcinoma sequence have been added to make mouse models of CRC more patient-relevant.
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