Abstract
BackgroundColorectal-cancer (CRC) research has greatly benefited from the availability of small animal tumor models. Spontaneous and chemically-induced CRC models are widely used yet limited in their resemblance to human disease and are often prolonged, not accurately repetitive, and associated with inflammatory side effects. In-situ murine or human tumor implantation in the gastrointestinal tract of mice is extremely challenging, and limited by inter-animal variability and procedure-related complications and mortality. As a result, in frequent studies CRC is implanted in distal sites, most commonly the subcutaneous region, an approach that is greatly limited by the absence of normal gastrointestinal tumor milieu and has substantial effects on tumor development.AimsIn this study we aimed to develop a well-tolerated repetitive tool to study CRC in small animals by adapting the murine colonoscopy system to serve as a platform for colonic sub-mucosal orthotopic implantation of human and murine CRC tumor cells.ResultsWe report the establishment of a novel small-animal CRC model that is minimally invasive, rapid, well-tolerated, highly reproducible, and confers precise control of tumor number, location and growth rate. Moreover, we show that this model uniquely allows the side-by-side induction of distinct genetically manipulated tumors, enabling the mechanistic study of tumor interaction and cross-talk within the native intestinal microenvironment.ConclusionsEmployment of this new approach may represent a major technical advance for the in-vivo study of CRC.
Highlights
Colorectal-cancer (CRC) is the second leading cause of cancer mortality in many industrialized countries [1]
We report the establishment of a novel small-animal CRC model that is minimally invasive, rapid, well-tolerated, highly reproducible, and confers precise control of tumor number, location and growth rate
We show that this model uniquely allows the side-by-side induction of distinct genetically manipulated tumors, enabling the mechanistic study of tumor interaction and cross-talk within the native intestinal microenvironment
Summary
Colorectal-cancer (CRC) is the second leading cause of cancer mortality in many industrialized countries [1]. Spontaneous CRC transgenic mouse strains closely imitate human cancer syndromes, such as hereditary nonpolyposis colorectal cancer (HNPCC) [4] and familial adenomatosis polyposis (FAP) [5] These models have been proven invaluable for the study of the effects of known genetic alterations on the disease course. Many of these mouse models form adenomas primarily in the small intestine, and are typically associated with a slow growth rate and considerable inter-animal variability [3] The ApcMin/+ mouse strain was established based on the results derived from a germ line mutagenesis study with Nethyl-N-nitrosourea combined with phenotypic screening [5]. In frequent studies CRC is implanted in distal sites, most commonly the subcutaneous region, an approach that is greatly limited by the absence of normal gastrointestinal tumor milieu and has substantial effects on tumor development
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