Forsøksdyr: The study of intestinal tumor initiation and development.

Godkjenningsdato 01.10.2018

Godkjenningsperiode 01.10.2018-01.09.2022

Our gastrointestinal tract (including small intestine and colon) is covered by an absorptive lining that guarantee nutrients and water intake. This lining (epithelium) constantly renews thanks to a population of adult stem cells that give rise to the rest of epithelial cells (1). This proliferation and differentiation process is finely controlled by a network of signaling pathways that when deregulated lead to malignant transformation. This fact is reflected in the number of gastrointestinal cancers worldwide. For example, colorectal cancer is the 4th most frequent reason for cancer associated death worldwide, which makes a medical necessity to understand the underlying mechanisms in stem cell regulation and intestinal tumor development (2).

So, we plan to address the study of tumor development in the small intestine and the colon using a mouse model that develops tumors due to unbalanced proliferation signaling on stem cells (ApcMin mouse)(3). These mice will be crossed to other mouse models deficient for our proteins of interest that will allow us to decipher the role of both proteins on tumor initiation and development.
Previous preliminary data of our lab suggest that these proteins can contribute to stem cell regulation and intestinal renewal, making them a possible part of the signaling network important to maintain homeostasis and that could be unbalanced during tumorigenesis.

Since ApcMin mice develop tumors located mainly in the small intestine, and human patients predominantly develop colonic tumors, we will also use an additional inflammation model to induce tumor formation in the colon(4).

Unfortunately, there are currently no alternatives to animals to analyze the factors that regulate intestinal tumor development. Since carcinogenesis is a complex, multifactorial process that is regulated by different cell types in constant communication with the environment, it is currently not possible to model this in vitro. However, to limit animal use, we will use in vitro organoid systems when possible. By doing this, we can grow organoids to perform specific analysis derived from a smaller number of mice.
In addition, we aim to use multiple tissues (e.g. lymph nodes, spleen, gut, feces, bones etc.) from each mouse at each endpoint and use multiparameter analyses.
So we estimate the total use of 196 mice in this project.

To guarantee the minimum distress level in these mice, animals will be checked daily for symptoms of pain, and will be sacrificed following human endpoints. We cannot avoid a certain amount of distress as derived from the tumor formation and the induction of inflammatory disease. However, mice will closely monitor to prevent unnecessary suffering.

(1)Barker et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007
(2)Gandomani, et al. Colorectal cancer in the world: incidence, mortality and risk factors. Biomed. Res. Therapy. 2017
(3)Yamada, Mori. Multistep carcinogenesis of the colon in Apc(Min/+) mouse. Cancer Sci. 2007
(4)Tanaka, et al. DSS strongly promotes colorectal carcinogenesis in Apc(Min/+) mice: inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms. Inc J Cancer 2006