Forsøksdyr: Breeding of the transgenic C57Bl6 Wnt-1 mice with the transgenic mouse strain B6.129P2-Axltm1Dgen/J in order to study the role of Axl in mammary tumor development (renew)

Godkjenningsdato 12.01.2018

Godkjenningsperiode 12.01.2018-11.01.2020

Axl is a member of the TAM (Tyro-Axl-Mer) receptor tyrosine kinases (RTK) transmembrane receptor tyrosine kinase. TAM family regulates whole range of cellular responses. Axl, particularly, is expressed in embryonic tissues and plays a role in the neural and mesenchymal development. In adult tissues its expression is restricted to smooth muscle cells. Relative to normal expression, increased level of Axl is specific for various disease states. In patients suffering from cancer Axl expression is associated with metastatic lesions and with poor overall patient survival. The B6.129P2-Axltm1Dgen/J mouse strain allows us to obtain a functional knockdown of Axl. The transgenic C57Bl6 Wnt-1 develop mammary tumors, by crossing this strain in an axl knockdown we showed a decrease of tumor incidence in the absencfe of Axl. This new animal model will allow us to compare the tumor signalisation in the presence or absences of 247 animals have been used for project 6638. We want to continue this project in order to confirm this effect and to understand the mechanisms explaining those effects. 500 animals maximum will be used, no other procedure than breeding will be done but animal will display moderate distress because of tumor development. After animal sacrifice, when they develop tumor, they will be used for molecular analysis such as immunohistochemistry, micro array and flow cytometry in order to compare tumor signalisation in the presence or absence of axl. The molecular differences between axl expressing and axl knockout tumors may help us to find new therapeutic targets against tumor development.
In previous project, 6638 as explained below, we showed differences of tumor incidence in the presence or absence of Axl, in order to understand the biological mechanisms underlying those defences we needs to use the same models. Furthermore it is difficult in vitro to reproduce all the tumor mechanisms and microenvironment as they occur in Vivo. We try to reduce the number of animals as much as possible, in project 6638 we used 237 animals, here we plan to reproduce the experiment and we will need more sample to do different molecular analysis so to double the number of animals appears to be the correct number. This breeding project will be stop when we get enough samples to perform all the molecular analysis.
The animals will develop mammary tumors, in order to reduce the pain and discomfort of the animals, they will be monitored and sacrifice before reching human endpoints as specified in the score sheet.