Extracellular Matrix and the functional barrier caused by interstitial hypertension
- Purpose of the study. The study will investigate the "functional barrier" caused by the elevated tissue pressure in cancers. This elevated pressure represents a "functional barrier" towards delivery of anticancer drugs from the blood to the tumour cells. The purpose of the study is to gain understanding of the role of the interaction between the extracellular matrix and the tumor cells in generating this elevated pressures and then search for treatment strategies to attenuate this elevated pressure. This interaction is mediated by the integrin receptors and the study will specifically focus on how altered expression of the integrin receptors, through which the cells attach to the collagen in the extracellular matrix, influences the tumor properties. Clinically available tyrosine kinase inhibitors will be investigated for their ability to limit tumor pressure and growth in these models.
- Expected harm/severity for the animals. The study requires implantation of well established cancers cell lines and an observation period of 12 days before the tumors are investigated.The harm during the 12 day experiment is considered minimal.
- Expected benefit for science or society. The scientific benefit is refined understanding about how integrin and growth factor receptor signalling control interstitial hypertension and how this can potentially be used as a therapeutic target. The societal benefit of such understanding is that once established, the drug can be reassessed as an interstitial hypertension lowering agent. Interstitial hypertension is considered a functional barrier to drug delivery to tumors, therefore lowering of interstitial hypertension could be used to increase drug treatment efficacy.
-How many and what kind of animals will be used. Two strains of genetically modified mice with altered integrin expression will be used in the study, a total of 66 animals in experiments are needed. The animals are sacrificed on day 12 of the study and all the tumour tissue is harvested and anlyzed.
Compliance with the requirements for replacement, reduction and refinement.
-Replacement. The study requires an intact cardiovascular system. Previous in vivo studies and also in vitro studies from our collaborators are the basis for selecting the drug dosage.
-Refinement. The methods are highly sensitive and well established in the research group. This will reduce the number of animals to a minimum. Also, all tumor material is harvested at the end of the experiment.
-Reduction. In vitro studies in cell cultures and the in vitro collagen assay, also together with our collaborator,s are the basis for selecting the drug dosage and design the study. In parallel we started work on an animal free 3D cell culture based experimental protocol for assessing the effect of growth factor receptor signalling on interstitial hypertension of cancer cells in vitro and these are used for repacement when possible.
- Expected harm/severity for the animals. The study requires implantation of well established cancers cell lines and an observation period of 12 days before the tumors are investigated.The harm during the 12 day experiment is considered minimal.
- Expected benefit for science or society. The scientific benefit is refined understanding about how integrin and growth factor receptor signalling control interstitial hypertension and how this can potentially be used as a therapeutic target. The societal benefit of such understanding is that once established, the drug can be reassessed as an interstitial hypertension lowering agent. Interstitial hypertension is considered a functional barrier to drug delivery to tumors, therefore lowering of interstitial hypertension could be used to increase drug treatment efficacy.
-How many and what kind of animals will be used. Two strains of genetically modified mice with altered integrin expression will be used in the study, a total of 66 animals in experiments are needed. The animals are sacrificed on day 12 of the study and all the tumour tissue is harvested and anlyzed.
Compliance with the requirements for replacement, reduction and refinement.
-Replacement. The study requires an intact cardiovascular system. Previous in vivo studies and also in vitro studies from our collaborators are the basis for selecting the drug dosage.
-Refinement. The methods are highly sensitive and well established in the research group. This will reduce the number of animals to a minimum. Also, all tumor material is harvested at the end of the experiment.
-Reduction. In vitro studies in cell cultures and the in vitro collagen assay, also together with our collaborator,s are the basis for selecting the drug dosage and design the study. In parallel we started work on an animal free 3D cell culture based experimental protocol for assessing the effect of growth factor receptor signalling on interstitial hypertension of cancer cells in vitro and these are used for repacement when possible.