Functional and anatomical monitoring of tumor progression by non-invasive imaging devices in various tumor models
Zusammenfassung der Projektergebnisse
The aim of the first funding period was to analyse the functional role of Discoidin Domain Receptors (DDRs) on mechanisms that promote tumor invasion and metastatic dissemination by applying tumor and transgenic mouse models in vivo. DDR1b and DDR2 overexpression in the mouse mammary gland induced hyperplasia, dysplasia and caused the development of mammary adenocarcinoma with late onsets associated with the development of lung metastases. DDR2 transgenic mice developed lung metastases without any macroscopically visible tumor within the mammary gland. The late onset and rather low frequency of the development of mammary carcinomas in both mammary carcinoma tumor models support the view that an aberrant stroma predisposes the mammary gland to cancer by increasing the frequency with which an initiated cell proceeds to neoplasia, Therefore, these DDR transgenic lines can be further applied to study stromal alterations promoting breast tumorigenesis and metastatic spread. Loss-of-function experiments in vivo demonstrated that deficiency of DDR2 creates an altered microenvironment that favors initial tumor take, and during tumor progression leads to a reduced cell proliferation and impaired migration and metastatic spread. This indicates that DDR2 plays an important role in tumor cell-stroma interaction as well as in processes remodeling the extracellular matrix. The aim of the second funding period was to support research projects of SPP investigators by applying flat panel Volume Computer Tomography (fpVCT) and Near infrared fluorescence (NIRF) imaging. High resolution fpVCT was used to monitor tumor-vessel density, changes in tumor volume, necrotic tumor areas and metastases of various tumor models. For example, in induced monotransgenic WAP-T NP8 mice and bi-transgenic WAP-T NP8W10 mice tumor growth in each mammary gland, and vessel development as well as occurence of metastasis were monitored. fpVCT in combination with a novel blood pool contrast agent was applied in induced WAP-T NP8CC1-knockout mice and WAP-T CEACAM endo+ mice over time to assess tumor vessel development and leakage. Monitoring tumor development in the absence of glutathione peroxidase demonstrated a vascular tumor phenotype. The effect of hyaluronic acid metabolism on tumor progression in oesophageal squamous cell carcinoma was evaluated. The sensitivity of tumor detection and assessment of molecular events in tumors in vivo by optical imaging could further be improved by the establishment of pH- and oxygen-sensing NIRF imaging probes as well as by enzyme-activatable probes. Furthermore, binding kinetics of fluorescence-labeled CD44v6-blocking peptide to CD44v6-expressing tumors in rat and mouse tumor models was performed using NIRF imaging. A software was developed to correlate fluorescence signals to anatomical structures obtained by fpVCT.
