Studies of patients with colorectal more information carcinoma using positron emission tomography (PET) demonstrate an inverse correlation between the expression of VEGF-B and k3, the most important kinetic parameter for determining uptake of the glucose analog 18F-FDG [45]. Whether the observed VEGFB-dependent changes in tumor growth rate in the RIP1-Tag2 model are due to an altered supply or utilization of glucose warrants further analysis by a PET-based approach. Pharmacological inhibitors of VEGF-signaling have now made their way into the clinic following successful pre-clinical studies. However, the patient benefit is comparatively modest and is typically measured in months [46], [47], [48].
The mechanism of action of VEGF inhibitors is still debated and has been suggested to include overt anti-angiogenic actions, vessel ��normalization��, inhibition of mobilization of endothelial precursor cells, suppression of intra-tumoral regulatory T-cells, as well as direct effects on tumor cells [49]. Given the diversity and complexity of signaling derived from the VEGF ligand/receptor system revealed by this and other studies, it is important to fully understand the contributions of each component. Despite the observed inhibition of tumor growth in the present study, human tumors, as well as wildtype RIP1-Tag2 tumors, readily express VEGF-B, indicative of functional significance. Again, it may be that a balance between the three different VEGFR-1 ligands must be maintained to achieve optimal conditions for endothelial cell function and growth.
Our results raise the possibility that indiscriminate blocking of VEGF signaling may lead to a mix of favorable and detrimental effects in terms of net tumor growth. Thus, further pre-clinical as well as clinical studies on the role of VEGF-B in tumor biology in the context of pharmacological inhibition of VEGF family signaling are justified in order to maximize patient benefit. Materials and Methods Mice All experimental procedures involving mice were approved by and performed according to the guidelines and regulations of the local committees for animal care (the Swiss Federal Veterinary Office (SFVO) – the Cantonal Veterinary Office of Basel Stadt, permit numbers 1878, 1907, 1908, and Stockholm North committee for animal experimentation, permit number N146/08) and all efforts were made to minimize suffering.
The RIP1-VEGFB vector encodes full length human VEGF-B167 (accession number EMBL: “type”:”entrez-nucleotide”,”attrs”:”text”:”U43369″,”term_id”:”1216397″,”term_text”:”U43369″U43369) under the control of the rat insulin gene II promoter (RIP1; [20]. For generation of transgenic Carfilzomib RIP1-VEGFB mice, a RIP1-VEGFB fragment, obtained by BamH1 digestions of the RIP1-VEGFB vector was injected into the pronucleus of fertilized C57BL/6 oocytes according to standard protocol [50].