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• W1573850291 abstract "Members of the vascular endothelial growth factor (VEGF) family and their receptors(VEGFR) play an essential role in the development and maintenance of the blood andlymphatic vasculature. To date, five VEGFs have been identified in the mammalian genome,VEGF-A, -B, -C, -D, and placental growth factor (PlGF), which display distinct bindingaffinities for VEGFR-1, -2, and -3. In addition to their central function in physiologicalangiogenesis and lymphangiogenesis, VEGFs and VEGFRs are upregulated duringcarcinogenesis and are involved in the remodeling of the tumoral blood and lymphaticvasculature. By activating VEGFR-1 and –2, which are both expressed on blood endothelialcells, VEGF-A promotes the formation of new tumoral blood vessels and thereby acceleratestumor growth. In contrast, upregulation of VEGF-C, a ligand for lymphatic endothelialVEGFR-3 as well as for VEGFR-2, induces the formation of tumor-associated lymphaticvessels and thus promotes the passive metastatic dissemination of tumor cells to regionallymph nodes. Much less is known about the functional consequences of tumor-expressedVEGF-B and PlGF, two selective ligands for VEGFR-1, as well as VEGF-D, the secondVEGFR-3- and -2-binding lymphangiogenic VEGF family member. Also, the biologicaleffects of selective VEGFR-1, -2 or -3 signaling on tumor angiogenesis and tumor growth aswell as tumor lymphangiogenesis and metastasis are incompletely studied. Only recently, theidentification of VEGF-E, a selective ligand for VEGFR-2, as well as the generation ofVEGF-C156S, a specific ligand for VEGFR-3, has enabled the study of the distinct roles ofthese receptors.To investigate the function of lymphangiogenic VEGF-D under physiologicalconditions, I analyzed transgenic mice, in which expression of VEGF-D is specificallytargeted to β-cells of pancreatic islets of Langerhans (Rip1VEGF-D mice). In these mice,expression of VEGF-D induces the formation of large lymphatic lacunae surrounding mostislets. A few of these lymphatic vessels may be dysfunctional, which causes intra-lymphaticaccumulations of immune cells. Moreover, lymphatic lacunae often contain erythrocytes,which may result from blood-lymphatic vessel shunts found in the vicinity of some islets.However, the fact that erythrocytes are drained to regional lymph nodes demonstrates thedraining capacity of the de novo formed lymphatic vessels. To address the impact of VEGF-Don tumorigenesis and metastasis, I crossed Rip1VEGF-D with Rip1Tag2 mice, a wellcharacterizedtransgenic model of poorly metastatic multistage β-cell carcinogenesis.Tumoral expression of VEGF-D in Rip1Tag2 mice promotes the growth of peri-tumorallymphatic vessels that frequently contain leucocyte clusters and hemorrhages. Concomitantly,these double-transgenic mice exhibit a high incidence of regional lymph node and distantlung metastases. Since expression of VEGF-D does not significantly affect the invasivenessof tumors and all metastases are well differentiated, these data indicate that VEGF-Dpromotes lymphogenous metastasis by upregulating tumor-associated lymphangiogenesis.Interestingly, the presence of VEGF-D significantly represses tumor angiogenesis and tumorgrowth, yet the mechanisms of this inhibition are thus far uncharacterized. Notably, syngenicand allogenic subcutaneous transplantation of VEGF-D-producing Rip1Tag2 tumor cell linesresults in the formation of tumors exhibiting a dense intra-tumoral lymphatic network butlacking peri-tumoral lymphatic vessels. In these transplanted tumors, no immune cell clustersor hemorrhages are formed in tumor-associated lymphatic vessels and tumor angiogenesis isunaffected by the expression of VEGF-D. These results demonstrate that the tumormicroenvironment critically modulates VEGF-D-elicited effects. It has been recently shownthat transgenic expression of VEGF-C during Rip1Tag2 tumorigenesis promotes metastasis toregional lymph nodes but not to the lungs by inducing peri-tumoral lymphangiogenesis.Tumor-associated lymphatic vessels of these mice neither contain immune cell accumulationsnor hemorrhages, and tumor angiogenesis and tumor growth are not affected by theproduction of VEGF-C. Thus, by employing the Rip1Tag2 tumor model, I was able toidentify not only similarities but also significant differences between VEGF-D and –Cfunction.Since VEGF-C and –D can bind both VEGFR-3 and –2, it is not fully establishedwhether selective activation of VEGFR-3 is sufficient to induce tumoral lymphangiogenesisand to promote lymphogenous metastasis. Therefore, I established transgenic mice expressingVEGF-C156S in the endocrine pancreas and crossed these mice with Rip1Tag2 animals. Theanalysis of single and double transgenic mice revealed that VEGF-C156S phenocopiesVEGF-C in all investigated aspects. These results indicate that VEGFR-3 may be thepredominant receptor mediating VEGF-C-elicited effects in Rip1Tag2 mice and that selectiveactivation of VEGFR-3 is sufficient to promote tumor-associated lymphangiogenesis andmetastasis. Hence, VEGFR-3 might represent a valuable target for future anti-metastaticstrategies.To further understand the specific roles of VEGFR-1 and –2 signaling in physiologicalangiogenesis as well as in tumorigenesis, I established transgenic mouselines, which expressthe VEGFR-1-specific ligands VEGF-B167 and PlGF-1 as well as the selective VEGFR-2ligand VEGF-ED1701 in β-cells of pancreatic islets (Rip1VEGF-B167, Rip1PlGF-1, andRip1VEGF-ED1701 mice). These single transgenic mice were analyzed with regard to isletblood vessel morphology and density. In a second set of experiments, I crossed singletransgenicanimals with Rip1Tag2 mice. These double-transgenic mice expressing eitherVEGF-B167, PlGF-1 or VEGF-ED1701 in tumor cells, were analyzed for changes in tumorangiogenesis, tumor growth, and tumor progression. The preliminary data provide evidencethat β-cell-specific upregulation of VEGF-B167 does not critically affect physiologicalangiogenesis of single-transgenic mice but results in a significant increase in the tumormicrovessel density of double-transgenic animals. However, tumor growth and tumorprogression are not promoted by the stimulation of tumor angiogenesis. In contrast,overexpression of PlGF-1 in single-transgenic mice leads to a prominent dilation of bloodcapillaries, which may at least in part be caused by a significant reduction of stabilizing bloodvessel-associated pericytes. Furthermore, tumoral expression of PlGF-1 significantly inhibitstumor angiogenesis and tumor growth, suggesting that this growth factor might be a naturalinhibitor of pathological angiogenesis. Hence, although binding to the same receptor, VEGFB167and PlGF-1 elicit opposing effects on the tumor blood vasculature. These results suggestthat the two growth factors induce distinct signaling pathways via VEGFR-1, which might beconsidered when designing inhibitors of angiogenesis involving VEGFR-1. Importantly, thephenotype of VEGF-B167- and PlGF-1- expressing Rip1Tag2 mice is different from therecently described VEGF-A165 transgenic Rip1Tag2 mice, which exhibited accelerated tumorgrowth and early death. The analysis of VEGF-ED1701-expressing mice and effects induced byselective activation of VEGFR-2 signaling is currently underway." @default.
• W1573850291 created "2016-06-24" @default.
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• W1573850291 date "2006-01-01" @default.
• W1573850291 modified "2023-09-24" @default.
• W1573850291 title "VEGF family members : modulators of tumor angiogenesis and lymphangiogenesis" @default.
• W1573850291 doi "https://doi.org/10.5451/unibas-004280632" @default.
• W1573850291 hasPublicationYear "2006" @default.
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