Suppressive effects of vascular endothelial growth factor-B on tumor growth in a mouse model of pancreatic neuroendocrine tumorigenesis

• Published in: PloS one 2010-11, Vol.5 (11), p.e14109-e14109
• Main Authors: Albrecht, Imke, Kopfstein, Lucie, Strittmatter, Karin, Schomber, Tibor, Falkevall, Annelie, Hagberg, Carolina E, Lorentz, Pascal, Jeltsch, Michael, Alitalo, Kari, Eriksson, Ulf, Christofori, Gerhard, Pietras, Kristian
• Format: Article
• Language: English
• Subjects: Analysis; Angiogenesis; Animal models; Animals; Apoptosis; Biochemistry; Biological effects; Biology; Biophysics; Blood; Blood vessels; Breast cancer; Cancer; Cardiovascular Disorders/Vascular Biology; Cell Biology/Cell Signaling; Clonal deletion; Colorectal cancer; Disease Models, Animal; Ectopic expression; Female; Gene deletion; Gene dosage; Gene expression; Genetic engineering; Growth factors; Humans; Immunoblotting; Immunohistochemistry; Infiltration; Insulin; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Islets of Langerhans; Kinases; Male; Medical research; Medicin och hälsovetenskap; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Morphology; Musculoskeletal system; Neovascularization; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - metabolism; Neuroendocrine Tumors - pathology; Nitric oxide; Oncology; Pancreas; Pancreas - blood supply; Pancreas - metabolism; Pancreas - pathology; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pathology/Molecular Pathology; Perfusion; Physiological aspects; Physiological effects; Placenta; Rats; Regulators; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Transgenic animals; Transgenic mice; Tumor Burden; Tumorigenesis; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor B - genetics; Vascular Endothelial Growth Factor B - metabolism; Vascular endothelial growth factor receptors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0014109

The family of vascular endothelial growth factors (VEGF) contains key regulators of blood and lymph vessel development, including VEGF-A, -B, -C, -D, and placental growth factor. The role of VEGF-B during physiological or pathological angiogenesis has not yet been conclusively delineated. Herein, we investigate the function of VEGF-B by the generation of mouse models of cancer with transgenic expression of VEGF-B or homozygous deletion of Vegfb. Ectopic expression of VEGF-B in the insulin-producing β-cells of the pancreas did not alter the abundance or architecture of the islets of Langerhans. The vasculature from transgenic mice exhibited a dilated morphology, but was of similar density as that of wildtype mice. Unexpectedly, we found that transgenic expression of VEGF-B in the RIP1-Tag2 mouse model of pancreatic neuroendocrine tumorigenesis retarded tumor growth. Conversely, RIP1-Tag2 mice deficient for Vegfb presented with larger tumors. No differences in vascular density, perfusion or immune cell infiltration upon altered Vegfb gene dosage were noted. However, VEGF-B acted to increase blood vessel diameter both in normal pancreatic islets and in RIP1-Tag2 tumors. Taken together, our results illustrate the differences in biological function between members of the VEGF family, and highlight the necessity of in-depth functional studies of VEGF-B to fully understand the effects of VEGFR-1 inhibitors currently used in the clinic.