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


RESULTS
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.


CONCLUSIONS
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.
Department of Biomedicine, Institute of Biochemistry and Genetics, University of Basel, Basel, Switzerland.
Imke
I
Albrecht
Lucie
L
Kopfstein
Karin
K
Strittmatter
Tibor
T
Schomber
Annelie
A
Falkevall
Carolina E
CE
Hagberg
Pascal
P
Lorentz
Michael
M
Jeltsch
Kari
K
Alitalo
Ulf
U
Eriksson
Gerhard
G
Christofori
Kristian
K
Pietras
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010179:Pancreas / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics / Q000378:metabolism*
D042561:Vascular Endothelial Growth Factor B