Suppressive Effects of Vascular Endothelial Growth Factor-B on Tumor Growth in a Mouse Model of Pancreatic Neuroendocrine Tumorigenesis

Abstract

BackgroundThe 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.Methodology/Principal FindingsEctopic 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/SignificanceTaken 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.

Vascular endothelial growth factor-B: Impact on physiology and pathology

“…Considering the cancer tissues had the higher VEGF-B level, 104 The VEGF-B might promote the cancer progression, especially in advanced cancers. However, the VEGF-B also retarded tumor growth in the RIP1-Tag2 mouse of pancreatic neuroendocrine tumorigenesis, 6 and the reduced blood perfusion in VEGF-B-T241 tumors might explain, at least in part, the anti-tumor growth effect. 105 The antigrowth effect might also be accounted for the approximate 15% heavier weight displayed in the VEGF-B −/− mice.…”

“…5 Conversely, the transduced VEGF-B in RIP1-Tag2 islets possibly replaced VEGF-A and PlGF from VEGFR-1, and then diminishing pro-angiogenic effect. 6 In addition, the VEGFs are also engaged in the conversion from white adipose tissue (WAT) to brown adipose tissue (BAT), 7 leading to increased energy expenditure, and resulting in protection from diet induced obesity. The coexistence of angiogenic and browning effect may coordinate the organism to obtain a better adaptation to the external.…”

“…9 , 13 Surprisingly, at the high levels, VEGF-B acted as a growth-inhibiting molecule to forestall overgrowth and tumor growth. 6 , 9 …”

“…(3). In the pancreatic islets, the lipid deposition would result in β -cell dysfunction and apoptosis, 6 , 46 and the weaken insulin production. (4).…”

“…105 The antigrowth effect might also be accounted for the approximate 15% heavier weight displayed in the VEGF-B −/− mice. 6 , 13 The VEGFR-1 may explained the antigrowth and antiangiogenic effect, since it is served as the decoy receptor of VEGF-A. 106 The VEGFR-1 had a negative role in developmental vascularization, and VEGFR-1 −/− embryos died early due to VEGF-A dependent vessels overgrowth and disorganization.…”