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

Albrecht I, Kopfstein L, Strittmatter K, Schomber T, Falkevall A, Hagberg CE, Lorentz P, Jeltsch M, Alitalo K, Eriksson U, Christofori G, Pietras K - PLoS ONE (2010)

Bottom Line: 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.No differences in vascular density, perfusion or immune cell infiltration upon altered Vegfb gene dosage were noted.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine, Institute of Biochemistry and Genetics, University of Basel, Basel, Switzerland.

ABSTRACT

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.

Methodology/principal findings: 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/significance: 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.

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Related in: MedlinePlus

Analysis of inflammatory cell infiltration in tumors derived from RIP1-Tag2; RIP1-VEGFB mice.A) Representative immunofluorescence microphotographs of pancreatic tumor sections of RIP1-Tag2 (left) and RIP1-Tag2; RIP1-VEGFB (right) mice stained for CD45. Scale bar: 100 µm. B) Quantification of tumor-infiltrating immune cells in RIP1-Tag2 (white bar, N =  5, n =  26-46) and RIP1-Tag2; RIP1-VEGFB (grey bar, N =  5, n = 27–45). The number of tumor-infiltrating CD45+ and F4/80+ cells as well as 7/4+ neutrophils was determined by quantification of the area stained for the selected marker in relation to the total tumor area using computer-assisted image analysis. N =  number of analyzed mice, n =  number of tumors.
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pone-0014109-g004: Analysis of inflammatory cell infiltration in tumors derived from RIP1-Tag2; RIP1-VEGFB mice.A) Representative immunofluorescence microphotographs of pancreatic tumor sections of RIP1-Tag2 (left) and RIP1-Tag2; RIP1-VEGFB (right) mice stained for CD45. Scale bar: 100 µm. B) Quantification of tumor-infiltrating immune cells in RIP1-Tag2 (white bar, N =  5, n =  26-46) and RIP1-Tag2; RIP1-VEGFB (grey bar, N =  5, n = 27–45). The number of tumor-infiltrating CD45+ and F4/80+ cells as well as 7/4+ neutrophils was determined by quantification of the area stained for the selected marker in relation to the total tumor area using computer-assisted image analysis. N =  number of analyzed mice, n =  number of tumors.

Mentions: Apart from its role in endothelial cell biology, VEGFR-1 is also expressed by various cells of the immune system, including macrophages [31] and hematopoietic progenitor cells [32]. Thus, we appraised the effects of transgenic expression of VEGF-B on the immune cell infiltration of RIP1-Tag2 lesions. As determined by immunostaining for CD45, there was no gross difference in the abundance of leukocytes in RIP1-Tag2; RIP1-VEGFB mice compared to wildtype RIP1-Tag2 mice (Figure 4a-b). Specifically, both macrophages and neutrophils have been implicated in the growth and angiogenesis of RIP1-Tag2 tumors [33], [34]. However, the infiltration of macrophages and neutrophils, as evaluated by immunostaining for F4/80 and Gr1, respectively, was not altered by the expression of VEGF-B in RIP1-Tag2 double transgenic mice (Figure 4a-b).


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

Albrecht I, Kopfstein L, Strittmatter K, Schomber T, Falkevall A, Hagberg CE, Lorentz P, Jeltsch M, Alitalo K, Eriksson U, Christofori G, Pietras K - PLoS ONE (2010)

Analysis of inflammatory cell infiltration in tumors derived from RIP1-Tag2; RIP1-VEGFB mice.A) Representative immunofluorescence microphotographs of pancreatic tumor sections of RIP1-Tag2 (left) and RIP1-Tag2; RIP1-VEGFB (right) mice stained for CD45. Scale bar: 100 µm. B) Quantification of tumor-infiltrating immune cells in RIP1-Tag2 (white bar, N =  5, n =  26-46) and RIP1-Tag2; RIP1-VEGFB (grey bar, N =  5, n = 27–45). The number of tumor-infiltrating CD45+ and F4/80+ cells as well as 7/4+ neutrophils was determined by quantification of the area stained for the selected marker in relation to the total tumor area using computer-assisted image analysis. N =  number of analyzed mice, n =  number of tumors.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2991338&req=5

pone-0014109-g004: Analysis of inflammatory cell infiltration in tumors derived from RIP1-Tag2; RIP1-VEGFB mice.A) Representative immunofluorescence microphotographs of pancreatic tumor sections of RIP1-Tag2 (left) and RIP1-Tag2; RIP1-VEGFB (right) mice stained for CD45. Scale bar: 100 µm. B) Quantification of tumor-infiltrating immune cells in RIP1-Tag2 (white bar, N =  5, n =  26-46) and RIP1-Tag2; RIP1-VEGFB (grey bar, N =  5, n = 27–45). The number of tumor-infiltrating CD45+ and F4/80+ cells as well as 7/4+ neutrophils was determined by quantification of the area stained for the selected marker in relation to the total tumor area using computer-assisted image analysis. N =  number of analyzed mice, n =  number of tumors.
Mentions: Apart from its role in endothelial cell biology, VEGFR-1 is also expressed by various cells of the immune system, including macrophages [31] and hematopoietic progenitor cells [32]. Thus, we appraised the effects of transgenic expression of VEGF-B on the immune cell infiltration of RIP1-Tag2 lesions. As determined by immunostaining for CD45, there was no gross difference in the abundance of leukocytes in RIP1-Tag2; RIP1-VEGFB mice compared to wildtype RIP1-Tag2 mice (Figure 4a-b). Specifically, both macrophages and neutrophils have been implicated in the growth and angiogenesis of RIP1-Tag2 tumors [33], [34]. However, the infiltration of macrophages and neutrophils, as evaluated by immunostaining for F4/80 and Gr1, respectively, was not altered by the expression of VEGF-B in RIP1-Tag2 double transgenic mice (Figure 4a-b).

Bottom Line: 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.No differences in vascular density, perfusion or immune cell infiltration upon altered Vegfb gene dosage were noted.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine, Institute of Biochemistry and Genetics, University of Basel, Basel, Switzerland.

ABSTRACT

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.

Methodology/principal findings: 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/significance: 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.

Show MeSH
Related in: MedlinePlus