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Dysregulation of the vascular endothelial growth factor and semaphorin ligand-receptor families in prostate cancer metastasis.

Bender RJ, Mac Gabhann F - BMC Syst Biol (2015)

Bottom Line: We found pro-lymphangiogenic signatures, including the genes encoding VEGFC and VEGFD, associated with primary tumors that ultimately became aggressive.To leverage our mechanistic understanding, and to link multigene expression changes to outcomes, we performed individualized computational simulations of competitive VEGF and Sema receptor binding across many tumor samples.Therapeutic inhibition of angiogenesis in metastatic prostate cancer should account for both of these routes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA. bender.rj@gmail.com.

ABSTRACT

Background: The vascular endothelial growth factor (VEGF) family is central to cancer angiogenesis. However, targeting VEGF as an anti-cancer therapeutic approach has shown success for some tumor types but not others. Here we examine the expression of the expanded VEGF family in prostate cancer, including the Semaphorin (Sema) family members that compete with VEGFs for Neuropilin binding and can themselves have pro- or anti-angiogenic activity.

Results: First, we used multivariate statistical methods, including partial least squares and clustering, to examine VEGF/Sema gene expression variability in previously published prostate cancer microarray datasets. We show that unlike some cancers, such as kidney cancer, primary prostate cancer is characterized by both a down-regulation of the pro-angiogenic members of the VEGF family and a down-regulation of anti-angiogenic members of the Sema family. We found pro-lymphangiogenic signatures, including the genes encoding VEGFC and VEGFD, associated with primary tumors that ultimately became aggressive. In contrast to primary prostate tumors, prostate cancer metastases showed increased expression of key pro-angiogenic VEGF family members and further repression of anti-angiogenic class III Sema family members. Given the lack of success of VEGF-targeting molecules so far in prostate cancer, this suggests that the reduction in anti-angiogenic Sema signaling may potentiate VEGF signaling and even promote resistance to VEGF-targeting therapies. Inhibition of the VEGF 'accelerator' may need to be accompanied by promotion of the Sema 'brake' to block cancer angiogenesis. To leverage our mechanistic understanding, and to link multigene expression changes to outcomes, we performed individualized computational simulations of competitive VEGF and Sema receptor binding across many tumor samples. The simulations suggest that loss of Sema expression promotes angiogenesis by lowering plexin signaling, not by potentiating VEGF signaling via relaxation of competition.

Conclusions: The combined analysis of bioinformatic data with computational modeling of ligand-receptor interactions demonstrated that enhancement of angiogenesis in prostate cancer metastases may occur through two different routes: elevation of VEGFA and reduction of class 3 Semaphorins. Therapeutic inhibition of angiogenesis in metastatic prostate cancer should account for both of these routes.

No MeSH data available.


Related in: MedlinePlus

Simulated VEGF/Sema ligand-receptor binding on endothelial cells. a VEGFR2 (left), VEGFR1 (middle), and Sema3-NRP1 (right) binding in benign prostate (n = 12), primary tumors (n = 49) and metastatic tumors (n = 27) in the GSE35988 dataset. The p-values are marked as follows: a single * indicates p < 0.05, a double ** indicates p < 0.01, and a triple *** indicates p < 0.001. b VEGF secretion and total Sema3 secretion most strongly affect their respective ligand-receptor complexes although weak competitive effects are observed. Lines represent least squares fits of the log-transformed simulated receptor binding data to the gene expression data. R2 values represent the proportion of variance explained by the least squares fit. c Scatter plots of simulated VEGFA-VEGFR2 and Sema3-NRP-PlxnA across tissue types show that only fraction of the metastatic samples fall into the expected anti-VEGFA responsive region, i.e. high VEGFA-VEGFR2 signaling and low Sema3-NRP-PlxnA signaling. Gradients correlate with expected favorability for angiogenesis: darker red for higher VEGFA-VEGFR2 and darker blue for lower Sema3-NRP-PlxnA. Colors indicate tissue type: Benign (green); Localized (orange); Metastasis (gray)
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Fig5: Simulated VEGF/Sema ligand-receptor binding on endothelial cells. a VEGFR2 (left), VEGFR1 (middle), and Sema3-NRP1 (right) binding in benign prostate (n = 12), primary tumors (n = 49) and metastatic tumors (n = 27) in the GSE35988 dataset. The p-values are marked as follows: a single * indicates p < 0.05, a double ** indicates p < 0.01, and a triple *** indicates p < 0.001. b VEGF secretion and total Sema3 secretion most strongly affect their respective ligand-receptor complexes although weak competitive effects are observed. Lines represent least squares fits of the log-transformed simulated receptor binding data to the gene expression data. R2 values represent the proportion of variance explained by the least squares fit. c Scatter plots of simulated VEGFA-VEGFR2 and Sema3-NRP-PlxnA across tissue types show that only fraction of the metastatic samples fall into the expected anti-VEGFA responsive region, i.e. high VEGFA-VEGFR2 signaling and low Sema3-NRP-PlxnA signaling. Gradients correlate with expected favorability for angiogenesis: darker red for higher VEGFA-VEGFR2 and darker blue for lower Sema3-NRP-PlxnA. Colors indicate tissue type: Benign (green); Localized (orange); Metastasis (gray)

Mentions: The results of simulating many individuals with tumors were divided into groups (benign, localized, metastatic) and the distribution of predicted signaling outputs across the population are calculated. Binding of the two major isoforms of VEGFA (VEGF165 and VEGF121) to VEGFR-2 and VEGFR-1 on endothelial cells was lowest in primary (localized) tumors, whereas the collective binding of the class 3 Semaphorins to endothelial plexins decreased in primary tumors relative to normal tissue and decreased further in metastatic tumors (Fig. 5a). The receptor binding trends closely followed ligand expression levels, with VEGFA expression being the predominant factor driving VEGFR-1/2 binding, while the total Sema3 expression accounted for most of the variation in Sema3-NRP-PlxnA binding (Fig. 5b). The receptor binding profiles on tumor cells (Additional file 1: Figure S12) were similar to those on endothelial cells. These results indicated that primary tumors are associated with both pro-angiogenic (decreased Sema3-NRP-PlxnA binding) and anti-angiogenic (decreased VEGFR-2 binding) alterations, making it difficult to predict whether primary tumors would benefit from therapies that inhibit VEGF signaling. On the other hand, the alterations in metastatic tumors were all pro-angiogenic: VEGFR-2 binding was higher and Sema3-NRP-PlxnA binding was lower. The range of VEGFR-2 binding was highest in metastatic samples, going beyond both the low and high ends of the range of normal samples. This suggested an important role for patient selection in the use of anti-angiogenic therapies, as only the patients with high baseline VEGFR-2 signaling would be expected to respond.Fig. 5


Dysregulation of the vascular endothelial growth factor and semaphorin ligand-receptor families in prostate cancer metastasis.

Bender RJ, Mac Gabhann F - BMC Syst Biol (2015)

Simulated VEGF/Sema ligand-receptor binding on endothelial cells. a VEGFR2 (left), VEGFR1 (middle), and Sema3-NRP1 (right) binding in benign prostate (n = 12), primary tumors (n = 49) and metastatic tumors (n = 27) in the GSE35988 dataset. The p-values are marked as follows: a single * indicates p < 0.05, a double ** indicates p < 0.01, and a triple *** indicates p < 0.001. b VEGF secretion and total Sema3 secretion most strongly affect their respective ligand-receptor complexes although weak competitive effects are observed. Lines represent least squares fits of the log-transformed simulated receptor binding data to the gene expression data. R2 values represent the proportion of variance explained by the least squares fit. c Scatter plots of simulated VEGFA-VEGFR2 and Sema3-NRP-PlxnA across tissue types show that only fraction of the metastatic samples fall into the expected anti-VEGFA responsive region, i.e. high VEGFA-VEGFR2 signaling and low Sema3-NRP-PlxnA signaling. Gradients correlate with expected favorability for angiogenesis: darker red for higher VEGFA-VEGFR2 and darker blue for lower Sema3-NRP-PlxnA. Colors indicate tissue type: Benign (green); Localized (orange); Metastasis (gray)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4559909&req=5

Fig5: Simulated VEGF/Sema ligand-receptor binding on endothelial cells. a VEGFR2 (left), VEGFR1 (middle), and Sema3-NRP1 (right) binding in benign prostate (n = 12), primary tumors (n = 49) and metastatic tumors (n = 27) in the GSE35988 dataset. The p-values are marked as follows: a single * indicates p < 0.05, a double ** indicates p < 0.01, and a triple *** indicates p < 0.001. b VEGF secretion and total Sema3 secretion most strongly affect their respective ligand-receptor complexes although weak competitive effects are observed. Lines represent least squares fits of the log-transformed simulated receptor binding data to the gene expression data. R2 values represent the proportion of variance explained by the least squares fit. c Scatter plots of simulated VEGFA-VEGFR2 and Sema3-NRP-PlxnA across tissue types show that only fraction of the metastatic samples fall into the expected anti-VEGFA responsive region, i.e. high VEGFA-VEGFR2 signaling and low Sema3-NRP-PlxnA signaling. Gradients correlate with expected favorability for angiogenesis: darker red for higher VEGFA-VEGFR2 and darker blue for lower Sema3-NRP-PlxnA. Colors indicate tissue type: Benign (green); Localized (orange); Metastasis (gray)
Mentions: The results of simulating many individuals with tumors were divided into groups (benign, localized, metastatic) and the distribution of predicted signaling outputs across the population are calculated. Binding of the two major isoforms of VEGFA (VEGF165 and VEGF121) to VEGFR-2 and VEGFR-1 on endothelial cells was lowest in primary (localized) tumors, whereas the collective binding of the class 3 Semaphorins to endothelial plexins decreased in primary tumors relative to normal tissue and decreased further in metastatic tumors (Fig. 5a). The receptor binding trends closely followed ligand expression levels, with VEGFA expression being the predominant factor driving VEGFR-1/2 binding, while the total Sema3 expression accounted for most of the variation in Sema3-NRP-PlxnA binding (Fig. 5b). The receptor binding profiles on tumor cells (Additional file 1: Figure S12) were similar to those on endothelial cells. These results indicated that primary tumors are associated with both pro-angiogenic (decreased Sema3-NRP-PlxnA binding) and anti-angiogenic (decreased VEGFR-2 binding) alterations, making it difficult to predict whether primary tumors would benefit from therapies that inhibit VEGF signaling. On the other hand, the alterations in metastatic tumors were all pro-angiogenic: VEGFR-2 binding was higher and Sema3-NRP-PlxnA binding was lower. The range of VEGFR-2 binding was highest in metastatic samples, going beyond both the low and high ends of the range of normal samples. This suggested an important role for patient selection in the use of anti-angiogenic therapies, as only the patients with high baseline VEGFR-2 signaling would be expected to respond.Fig. 5

Bottom Line: We found pro-lymphangiogenic signatures, including the genes encoding VEGFC and VEGFD, associated with primary tumors that ultimately became aggressive.To leverage our mechanistic understanding, and to link multigene expression changes to outcomes, we performed individualized computational simulations of competitive VEGF and Sema receptor binding across many tumor samples.Therapeutic inhibition of angiogenesis in metastatic prostate cancer should account for both of these routes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA. bender.rj@gmail.com.

ABSTRACT

Background: The vascular endothelial growth factor (VEGF) family is central to cancer angiogenesis. However, targeting VEGF as an anti-cancer therapeutic approach has shown success for some tumor types but not others. Here we examine the expression of the expanded VEGF family in prostate cancer, including the Semaphorin (Sema) family members that compete with VEGFs for Neuropilin binding and can themselves have pro- or anti-angiogenic activity.

Results: First, we used multivariate statistical methods, including partial least squares and clustering, to examine VEGF/Sema gene expression variability in previously published prostate cancer microarray datasets. We show that unlike some cancers, such as kidney cancer, primary prostate cancer is characterized by both a down-regulation of the pro-angiogenic members of the VEGF family and a down-regulation of anti-angiogenic members of the Sema family. We found pro-lymphangiogenic signatures, including the genes encoding VEGFC and VEGFD, associated with primary tumors that ultimately became aggressive. In contrast to primary prostate tumors, prostate cancer metastases showed increased expression of key pro-angiogenic VEGF family members and further repression of anti-angiogenic class III Sema family members. Given the lack of success of VEGF-targeting molecules so far in prostate cancer, this suggests that the reduction in anti-angiogenic Sema signaling may potentiate VEGF signaling and even promote resistance to VEGF-targeting therapies. Inhibition of the VEGF 'accelerator' may need to be accompanied by promotion of the Sema 'brake' to block cancer angiogenesis. To leverage our mechanistic understanding, and to link multigene expression changes to outcomes, we performed individualized computational simulations of competitive VEGF and Sema receptor binding across many tumor samples. The simulations suggest that loss of Sema expression promotes angiogenesis by lowering plexin signaling, not by potentiating VEGF signaling via relaxation of competition.

Conclusions: The combined analysis of bioinformatic data with computational modeling of ligand-receptor interactions demonstrated that enhancement of angiogenesis in prostate cancer metastases may occur through two different routes: elevation of VEGFA and reduction of class 3 Semaphorins. Therapeutic inhibition of angiogenesis in metastatic prostate cancer should account for both of these routes.

No MeSH data available.


Related in: MedlinePlus