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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

Down-regulation of pro- and anti-angiogenic ligands in primary prostate tumors. a-d: VEGFA (a), PGF (b), and the receptor gene KDR (c) are expressed at lower levels in prostate tumors than in normal prostate tissue in the TCGA dataset, as shown by the density plots (top), box plots (middle), and spike plots (bottom). The co-receptor gene NRP1 (d) is expressed at slightly higher levels in tumors but has a similar overall distribution to normal tissues. e-h: This contrasts with the TCGA renal cell carcinoma (kidney) dataset, where VEGFA (e), PGF (f), KDR (g), and NRP1 (h) are heavily up-regulated in tumors. iVEGFA down-regulation in primary prostate cancer is observed across TCGA and microarray datasets, as is consistent down-regulation of class three semaphorins. The number in the boxes indicates the two-tailed t-test p-value after multiple testing correction with the Benjamini-Hochberg procedure. Only comparisons with corrected p-values less than 0.05 are displayed. The colors of the boxes indicate the magnitude of the t-statistic. The blue boxes to the right of the rows indicate that a gene is significantly down-regulated in two or more datasets with no significant differences in other datasets
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Fig1: Down-regulation of pro- and anti-angiogenic ligands in primary prostate tumors. a-d: VEGFA (a), PGF (b), and the receptor gene KDR (c) are expressed at lower levels in prostate tumors than in normal prostate tissue in the TCGA dataset, as shown by the density plots (top), box plots (middle), and spike plots (bottom). The co-receptor gene NRP1 (d) is expressed at slightly higher levels in tumors but has a similar overall distribution to normal tissues. e-h: This contrasts with the TCGA renal cell carcinoma (kidney) dataset, where VEGFA (e), PGF (f), KDR (g), and NRP1 (h) are heavily up-regulated in tumors. iVEGFA down-regulation in primary prostate cancer is observed across TCGA and microarray datasets, as is consistent down-regulation of class three semaphorins. The number in the boxes indicates the two-tailed t-test p-value after multiple testing correction with the Benjamini-Hochberg procedure. Only comparisons with corrected p-values less than 0.05 are displayed. The colors of the boxes indicate the magnitude of the t-statistic. The blue boxes to the right of the rows indicate that a gene is significantly down-regulated in two or more datasets with no significant differences in other datasets

Mentions: We used three types of plots to show differences in gene expression between tissue types (e.g. Fig. 1a-d and Additional file 1: Figures S2-S5): density plots show differences in the shapes of the distributions, with the densities estimated using the R function density with default kernel bandwidth; box plots show the range of variation with statistics such as the median and quartiles; and spike plots showed the individual points to emphasize the range.Fig. 1


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)

Down-regulation of pro- and anti-angiogenic ligands in primary prostate tumors. a-d: VEGFA (a), PGF (b), and the receptor gene KDR (c) are expressed at lower levels in prostate tumors than in normal prostate tissue in the TCGA dataset, as shown by the density plots (top), box plots (middle), and spike plots (bottom). The co-receptor gene NRP1 (d) is expressed at slightly higher levels in tumors but has a similar overall distribution to normal tissues. e-h: This contrasts with the TCGA renal cell carcinoma (kidney) dataset, where VEGFA (e), PGF (f), KDR (g), and NRP1 (h) are heavily up-regulated in tumors. iVEGFA down-regulation in primary prostate cancer is observed across TCGA and microarray datasets, as is consistent down-regulation of class three semaphorins. The number in the boxes indicates the two-tailed t-test p-value after multiple testing correction with the Benjamini-Hochberg procedure. Only comparisons with corrected p-values less than 0.05 are displayed. The colors of the boxes indicate the magnitude of the t-statistic. The blue boxes to the right of the rows indicate that a gene is significantly down-regulated in two or more datasets with no significant differences in other datasets
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4559909&req=5

Fig1: Down-regulation of pro- and anti-angiogenic ligands in primary prostate tumors. a-d: VEGFA (a), PGF (b), and the receptor gene KDR (c) are expressed at lower levels in prostate tumors than in normal prostate tissue in the TCGA dataset, as shown by the density plots (top), box plots (middle), and spike plots (bottom). The co-receptor gene NRP1 (d) is expressed at slightly higher levels in tumors but has a similar overall distribution to normal tissues. e-h: This contrasts with the TCGA renal cell carcinoma (kidney) dataset, where VEGFA (e), PGF (f), KDR (g), and NRP1 (h) are heavily up-regulated in tumors. iVEGFA down-regulation in primary prostate cancer is observed across TCGA and microarray datasets, as is consistent down-regulation of class three semaphorins. The number in the boxes indicates the two-tailed t-test p-value after multiple testing correction with the Benjamini-Hochberg procedure. Only comparisons with corrected p-values less than 0.05 are displayed. The colors of the boxes indicate the magnitude of the t-statistic. The blue boxes to the right of the rows indicate that a gene is significantly down-regulated in two or more datasets with no significant differences in other datasets
Mentions: We used three types of plots to show differences in gene expression between tissue types (e.g. Fig. 1a-d and Additional file 1: Figures S2-S5): density plots show differences in the shapes of the distributions, with the densities estimated using the R function density with default kernel bandwidth; box plots show the range of variation with statistics such as the median and quartiles; and spike plots showed the individual points to emphasize the range.Fig. 1

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