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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

Pro-angiogenic VEGF/Sema gene expression in prostate cancer metastasis. a-b: A greater number of VEGF/Sema genes have recurrent expression alterations when comparing metastases to normal samples (b) than to primary tumor samples (a). The p-values are displayed according to the same criteria as in Fig. 1, and red and blue boxes on the right hand sides of panels a and b indicate recurrent up- and down-regulation, respectively. c-d: PLS-DA scores plots show separation of metastases and primary tumors in GSE35988 (c) and of metastases and normal tissues in GSE38241 (d). Each dot represents a sample with colors as indicated. Arrows correspond to gene loadings in the PLS-DA models, with the names of the genes displayed in the vicinity of the arrowhead. Only the genes with the largest magnitude loadings vectors are displayed. Accuracy refers to the accuracy of the LOOCV predictions; AUC refers to the area under the curve of the LOOCV ROC curve. In both cases, values of one indicate perfect prediction
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Fig3: Pro-angiogenic VEGF/Sema gene expression in prostate cancer metastasis. a-b: A greater number of VEGF/Sema genes have recurrent expression alterations when comparing metastases to normal samples (b) than to primary tumor samples (a). The p-values are displayed according to the same criteria as in Fig. 1, and red and blue boxes on the right hand sides of panels a and b indicate recurrent up- and down-regulation, respectively. c-d: PLS-DA scores plots show separation of metastases and primary tumors in GSE35988 (c) and of metastases and normal tissues in GSE38241 (d). Each dot represents a sample with colors as indicated. Arrows correspond to gene loadings in the PLS-DA models, with the names of the genes displayed in the vicinity of the arrowhead. Only the genes with the largest magnitude loadings vectors are displayed. Accuracy refers to the accuracy of the LOOCV predictions; AUC refers to the area under the curve of the LOOCV ROC curve. In both cases, values of one indicate perfect prediction

Mentions: While primary tumors are often treated with surgery and radiation, targeted therapeutics such as VEGF inhibitors are used more often in metastatic disease. Therefore, we next considered VEGF/Sema gene expression in datasets with metastatic tumors (Additional file 1: Table S1, note that only GSE6919, GSE21034, GSE32269, and GSE35988 contain both primary and metastatic tumors, while only GSE6919, GSE21034, GSE38241, and GSE35988 contain both normal prostate tissue and metastatic tumors). In contrast to the reduced expression of VEGF ligands in primary tumors, metastatic tumors tended to have higher expression of the major pro-angiogenic ligand, VEGFA (Fig. 3a, b). This ligand was up-regulated in metastases relative to primary tumors and normal tumors in the GSE6919, GSE35988, and GSE38241 datasets, but was actually down-regulated in GSE21034 and GSE32269. Notably, metastatic samples in the three datasets with up-regulated VEGFA were all obtained from warm autopsy programs where samples were processed rapidly upon the death of the patient. Metastatic samples in GSE32269 were from bone marrow biopsies of live patients, and no details were given regarding how metastatic samples were obtained in the GSE21034 dataset. The class 3 semaphorins were down-regulated in metastases relative to normal prostate tissue (Fig. 3b), suggesting that the loss of semaphorin expression in primary prostate tumors was maintained upon metastasis. SEMA3C was further down-regulated relative to primary tumors as well. Other expression alterations recurrent across datasets included up-regulation of NRP1, PLXNA1, and PLXNA3 relative to both normal tissue and primary tumors. These three genes participate in class 3 semaphorin signaling, while only NRP1 participates in VEGF signaling. KDR and NRP2 were recurrently down-regulated in metastases relative to normal tissue but not relative to primary tumors.Fig. 3


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)

Pro-angiogenic VEGF/Sema gene expression in prostate cancer metastasis. a-b: A greater number of VEGF/Sema genes have recurrent expression alterations when comparing metastases to normal samples (b) than to primary tumor samples (a). The p-values are displayed according to the same criteria as in Fig. 1, and red and blue boxes on the right hand sides of panels a and b indicate recurrent up- and down-regulation, respectively. c-d: PLS-DA scores plots show separation of metastases and primary tumors in GSE35988 (c) and of metastases and normal tissues in GSE38241 (d). Each dot represents a sample with colors as indicated. Arrows correspond to gene loadings in the PLS-DA models, with the names of the genes displayed in the vicinity of the arrowhead. Only the genes with the largest magnitude loadings vectors are displayed. Accuracy refers to the accuracy of the LOOCV predictions; AUC refers to the area under the curve of the LOOCV ROC curve. In both cases, values of one indicate perfect prediction
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4559909&req=5

Fig3: Pro-angiogenic VEGF/Sema gene expression in prostate cancer metastasis. a-b: A greater number of VEGF/Sema genes have recurrent expression alterations when comparing metastases to normal samples (b) than to primary tumor samples (a). The p-values are displayed according to the same criteria as in Fig. 1, and red and blue boxes on the right hand sides of panels a and b indicate recurrent up- and down-regulation, respectively. c-d: PLS-DA scores plots show separation of metastases and primary tumors in GSE35988 (c) and of metastases and normal tissues in GSE38241 (d). Each dot represents a sample with colors as indicated. Arrows correspond to gene loadings in the PLS-DA models, with the names of the genes displayed in the vicinity of the arrowhead. Only the genes with the largest magnitude loadings vectors are displayed. Accuracy refers to the accuracy of the LOOCV predictions; AUC refers to the area under the curve of the LOOCV ROC curve. In both cases, values of one indicate perfect prediction
Mentions: While primary tumors are often treated with surgery and radiation, targeted therapeutics such as VEGF inhibitors are used more often in metastatic disease. Therefore, we next considered VEGF/Sema gene expression in datasets with metastatic tumors (Additional file 1: Table S1, note that only GSE6919, GSE21034, GSE32269, and GSE35988 contain both primary and metastatic tumors, while only GSE6919, GSE21034, GSE38241, and GSE35988 contain both normal prostate tissue and metastatic tumors). In contrast to the reduced expression of VEGF ligands in primary tumors, metastatic tumors tended to have higher expression of the major pro-angiogenic ligand, VEGFA (Fig. 3a, b). This ligand was up-regulated in metastases relative to primary tumors and normal tumors in the GSE6919, GSE35988, and GSE38241 datasets, but was actually down-regulated in GSE21034 and GSE32269. Notably, metastatic samples in the three datasets with up-regulated VEGFA were all obtained from warm autopsy programs where samples were processed rapidly upon the death of the patient. Metastatic samples in GSE32269 were from bone marrow biopsies of live patients, and no details were given regarding how metastatic samples were obtained in the GSE21034 dataset. The class 3 semaphorins were down-regulated in metastases relative to normal prostate tissue (Fig. 3b), suggesting that the loss of semaphorin expression in primary prostate tumors was maintained upon metastasis. SEMA3C was further down-regulated relative to primary tumors as well. Other expression alterations recurrent across datasets included up-regulation of NRP1, PLXNA1, and PLXNA3 relative to both normal tissue and primary tumors. These three genes participate in class 3 semaphorin signaling, while only NRP1 participates in VEGF signaling. KDR and NRP2 were recurrently down-regulated in metastases relative to normal tissue but not relative to primary tumors.Fig. 3

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