Dysregulation of the vascular endothelial growth factor and semaphorin ligand-receptor families in prostate cancer metastasis.
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.
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA. bender.rj@gmail.com.|Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, 21218, USA. bender.rj@gmail.com.
R Joseph
RJ
Bender
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA. feilim@jhu.edu.|Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, 21218, USA. feilim@jhu.edu.
Feilim
F
Mac Gabhann
D014408:Biomarkers, Tumor / Q000378:metabolism; D016000:Cluster Analysis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016018:Least-Squares Analysis; D008024:Ligands; D042583:Lymphangiogenesis; D008297:Male; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D039961:Semaphorins / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D014408:Biomarkers, Tumor; D008024:Ligands; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; D011956:Receptors, Cell Surface; D039961:Semaphorins; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor