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Dysregulation of the vascular endothelial growth factor and semaphorin
ligand-receptor families in prostate cancer metastasis
#MMPMID26341082
Bender RJ
; Mac Gabhann F
BMC Syst Biol
2015[Sep]; 9
(?): 55
PMID26341082
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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.
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