Table 5.

Summary of functional role, relation to angiogenesis and prostate cancer (PCa) etiology of the 11 candidate genes

Gene	Functional role	Relation to angiogenesis	Relation to prostate cancer etiology
FBLN5	FBLN5 is one of the extracellular matrix (ECM) glycoproteins and interacts with other ECM components, such as laminin, elastin, endostatin and fibronectin (43). These FBLN proteins are involved in the formation and stabilization of basement membranes, fibers, and connective tissues (44). Fibulins are also involved in fibrogenesis, vasculogenesis and tumorigenesis (45)	FBLN5 regulate angiogenesis, thus is an endogenous inhibitor of angiogenesis during development via the control of VEGF and angiopoietins (46)	The expression of Fibulin-5 is consistently down-regulated in prostate tumors and is impaired in various human cancer including PCa (13)
ROBO1	ROBO1, a roundabout (ROBO) immunoglobulin, is involved in cell motility and migration (47)	SLIT2-ROBO receptor signaling is involved in angiogenesis. ROBO1-dependent tumor angiogenesis is affected by SLIT2 released from tumor cells. Interaction with ROBO4 can stabilize the vasculature and inhibit VEGF-induced endothelial cell migration and permeability, and prevent pathologic angiogenesis in animal study (48)	ROBO1 acts like a natural inhibitor of metastasis (14). Thus, ROBO1 acts as a tumor suppressor gene and downregulation of ROBO1 was significantly associated with invasive PCa (14)
E2F1	E2F1 is a cell cycle-specific transcription factor and induces apoptosis as a protection from malignant transformation and suppression of tumorigenesis (49)	Expression of E2F1 regulates VEGF-C and VEGFR-3 in cancer cells through transcriptional control. In addition, VEGFR-3 also positively regulates E2F1 in a feedback circuit. This E2F1-VEGF-C/VEGFR-3 loop is a main mechanism for angiogenesis in tumor (49)	Overexpression of E2F1 is associated with progression of PCa, especially PCa metastasis (15–18)
STAT1	STAT family members are phosphorylated by the receptor associated kinases, and translocate to the cell nucleus where they act as transcription activators. STAT1 mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli	Activated STAT1 signaling has tumor suppressive roles by promoting apoptosis and by inhibiting angiogenesis, tumor growth and metastasis (50,51)	STAT1 expression affects the chemoresistant phenotype, especially to docetaxel treatment. Therefore, STAT1 plays a key role in resistance in PCa treatment (19)
HSPG2	The HSPG2 is a five-domain proteoglycan that interacts with extracellular matrix components and cell-surface molecules	HSPG2 is required for activating VEGFR signaling of endothelial cells for vascular invasion. Thus, HSPG2 plays a critical role in endochondral bone formation by promoting angiogenesis (52)	Expression of HSPG2 is associated with high Gleason scores (20), prostate tumor growth, and enhancing angiogenesis (21). Overexpression of HSPG2 is required for invasion of prostate tumors (22)
MMP16	MMP16 activates pro-MMP2 and can promote the migration and invasion of tumor cells by denaturing collagens and other ECM proteins in basement membrane (53)	MMPs, including MMP16 have been implicated in angiogenesis, and tumor cell invasion (53)	MMP16 has been shown to be down-regulated in malignant prostate tissues (23)
ITGB3	The ITGB3 is a key player in tumor growth and metastasis and a key regulator in reactive oxygen species-induced migration and invasion of cancer cells (54). Downregulated expression of ITGB3 reduced cell proliferation, migration, and invasion in cancer cells (55)	ITGB is required for angiogenesis (56). ITGB3 antagonists promoted tumor regression by inducing apoptosis of angiogenesis (57). Enhanced angiogenesis and tumor growth were also observed in animal lacking ITGB3 (58)	ITGB3 was identified as one of the genes related to tumor metastasis (24). ITGB3 is a part of a gene expression signature for detecting the presence of prostate tumors in stroma with 97% accuracy (59). ITGB3 expression was significantly lower in tumor-adjacent stroma compared to normal stroma (60)
ESR1	Estrogen receptor 1 (ESR1) is one of ligand-activated transcription factors with domains for binding to hormones and DNA and is present in the vascular endothelium	ESR1 enhanced ROCK-II signaling pathway promote angiogenesis in endothelial cells, and cell migration (61)	ESR1 is associated with PCa risk by stimulating proliferation of prostate cells and deregulating apoptosis (25)
EGFR	EGFR is involved in the proliferation of epithelial cells and tumorigenesis	Constitutive activation of EGFR upregulates p38 MAPK, resulting in activation of HIF-1α and further upregulations of MMP-1 and VEGF, leading to increase in angiogenesis in transformed cells (62)	The EGFR binds the EGF and plays an important role in regulating prostate cellular growth and function (26–28). Multiple studies identified EGFR in both analyses of gene and pathway levels associated with PCa risk (12,63)
CSF1	CSF1 controls the production, differentiation, and function of macrophages	CSF1 recruits tumor associate macrophages (TAMs), which stimulate angiogenesis in PCa. TAMs produce a variety of pro-angiogenic factors that include VEGF, basic fibroblast growth factor, tumor necrosis factor α (TNFα), and others	Overexpression of CSF1 was observed in various cancer patients, increased tumor angiogenesis, promoted metastatic potential in breast cancer (64) and was associated with poor outcome in ovarian cancer (65). A recent animal study demonstrated that CSF1 can be a potential target for PCa treatment (66)
SP1	SP1 is a transcription factor that affects the expression of genes involved in various cellular processes and oncogenesis	Overexpression of SP1 increased angiogenesis (29)	Over expression of SP1 was observed in prostate cancer, and decreased cancer cell death (29). Expression of SP1 is associated with PCa prognosis (67), and recurrence (68)