Prostate cancer is the most common malignancy in men in the USA and the second leading cause of cancer deaths. Fibroblast growth factors (FGFs), including FGF1 (acidic FGF), FGF2 (basic FGF), FGF6 and FGF8 are all expressed at increased levels in prostate cancer as paracrine and/or autocrine growth factors for the prostate cancer cells. In addition, increased mobilization of FGFs from the extracellular matrix in cancer tissues can increase the availability of FGFs to cancer cells. Prostate cancer epithelial cells express all four types of FGF receptors (FGFR-1 to -4) at variable frequencies. Expression of FGFR-1 and FGFR-4 is most closely linked to prostate cancer progression, while the role of FGFR-2 remains controversial. Activation of FGF receptors can activate multiple signal transduction pathways including the phospholipase Cγ, phosphatidyl inositol 3-kinase, mitogen-activated protein kinase and signal transducers and activators of transcription (STAT) pathways, all of which play a role in prostate cancer progression. Sprouty proteins can negatively regulate FGF signal transduction, potentially limiting the impact of FGF signaling in prostate cancer, but in a significant fraction of prostate cancers there is decreased expression of Sprouty1 mRNA and protein. The effects of increased FGF receptor signaling are wide ranging and involve both the cancer cells and surrounding stroma, including the vasculature. The net result of increased FGF signaling includes enhanced proliferation, resistance to cell death, increased motility and invasiveness, increased angiogenesis, enhanced metastasis, resistance to chemotherapy and radiation and androgen independence, all of which can enhance tumor progression and clinical aggressiveness. For this reason, the FGF signaling system it is an attractive therapeutic target, particularly since therapies targeting FGF receptors and/or FGF signaling can affect both the tumor cells directly and tumor angiogenesis. A number of approaches that could target FGF receptors and/or FGF receptor signaling in prostate cancer are currently being developed.

The PTEN gene encodes a lipid phosphatase that negatively regulates the phosphatidylinositol 3-kinase pathway and is inactivated in a wide variety of malignant neoplasms. High rates of loss of heterozygosity are observed at the 10q23.3 region containing the human PTEN gene in prostate cancer and other human malignancies, but the demonstrated rate of biallelic inactivation of the PTEN gene by mutation or homozygous deletion is significantly lower than the rate of loss of heterozygosity. The transgenic adenocarcinoma of mouse prostate model is a well characterized animal model of prostate cancer. Analysis of prostate cancer progression in transgenic adenocarcinoma of mouse prostate mice bred to Pten ^+/− heterozygous mice, coupled with analysis of the Pten gene and protein in the resulting tumors, reveals that haploinsufficiency of the Pten gene promotes the progression of prostate cancer in this model system. This observation provides a potential explanation for the discordance in rates of loss of heterozygosity at 10q23 and biallelic PTEN inactivation observed in prostate cancer and many human malignancies.

Purpose: Prostate cancer is a leading cause of cancer death among the aging male population but the mechanism underlying this association is unclear. Aberrant methylation of promoter CpG islands is associated with silencing of genes and age-dependent methylation of several genes has been proposed as a risk factor for sporadic cancer. We examined the extent of gene methylation in pathologically normal human prostate as a function of age. Experimental Design: We used pyrosequencing to quantitatively analyze the methylation status of nine CpG islands in normal prostate tissue DNA from 45 organ donors and 45 patients who had undergone cystoprostatectomy for bladder cancer. We also analyzed 12 pairs of matched benign and prostate cancer tissue DNA from patients with prostate cancer. Results: Linear regression analysis revealed a significant increase in promoter methylation levels correlating with age for CpG islands at RARβ2 (r = 0.4; P < 0.0001), RASSF1A (r = 0.27; P = 0.01), GSTP1 (r = 0.59; P < 0.0001), NKX2-5 (r = 0.27; P = 0.008), and ESR1 (r = 0.244; P = 0.023) in the normal prostate tissue samples studied. A calculated average methylation (z score) at all nine CpG loci analyzed in the normal prostate tissues showed a strong correlation with age (r = 0.6; P < 0.001). Comparison of the methylation level for the matched benign and prostate cancer tissues from individual patients with prostate cancer showed significantly higher methylation in the prostate cancer tissue samples for RARβ2 (P < 0.001), RASSF1A (P = 0.005), GSTP1 (P < 0.001), NKX2-5 (P = 0.003), ESR1 (P = 0.016), and CLSTN1 (P = 0.01). Conclusions: Our findings show aberrant hypermethylation as a function of age in the normal prostate tissues. Such age-related methylation may precede and predispose to full-blown malignancy.

Epigenetic mechanisms may be important in the progression of chronic kidney disease (CKD). We studied the genome-wide DNA methylation pattern associated with rapid loss of kidney function using the Infinium HumanMethylation 450 K BeadChip in 40 Chronic Renal Insufficiency (CRIC) study participants (n = 3939) with the highest and lowest rates of decline in estimated glomerular filtration rate. The mean eGFR slope was 2.2 (1.4) and −5.1 (1.2) mL/min/1.73 m² in the stable kidney function group and the rapid progression group, respectively. CpG islands in NPHP4, IQSEC1 and TCF3 were hypermethylated to a larger extent in subjects with stable kidney function (P-values of 7.8E−05 to 9.5E−05). These genes are involved in pathways known to promote the epithelial to mesenchymal transition and renal fibrosis. Other CKD-related genes that were differentially methylated are NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 and TGFBI, which are involved in oxidative stress and inflammatory pathways (P-values of 4.5E−03 to 0.046). Pathway analysis using Ingenuity Pathway Analysis showed that gene networks related to cell signaling, carbohydrate metabolism and human behavior are epigenetically regulated in CKD. Epigenetic modifications may be important in determining the rate of loss of kidney function in patients with established CKD.