Identification of SFRP1 as a Candidate Mediator of Stromal-to-Epithelial Signaling in Prostate Cancer

Abstract

Genetic changes in epithelial cells initiate the development of prostatic adenocarcinomas. As nascent tumors grow and undergo progression, epithelial tumor cells are intimately associated with stromal cells. Stromal cells within the tumor microenvironment acquire new properties, including the capacity to promote phenotypic and genetic progression in adjacent epithelial cells. Affymetrix microarrays were used to identify 119 genes differentially expressed between normalderived and carcinoma-derived prostatic stromal cells. These included 31 genes encoding extracellular proteins that may act as stromal-to-epithelial paracrine signals. Further investigation of one of these genes, secreted frizzled related protein 1 (SFRP1), revealed that its expression parallels prostatic growth with high expression during prostatic development, low expression in the adult prostate, and elevated expression in prostatic tumor stroma. In addition, as prostatic epithelial cells progressed to a tumorigenic state under the influence of tumor stroma, SFRP1 became overexpressed in the progressed epithelial cells. To further understand the roles of SFRP1 in the prostate, we tested the affects of increased SFRP1 levels on prostatic tissues and cells. Treatment of developing prostates with SFRP1 in culture led to increased organ growth. Treatment of a human prostatic epithelial cell line with SFRP1 led to increased proliferation, decreased apoptosis, and decreased signaling through the Wnt/B-catenin pathway in vitro and increased proliferation in vivo. These data suggest that overexpression of SFRP1 by prostatic tumor stroma may account for the previously reported capacity of prostatic tumor stroma to provide a pro-proliferative paracrine signal to adjacent epithelial cells. (Cancer Res 2005; 65(22): 10423-30)

Human Epithelial Basal Cells Are Cells of Origin of Prostate Cancer, Independent of CD133 Status

“…Single cells obtained through out protocol were then cultured in RPMI 1640 with 5% FCS and 1 nM testosterone that allows continual growth of only the stromal populations. Each line was confirmed to display properties of CAFs in vitro including growth characteristics, immunomarkers, and RNA expression similar to previous reports [13,14]. In Supporting Information Figure S1, we show that SFRP-1 gene expression was significantly elevated in CAFs used in this study, compared to patientmatched normal prostatic fibroblasts (NPF)s; stromal lines were used between passages 3-6.…”

“…While other investigators have studied the direct oncogenic activation of epithelial cells, we chose to apply two different stromal-based assays to indirectly test the effects on subpopulations of prostatic epithelia. First, CAFs derived from primary prostate cancer specimens show distinct genotypic and phenotypic differences compared to their nonmalignant matched controls and have been studied extensively in this BPH-1 cell assay [13,14,36,37]. The second model of hormonal carcinogenesis is based on administration of high doses of testosterone in combination with 17b-estradiol.…”

ADAR1 is required for differentiation and neural induction by regulating microRNA processing in a catalytically independent manner

“…However, we have noticed that the clone formation efficiency was lower in ADAR1-knockdown H9 cells than that in control cells (Supplementary information, Figure S1F). RNA-seq and RT-qPCR results further revealed that some key pro-apoptotic genes, such as S100A6 and BAX [31][32][33], were upregulated and the anti-apoptotic gene SFRP1 [34,35] was downregulated in ADAR1-knockdown H9 cells (Supplementary information, Figure S1G and Table S2), suggesting that ADAR1 deficiency can promote apoptosis of hESCs under certain stresses, such as enzymatic detachment. This is consistent with a previous report that cells cultured from ADAR1-deficient embryos exhibited increased apoptosis when a stress response was induced [24].…”

Origin of carcinoma associated fibroblasts

“…We consider the CAFs as part of these cancer microenvironment changes that occur in tissue lesions and serve as precursors for malignant disease. Several hypotheses have been presented for the origin of these altered cells, including standard connective tissue acute phase and stress response, 55,80,81 and fibroblast senescence, [82][83][84][85] reciprocal interactions with the cancer cells, 5,20,[86][87][88][89][90] fibroblast specific somatic mutations, [91][92][93][94][95] differentiation precursors and infiltrating mesenchymal stem cell. 96,97 …”