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Molecular origins of mpMRI visibility

ABSTRACT: Multiparametric magnetic resonance imaging (mpMRI) has transformed the landscape of prostate cancer (PCa) management. Prostate Imaging Reporting and Data System (PI-RADSv2) scores reflect function and correlate phenotypic features with tumor aggressiveness, is an independent predictor of biochemical recurrence, and may distinguish low-risk tumors requiring no treatment from high-risk tumors requiring aggressive management. We hypothesize that differences in functional mpMRI of prostate tumors reflect the genetic and epigenetic heterogeneity of PCa. We profiled the genomes and transcriptomes of 40 Gleason score 3+4 tumors, of which 20 tumors were mpMRI invisible (not PI-RADSv2 3-5) and 20 tumors were visible (PI-RADSv2 5). Genomes of visible tumors were more unstable than those of invisible tumors. We identified 62 enriched transcripts, including numerous snoRNAs, Relaxin 1 and SCHLAP1, in visible tumors. These data suggest a confluence of aggressive pathological and microenvironmental phenomenon in PI-RADSv2 5 tumors reminiscent of nimbosus, while linking the molecular profiles of tumor aggressiveness with their functional features on mpMRI.

PROVIDER: EGAS00001003179 | EGA |

REPOSITORIES: EGA

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Project description:Background: Aldo-keto reductase (AKR) 1C family member 3 (AKR1C3), one of four identified human AKR enzymes, catalyzes steroid, prostaglandin, and xenobiotic metabolism. In the prostate, AKR1C3 is up-regulated in localized and advanced prostate adenocarcinoma, and is associated with prostate cancer (PCa) aggressiveness. Here we provide initial evidence for potential roles of AKR1C3 in PCa progression. Methods: Spatial distribution of AKR1C3 was analyzed using immunohistochemical staining in prostate adenocarcinoma tissue array. Human PCa PC-3 cells were stably transfected with AKR1C3 cDNA to establish PC3-AKR1C3 transfectants. Microarray and bioinformatics analyses were performed to identify pathways that are activated by elevated AKR1C3 expression in PCa cells. Functional confirmation of microarray and bioinformatics results was performed by immunoblot analysis and an in vitro Matrigel angiogenesis assay. Results: Elevated AKR1C3 expression was specifically limited to human prostate adenocarcinoma. Microarray and bioinformatics analysis suggested that elevated AKR1C3 expression in PC-3 cells modulates estradiol and androgen metabolism and activates insulin growth factor (IGF)-1 and Akt signaling pathways. Immunoblots confirmed that phosphorylated levels of IGF-1 receptor (IGF-1R) and Akt are significantly up-regulated in PC3-AKR1C3 as compared to mock transfectants. PC3-AKR1C3 transfectants promoted endothelial cell tube formation in Matrigel as compared to parental PC-3 cells and mock transfectants. Conclusion: Microarray and bioinformatics data followed by biological analyses suggest that elevated AKR1C3 expression in PC-3 cells promotes PCa angiogenesis and aggressiveness. These results suggest AKR1C3 can promote the aggressiveness of PCa through modulating estrogen and androgen metabolism with subsequent activation of growth factor IGF-1 and cytoplasmic Akt signaling pathways. Total RNA from mock- and ACR1C3 transfected PC-3 cells was isolated, with 2 or 3 biological replicates each. Gene expression data from AKR1C3 transfected PC-3 cells were compared with mock-transfected data.

Project description:Prostate cancer (PCa) is the second most prevalent malignancy in Western countries and the fifth leading cause of cancer-related death in men. The risk factors for PCa include obesity, age, and family history. Visceral fat has been linked to PCa risk, which has prompted researchers to investigate the influence of body composition and fat distribution on PCa prognosis. This study investigated the correlation between the composition of pelvic adipose tissue (PAT) and PCa aggressiveness to understand the role played by this tissue in PCa progression. Moreover, we prepared a periprostatic adipose tissue (PPAT)-conditioned medium (CM) to determine the influence of the PPAT secretome on the pathophysiology of PCa. This study included 60 patients with localized PCa who received robot-assisted radical prostatectomy. Medical records were collected, and magnetic resonance imaging scans were analyzed, and body compositions were calculated to identify the correlations between adipose tissue volume and clinical PCa aggressiveness. CM was prepared using PPAT and perivesical adipose tissue (PVAT) collected from 25 patients during surgery, and its influence was investigated using the PCa cell lines C4-2 and LNCaP and the prostate epithelial cell line PZ-HPV-7. Cell proliferation assays and RNA sequencing were performed. The initial prostate-specific antigen level was significantly correlated with pelvic and perirectal adipose tissue volumes. PPAT volume was significantly higher in patients with extracapsular tumor extension. PCa cells proliferated was significantly slower when cultured in PPAT-CM compared with when cultured in control- and PVAT-CM. RNA sequencing revealed that immune responses and the cell death and apoptosis pathways were enriched in PPAT-CM-cultured cells. The cytokines or other secreted factors in PPAT-CM induced PCa cell apoptosis. This in vitro study revealed that the PPAT secretome inhibits PCa cells proliferation by activating immune responses and promoting cancer cell apoptosis. This mechanism may act as a first-line defense during the early stages of PCa.

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Molecular origins of mpMRI visibility

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