ASSOCIATION BETWEEN CHRONIC INFLAMMATION AND THE DEVELOPMENT OF PROSTATE CANCER

Abstract

Background: Chronic inflammation is gradually being identified as a risk factor of many malignancies, however, the role of this inflammation in causing prostate cancer (PCa) and the mechanism behind it are yet to be fully established. This paper sought to measure the relationship between chronic prostate inflammation and PCa progression, profile the microenvironment of inflammation, and simulate the dynamics of genomic instability driven by inflammation.Methods: A multi-stage design was used: a retrospective cohort of 1,247 men with prostate biopsies were followed over five years, a prospective case/control study with 320 PCa patients and 320 controls, and an in vitro study exposing RWPEêm1 and PNT2 cells to macrophageLTMedium over 14 days. Inflammation grading of histopathological inflammation, serum and tissue cytokines levels oxidative stress (8plessOHdG, ROS), and DNA doublenezstrand breaks (-H2AX) were measured. The firstorder kinetic modeling and logistic regression were used. Epigenetic modifications (GSTP1 methylation, MYC amplification and PTEN loss) were evaluated in proliferative inflammatory atrophy (PIA), prostate intraepithelial neoplasia (PIN) tissues and PCa tissues.Findings: A severe chronic inflammation (Grade 3 4 ) was linked to a 5 dieser PCa incidence of 41.2 to 53.6% and an adjusted hazard ratio of 9.87  in the highest CIBI quartile. PCa patients exhibited a dramatic increase in IL peque1b (5.15 plusieursfoit, p<0.001) and 8 nous OHdG \. The logistic regression model had an AUC of 0.92. Chronic inflammatory response in vitro raised the rate constant \The hypermethylation of GSTP1 rose steadily between 11.5 per cent in low grade PIA to 92.3 per cent in high grade PCa. The population attributable fraction of PCa in high CIBI was 54.2%.Conclusions: Chronic prostate inflammation facilitates the process of prostate carcinogenesis by causing oxidative DNA damage, impaired repair and progressive epigenetic changes. Chronic inflammation is an important and modifiable risk factor of aggressive PCa, with the inflammatory burden index being a strong predictor of cancer risk and upgrading. These results justify antiinflammatory methods of chemoprevention.