Prostate cancer and inflammatory genes

Sammanfattning: Prostate cancer remains a significant health concern for men throughout the world. Accumulating epidemiologic and molecular evidence suggests that inflammation is an important component in the aetiology of prostate cancer. Supporting this hypothesis, population studies have found an increased risk of prostate cancer in men with a prior history of certain sexually transmitted infections or prostatitis. More general evidence of a relationship between inflammation and prostate cancer has been provided by reports indicating that daily use of non steroidal anti-inflammatory drugs (NSAIDs) may be associated with a lower incidence of prostate cancer. The exact mechanism whereby inflammation might act in tumour development and progression remains to be elucidated, but is likely to be complex. The genetic contribution to inflammatory responses involved in the development of prostate cancer has not yet been extensively or systematically studied.However, this thesis evaluates the role of various inflammation-related genes in the pathogenesis of prostate cancer. The macrophage scavenger receptor 1 (MSR1) is a transmembrane protein that is mainly expressed by macrophages. This receptor mediates the binding, internalization and processing of a wide range of macromolecules, and is suggested to play a major role in the recognition and clearance of pathogenic and damaged cells. Recent reports have suggested MSR1 to be a candidate gene for hereditary prostate cancer. Therefore, we screened the MSR1 gene among men with hereditary prostate cancer and identified 18 sequence variants. One previously reported truncation mutation was found more frequently in men with prostate cancer than in unaffected men, in accordance with previously published results. However, the difference in frequencies we found between these groups was not statistically significant. In addition, we genotyped five common polymorphisms in MSR1 in 215 men with unselected prostate cancer and 425 controls. No association between any of the five common variants and prostate cancer were found.We then performed a comprehensive genetic study using extensive populationbased case-control material to evaluate possible associations between sequence variants in inflammation-related genes and prostate cancer. The first gene to be examined was interleukin-1 receptor antagonist (IL-1-RN), encoding a cytokine that plays an important role in regulation of the inflammatory response by binding to the IL-1 receptor and thus inhibiting the binding of the pro-inflammatory cytokines IL-1? and IL-1?. Collectively, these three cytokines exert a central role in the protection against diverse lesions, ranging from microbial colonisation to infection and malignant transformation. The genetic analysis of IL-1RN revealed that the most common haplotype was significantly associated with prostate cancer risk for patients with prostate cancer, and further this association appears to be stronger in cases with advanced disease.The macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth-factor-? superfamily has been shown to exert diverse biological functions, including regulation of macrophage activity in the inflammatory response and both growth inhibition and induction of apoptosis in epithelial and other tumour cell lines. The genetic analysis of MIC-1 revealed that a seuqence variant (H6D) appears to be associated with a decreased prostate cancer risk. We also performed measurements of MIC-1 serum levels among patients with prostate cancer and healthy controls. These data indicate that serum MIC-1 levels are associated with an increased risk for prostate cancer. Further, the clear relation between clinical stage and MIC-1 level also suggest that MIC-1 may be useful as a prognostic factor, where high serum concentration is associated with a poor prognosis.In summary, our results provide further support for the assumption that polymorphisms in inflammatory genes play critical roles in prostate cancer susceptibility. Additional studies are needed to elucidate the mechanisms whereby the demonstrated variations contribute to prostate cancer development.