Biological ageing and colorectal cancer: fetuin A, sirtuins and telomeres at the interface between inflammation, metabolism and cancer

[摘要] Colorectal cancer is a common, age-associated disease with significant comorbidityand mortality. Biomarkers of ageing may have prognostic or predictivevalue in colorectal cancer. Fetuin A, members of the sirtuin family of proteinsand telomeres have shown promise as potential biomarkers of ageing.AIM: To evaluate these potential biomarkers in the context of colorectal cancer.METHODS: Two cohorts of patients were used. Telomere length was measured inperipheral blood leukocytes (PBL), and for a subset of patients, in normalcolorectal and colorectal tumour tissue. Serum fetuin A was measured for thesepatients and data on clinico-pathological factors of accepted significance incolorectal cancer was collected prospectively. Telomere length in the matchedsamples of leukocytes, normal colorectal and colorectal tumour tissue wascompared. Associations between telomere length in the different tissues, serumfetuin A and clinico-pathological factors of accepted significance in colorectalcancer were evaluated. A systematic review of the literature was performed toexamine the evidence for correlation between telomere length in differenttissues in humans.Tissue from colorectal tumours from the second cohort patients was mountedin a tissue microarray (TMA) and stained for sirtuin proteins (SIRT2-SIRT7). ThisTMA also contained tissue from a subset of matched samples of adjacent normalcolorectal mucosa. Staining of normal colorectal and colorectal tumour tissuewas evaluated by the weighted Histoscore method and compared. The effect ofstaining in tumour tissue on cancer-specific survival was examined. Associationsbetween Histoscores and clinico-pathological factors of accepted significance incolorectal cancer were assessed.RESULTS: Systematic review of the literature did not show robust evidence ofcorrelation between telomere length in different tissues in humans. Telomerelength in peripheral blood leukocytes did not show correlation with telomerelength in normal colorectal mucosa, or in colorectal tumour tissue. PBL telomere length was potentially related to the presence of distantmetastases. Fetuin A was inversely associated with markers of systemicinflammation and with T stage.Novel nuclear localisation was described for SIRT4 and SIRT5. Protein expressionof the sirtuins was reduced in tumour tissue in comparison to normal colorectalmucosa, apart from SIRT3 cytoplasmic and nuclear and SIRT6 nuclear stainng.Lowest and highest quartile SIRT2 expression was associated with worse survival.Sirtuin protein expression levels and localisation correlate with increasedsystemic inflammation and pathological markers of poor prognosis in tumourtissue.Intercorrelations between sirtuin expression levels in normal tissue are not seenin tumour tissue, possibly indicating a breakdown of signalling and control.

[发布机构] University:University of Glasgow;Department:Institute of Cancer Sciences

[关键词] RC0254 Neoplasms. Tumors. Oncology (including Cancer)