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

Monaghan, Eimear McAlister (2015) Biological ageing and colorectal cancer: fetuin A, sirtuins and telomeres at the interface between inflammation, metabolism and cancer. MD thesis, University of Glasgow.

Abstract

Colorectal cancer is a common, age-associated disease with significant comorbidity
and mortality. Biomarkers of ageing may have prognostic or predictive
value in colorectal cancer. Fetuin A, members of the sirtuin family of proteins
and 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 in
peripheral blood leukocytes (PBL), and for a subset of patients, in normal
colorectal and colorectal tumour tissue. Serum fetuin A was measured for these
patients and data on clinico-pathological factors of accepted significance in
colorectal cancer was collected prospectively. Telomere length in the matched
samples of leukocytes, normal colorectal and colorectal tumour tissue was
compared. Associations between telomere length in the different tissues, serum
fetuin A and clinico-pathological factors of accepted significance in colorectal
cancer were evaluated. A systematic review of the literature was performed to
examine the evidence for correlation between telomere length in different
tissues in humans.
Tissue from colorectal tumours from the second cohort patients was mounted
in a tissue microarray (TMA) and stained for sirtuin proteins (SIRT2-SIRT7). This
TMA also contained tissue from a subset of matched samples of adjacent normal
colorectal mucosa. Staining of normal colorectal and colorectal tumour tissue
was evaluated by the weighted Histoscore method and compared. The effect of
staining in tumour tissue on cancer-specific survival was examined. Associations
between Histoscores and clinico-pathological factors of accepted significance in
colorectal cancer were assessed.
RESULTS: Systematic review of the literature did not show robust evidence of
correlation between telomere length in different tissues in humans. Telomere
length in peripheral blood leukocytes did not show correlation with telomere
length in normal colorectal mucosa, or in colorectal tumour tissue. PBL telomere length was potentially related to the presence of distant
metastases. Fetuin A was inversely associated with markers of systemic
inflammation and with T stage.
Novel nuclear localisation was described for SIRT4 and SIRT5. Protein expression
of the sirtuins was reduced in tumour tissue in comparison to normal colorectal
mucosa, 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 increased
systemic inflammation and pathological markers of poor prognosis in tumour
tissue.
Intercorrelations between sirtuin expression levels in normal tissue are not seen
in tumour tissue, possibly indicating a breakdown of signalling and control.

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Supervisor's Name: Shiels, Prof. Paul
• Date of Award: 2015
• Depositing User: Ms Eimear Monaghan
• Unique ID: glathesis:2015-6559
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 29 Jul 2015 08:36
• Last Modified: 10 Jul 2018 08:48
• URI: https://theses.gla.ac.uk/id/eprint/6559