Currently, many patients with early-stage localized prostate cancer (PrCa) (D’Amico: low
risk or low-intermediate risk) do not receive immediate therapy but are monitored within
systematic AS programs. Prospective trials showed rates of stage reclassification and
progression to the treatment of 20–40% over 2–5 years. However, in certain patients, PrCa
progresses rapidly to an advanced stage that requires combined modality therapies, which
carry increased risk for toxicity and poor outcomes. There is a need to identify biomarkers
that can predict the risk for disease progression in this population. Research showed that
dysregulation of metabolism is an important hallmark of cancer progression. Here, we
pursued a pilot investigation of enzymes of de novo lipogenesis [ATP-citrate lyase
(ACLY), Acetyl-CoA Carboxylase (ACC)], lipid oxidation [a-Methylacyl-CoA Racemase
(AMACR)], glucose uptake [facilitative glucose transporter 1 (GLUT1)], and folate –
glutamate metabolism (PSMA: prostate-specific membrane antigen) as potential
biomarkers of PrCa progression in AS patients. With ethics approval from the Hamilton
Integrated Research Ethics Board (HiREB), 40 AS patients were accrued prospectively
from the Niagara Health System PrCa diagnostic program clinics and were asked to donate
their biopsy tissue. 28 patients progressed on repeat biopsies at 12 or 24 months after initial
diagnosis and were included in the “Progressed” group, and 12 did not who were included
in the “Non-Progressed” group. Baseline diagnostic prostate core biopsy tissues of both
groups were evaluated with H&E and immunohistochemistry (IHC) staining for ACLY,
ACC, GLUT1, AMACR and PSMA expression (quantified by H-score). H-scores were
evaluated in benign and malignant components (epithelial cells) and were compared
between the two groups of patients. We observed statistically significant increased GLUT1
expression in malignant epithelial cells of the progressed group compared to the non-progressed group. Also, we found statistically significant increased PSMA expression in
the benign epithelial cells of the progressed group compared to the non-progressed group.
Further, our results demonstrated a statistically significant increase in ACLY and ACC
expression in malignant epithelial cells compared to benign epithelial cells in the
progressed group, while AMACR was detected solely in the malignant component.
Overall, the results of this pilot study are consistent with the notion of induction of
glycolytic metabolism, de novo lipogenesis and increased PSMA expression associated
with the risk for PrCa progression. The levels of expression of PSMA within benign
epithelial cells and GLUT1 within malignant epithelial cells may have value as predictive
markers of risk for PrCa progression in AS patients. Future studies should investigate this
concept systematically in larger AS cohorts. / Thesis / Master of Science (MSc) / Currently, many patients with localized prostate cancer do not receive immediate therapy
and are monitored within systematic active surveillance (AS) programs. The main aim of
AS management is to prevent overtreatment and treatment-related complications in
patients who would otherwise have a good quality of life despite dealing with prostate
cancer. However, many of these patients, especially those with low intermediate-risk
prostate cancer have a significant risk for disease progression and metastasis.
Additionally, there is a lack of promising tissue biomarkers to predict the risk for
progression in AS patients at the time of initial diagnosis. Research showed that
metabolism dysregulation is an essential hallmark of cancer progression, including
prostate cancer. In this pilot study, we examined whether the expression of enzymes
involved in lipid, glucose and protein metabolism could have value as biomarkers of risk
for prostate cancer progression in patients managed with AS. The expression of five
metabolic enzymes (ACLY, ACC, GLUT1, AMACR and PSMA) was examined in tumor
and benign regions of diagnostic biopsies of the prostate obtained from men managed
with AS. Our early results suggest that the expression of enzymes of protein (PSMA) and
glucose (GLUT1) metabolism may have value as biomarkers of risk for prostate cancer
progression and should be investigated further in systematic studies.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27997 |
| Date | January 2022 |
| Creators | Ahmadi, Elham |
| Contributors | Tsakiridis, Theos, Health Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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