Lactate dehydrogenase-5 is an independent prognostic factor in colorectal cancer: implications for future therapies
S Yeluri1, P Prasad3, B Madhok1, H Thorpe4, SL Perry2, TA Hughes2, KR Prasad1, P Quirke2, DG Jayne1
1Leeds Institute of Molecular Medicine, University of Leeds & St. James's University Hospital, Leeds, UK, 2Leeds Institute of Molecular Medicine, University of Leeds, UK, 3St.James's University Hospital, Leeds, UK, 4Clinical Trials Research Unit, University of Leeds, UK
Proffered paper presentation
Background
Recent evidence suggests that cancers undergoing a high level of aerobic glycolysis
(Warburgs effect) behave in a more aggressive fashion, with implications for
selectively targeting cancer bioenergetics. Lactate dehydrogenase 5 (LDH-5)
plays an important role in the control of aerobic glycolysis by regulating the
transformation of pyruvate to lactate. This study aimed to investigate the
prognostic relevance of LDH-5 in a large clinical series of colorectal cancers,
to identify the impact of Warburgs effect on tumour biology and its potential
implications for anti-cancer chemotherapy.
Method
Immunohistochemistry
(IHC) for LDH-5 was performed on tissue micro arrays incorporating 280
colorectal cancers from the MRC- CLASICC trial. Immunoreactivity was scored
semi-quantitatively by two independent assessors. Correlations between LDH-5
expression and clinicopathological variables including prospectively collected
5-year survival data were examined.
Results
LDH-5
expression was both cytoplasmic and nuclear. 167 (61%) cases showed high LDH-5
expression. Kappa score on agreement between the two scorers was 0.58. High
LDH-5 expression significantly correlated with biological aggressiveness- lymph
node involvement (p= 0.012), extramural vascular invasion (p= 0.014), and
worsening TNM and Dukes staging (p= 0.008). LDH-5 expression was not
significantly different between left and right sided colonic tumours or between
colonic and rectal tumours. Patients with high LDH-5 had worse 5-year
disease-free survival (47% vs. 66%, p=0.002) as compared to patients with low
LDH-5. On multivariate analysis, high LDH-5 expression was an independent
predictor of poor disease-free survival (p=0.034, HR 1.6: 95% CI: 1.04, 2.5).
Conclusion
Colorectal
cancers demonstrating high LDH-5 expression had worse disease-free survival
supporting a link between aerobic glycolysis and aggressive cancer biology.
This was seen for both colonic and rectal tumours. LDH-5 may enable the
selection of patients for treatment with drugs targeting cancer bio-energetics
such as dichloroacetate, glufosfamide, etc.
