Journal
CANCER
Volume 119, Issue 3, Pages 575-585Publisher
WILEY-BLACKWELL
DOI: 10.1002/cncr.27611
Keywords
pyruvate kinase M2; cholangiocarcinoma; invasion; angiogenesis; diagnosis
Categories
Funding
- US National Institutes of Health [PO1CA84203]
- UK Medical Research Council [G0801588]
- Charitable Research Fund East and North Herts National Health Service Trust
- Jason Boas Charitable Fund
- UK Department of Health's National Institute for Health Research Biomedical Research Centres
- Medical Research Council [G0801588] Funding Source: researchfish
- MRC [G0801588] Funding Source: UKRI
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BACKGROUND: The early diagnosis of biliary tract cancer (BTC) remains challenging, and there are few effective therapies. This study investigated whether the M2 isotype of pyruvate kinase (M2-PK), which serves as the key regulator of cellular energy metabolism in proliferating cells, could play a role in the diagnosis and therapy of BTC. METHODS: Plasma and bile M2-PK concentrations were measured by enzyme-linked immunosorbent assay in 88 patients with BTC, 79 with benign biliary diseases, and 17 healthy controls. M2-PK expression was assayed in a BTC tissue array by immunohistochemistry. The role of M2-PK in tumor growth, invasion, and angiogenesis was evaluated in BTC cell lines by retrovirus-mediated M2-PK transfection and short hairpin RNA silencing techniques. RESULTS: Sensitivity (90.3%) and specificity (84.3%) of bile M2-PK for malignancy were significantly higher than those for plasma M2-PK and serum carbohydrate antigen 19-9. M2-PK expression was specific for cancer cells and correlated with microvessel density. M2-PK positivity was a significant independent prognostic factor by multivariable analysis. Transfection of M2-PK in a negatively expressed cell line (HuCCT-1 cells) increased cell invasion, whereas silencing in an M2-PKpositive cell line (TFK cells) decreased tumor nodule formation and cellular invasion. A significant increase in endothelial tube formation was noted when supernatants from M2-PKtransfected cells were added to an in vitro angiogenesis assay, whereas supernatants from silenced cells negated endothelial tube formation. CONCLUSIONS: Bile M2-PK is a novel tumor marker for BTC and correlates with tumor aggressiveness and poor outcome. Short hairpin RNAmediated inhibition of M2-PK indicates the potential of M2-PK as a therapeutic target. Cancer 2013. (C) 2012 American Cancer Society.
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