Abstract
BackgroundTransketolase-like 1 (TKTL1) induces glucose degradation through anaerobic pathways, even in presence of oxygen, favoring the malignant aerobic glycolytic phenotype characteristic of tumor cells. As TKTL1 appears to be a valid biomarker for cancer prognosis, the aim of the current study was to correlate its expression with tumor stage, probability of tumor recurrence and survival, in a series of colorectal cancer patients.Methodolody/Principal FindingsTumor tissues from 63 patients diagnosed with colorectal cancer at different stages of progression were analyzed for TKTL1 by immunohistochemistry. Staining was quantified by computational image analysis, and correlations between enzyme expression, local growth, lymph-node involvement and metastasis were assessed. The highest values for TKTL1 expression were detected in the group of stage III tumors, which showed significant differences from the other groups (Kruskal-Wallis test, P = 0.000008). Deeper analyses of T, N and M classifications revealed a weak correlation between local tumor growth and enzyme expression (Mann-Whitney test, P = 0.029), a significant association of the enzyme expression with lymph-node involvement (Mann-Whitney test, P = 0.0014) and a significant decrease in TKTL1 expression associated with metastasis (Mann-Whitney test, P = 0.0004).Conclusions/SignificanceTo our knowledge, few studies have explored the association between variations in TKTL1 expression in the primary tumor and metastasis formation. Here we report downregulation of enzyme expression when metastasis appears, and a correlation between enzyme expression and regional lymph-node involvement in colon cancer. This finding may improve our understanding of metastasis and lead to new and more efficient therapies against cancer.
Highlights
Tumor development is caused by a sequential accumulation of genetic and epigenetic changes that lead cells through a multistep process that renders healthy cells malignant [1,2,3,4]
The high glycolytic rate is not justified by energetic requirements, since more than 80% of ATP synthesis in tumor cells occurs through oxidative phosphorylation, and only about 17% occurs through the Embden-Meyerhof pathway (EMP)
NADPH formation is important for tumor-cell metabolism, since it protects them against oxidative stress and provides fuel for the increased rate of fatty acid synthesis characteristic of cancer cells
Summary
Tumor development is caused by a sequential accumulation of genetic and epigenetic changes that lead cells through a multistep process that renders healthy cells malignant [1,2,3,4]. Carcinogenesis onset is due to deregulation of cell-cell and cell-matrix growth inhibitory interactions and the accumulation of further genetic alterations that leads to activation of protooncogenes and inhibition of tumor-suppressor genes [7,8] After these early events, malignant transformation progresses, governed by a process of Darwinian selection during which phenotypes, rather than genotypes, are selected. One of the main phenotypic characteristics of cancer cells is the aerobic glycolysis associated with elevated, but inefficient, ATP production, as well as high production of NADPH and acids (H+) such as lactate [10] This phenomenon, known as the ‘‘Warburg effect’’, was described by Otto Warburg in 1924 [11].
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