Outcome Prediction Using Markers of Aerobic Glycolysis (the Warburg effect) Varies Between Tumor Regions in Stage I Non-Small Cell Lung Cancer

Abstract

Lung cancer, even early stage disease, is an important cause of cancer related death in the US. The Warburg Effect, a phenomenon first described by Otto Warburg, occurs when tumor cells utilize glucose through glycolysis even in the presence of adequate oxygen (aerobic glycolysis). Previously described markers of the Warburg effect and altered tumor metabolism include hypoxia inducible factor 1 (HIF-1), pyruvate dehydrogenase kinase 1 (PDK-1), mammalian target of rapamycin (mTOR), carbonic anhydrase 9 (CA-9), hexokinase 2 (HK-2), and phosphorylated AMP-activated protein kinase (pAMPK). The presence of these antigens was assessed in peripheral and central regions of 58 resected stage I non-small cell lung carcinomas by tissue microarray (TMA) and immunohistochemistry (IHC). Using the median staining intensity as a cut off between high and low expression, peripheral and central antigen expression was correlated with overall and recurrence free survival in univariate and multivariate analysis. In our study population high levels of HIF-1? in peripheral tumor regions were associated with worse overall and recurrence free survival. Central tumor expression of HIF-1? did not significantly correlate with outcome. A similar trend in the peripheral tumor was seen with PDK-1. In contrast, high levels of mTOR in central tumor cells were associated with improved overall survival. These findings suggest features of the Warburg effect even in early stage (small) lung tumors. Furthermore, they highlight the importance of assessing metabolic markers in the context of oxygen tension and tumor microenvironment. The significance of high HIF-1? expression may be different in relatively oxygenated tumor periphery than it is in the cells of more hypoxic tumor center.