New aspects of the Warburg effect in cancer cell biology

Abstract

Altered cellular metabolism is a defining feature of cancer [1]. The best studied metabolic phenotype of cancer is aerobic glycloysis – also known as the Warburg effect – characterized by increased metabolism of glucose to lactate in the presence of sufficient oxygen. Interest in the Warburg effect has escalated in recent years due to the proven utility of FDG-PET for imaging tumors in cancer patients and growing evidence that mutations in oncogenes and tumor suppressor genes directly impact metabolism. The goals of this review are to provide an organized snapshot of the current understanding of regulatory mechanisms important for Warburg effect and its role in tumor biology. Since several reviews have covered aspects of this topic in recent years, we focus on newest contributions to the field and reference other reviews where appropriate.

Introduction

In the 1920s, Otto Warburg made his seminal observation that tumor cells metabolize more glucose to lactate than normal cells. By directly measuring lactate production and oxygen consumption rates in thin slices of rat liver carcinoma and normal liver tissue, Warburg and colleagues found that normal liver tissue exhibited the Pasteur effect (inhibition of lactate production in the presence of oxygen), whereas tumor tissue maintained lactate production regardless of oxygen tension [2], [3]. Sustained lactic acid production in the presence of oxygen was also observed in several human carcinomas. Warburg determined that cancer tissue consumes ten-fold more glucose than can be accounted for by respiration, and the amount of lactic acid produced is two orders of magnitude greater than the amount produced by normal tissue [2]. For a detailed description of Dr. Warburg's life and research, we direct the reader to an eloquent recent review by Dang and colleagues [4].

FDG-PET (2-deoxy-2-[¹⁸F]fluoro-d-glucose positron emission tomography) is a molecular imaging technique that exploits cancer cells’ preferential utilization of aerobic glycolysis. Similar to glucose, FDG enters cancer cells via glucose transporters GLUT1 and GLUT3 and is subsequently phosphorylated by hexokinase to FDG-6-phosphate. While glucose-6-phosphate undergoes further isomerization to fructose-6-phospate in the glycolytic pathway or oxidation to 6-phosphogluconolactone in the pentose phosphate pathway, FDG-6-phosphate cannot be further catabolized due to lack of an oxygen atom at the C-2 position. FDG-6-phosphate is unable to diffuse out of cells, and the rate of dephosphorylation occurs slowly; therefore, it becomes trapped and accumulates at a rate proportional to glucose utilization. Thus, FDG uptake depends on both glucose transporter expression and hexokinase activity and provides a way to assess glucose uptake rates in cells [5]. Tumors that take up more glucose than surrounding tissues can be non-invasively visualized in cancer patients by FDG-PET.

FDG-PET has been used in cancer patients since the 1980s and is now a widely used clinical imaging tool in oncology. It is approved for disease diagnosis, staging, restaging, and therapy monitoring in many but not all cancers [5]. Table 1 shows a current list of select cancers for which FDG-PET has established applications [6]. Despite its widespread use in clinical oncology, some cancers remain difficult to image by FDG-PET, such as hepatocellular carcinoma, prostate cancer, and pancreatic cancer. It is possible that these tumor types do not exhibit the Warburg effect metabolic phenotype and instead rely on alternative carbon sources than glucose to fuel proliferation. Alternatively, these tumor types may be difficult to image by FDG-PET for imaging-related reasons such as poor perfusion of the tumor by the probe, low density of tumor cells in the tumor tissue (high stromal cell to tumor cell ratio) or high background signal (such as bladder signal in the case of prostate cancer). Some cancers, such as well-differentiated hepatocellular carcinoma, exhibit high expression levels of glucose-6-phosphatase, which by dephosphorylating FDG-6-phosphate, allows efflux of FDG from cancer cells [7]. Further work is needed to address these issues in FDG-PET negative cancers. However, the large number of tumor types for which FDG-PET has proven utility has helped spur interest in the Warburg effect and its regulation and role in tumor biology.