Douglas Hanahan, Robert A. Weinberg. Hallmarks of cancer: the next generation. Cell, Volume 144, Issue 5, p646–674, 4 March 2011
The chronic and often uncontrolled cell proliferation that represents the essence of neoplastic disease involves not only deregulated control of cell proliferation but also corresponding adjustments of energy metabolism in order to fuel cell growth and division. Under aerobic conditions, normal cells process glucose, first to pyruvate via glycolysis in the cytosol and thereafter to carbon dioxide in the mitochondria; under anaerobic conditions, glycolysis is favored and relatively little pyruvate is dispatched to the oxygen-consuming mitochondria. Otto Warburg first observed an anomalous characteristic of cancer cell energy metabolism: even in the presence of oxygen, cancer cells can reprogram their glucose metabolism, and thus their energy production, by limiting their energy metabolism largely to glycolysis, leading to a state that has been termed «aerobic glycolysis».
The existence of this metabolic switch in cancer cells has been substantiated in the ensuing decades. Such reprogramming of energy metabolism is seemingly counterintuitive, in that cancer cells must compensate for the ∼18-fold lower efficiency of ATP production afforded by glycolysis relative to mitochondrial oxidative phosphorylation. They do so in part by upregulating glucose transporters, notably GLUT1, which substantially increases glucose import into the cytoplasm. Indeed, markedly increased uptake and utilization of glucose have been documented in many human tumor types, most readily by noninvasively visualizing glucose uptake using positron emission tomography (PET) with a radiolabeled analog of glucose (18F-fluorodeoxyglucose, FDG) as a reporter.
Glycolytic fueling has been shown to be associated with activated oncogenes (e.g., RAS, MYC) and mutant tumor suppressors (e.g., TP53), whose alterations in tumor cells have been selected primarily for their benefits in conferring the hallmark capabilities of cell proliferation, avoidance of cytostatic controls, and attenuation of apoptosis. This reliance on glycolysis can be further accentuated under the hypoxic conditions that operate within many tumors: the hypoxia response system acts pleiotropically to upregulate glucose transporters and multiple enzymes of the glycolytic pathway. Thus, both the Ras oncoprotein and hypoxia can independently increase the levels of the HIF1α and HIF2α transcription factors, which in turn upregulate glycolysis.
A functional rationale for the glycolytic switch in cancer cells has been elusive, given the relatively poor efficiency of generating ATP by glycolysis relative to mitochondrial oxidative phosphorylation. According to one long-forgotten and recently revived and refined hypothesis, increased glycolysis allows the diversion of glycolytic intermediates into various biosynthetic pathways, including those generating nucleosides and amino acids; this facilitates, in turn, the biosynthesis of the macromolecules and organelles required for assembling new cells. Moreover, Warburg-like metabolism seems to be present in many rapidly dividing embryonic tissues, once again suggesting a role in supporting the large-scale biosynthetic programs that are required for active cell proliferation.
Interestingly, some tumors have been found to contain two subpopulations of cancer cells that differ in their energy-generating pathways. One subpopulation consists of glucose-dependent («Warburg-effect») cells that secrete lactate, whereas cells of the second subpopulation preferentially import and utilize the lactate produced by their neighbors as their main energy source, employing part of the citric acid cycle to do so. These two populations evidently function symbiotically: the hypoxic cancer cells depend on glucose for fuel and secrete lactate as waste, which is imported and preferentially used as fuel by their better-oxygenated brethren. Although this provocative mode of intratumoral symbiosis has yet to be generalized, the cooperation between lactate-secreting and lactate-utilizing cells to fuel tumor growth is in fact not an invention of tumors but rather again reflects cooption of a normal physiological mechanism, in this case one operating in muscle. Additionally, it is becoming apparent that oxygenation, ranging from normoxia to hypoxia, is not necessarily static in tumors but instead fluctuates temporally and regionally, likely as a result of the instability and chaotic organization of the tumor-associated neovasculature.
Altered energy metabolism is proving to be as widespread in cancer cells as many of the other cancer-associated traits that have been accepted as hallmarks of cancer. This realization raises the question of whether deregulating cellular energy metabolism is therefore a core hallmark capability of cancer cells that is as fundamental as the six well-established core hallmarks. In fact, the redirection of energy metabolism is largely orchestrated by proteins that are involved in one way or another in programming the core hallmarks of cancer. When viewed in this way, aerobic glycolysis is simply another phenotype that is programmed by proliferation-inducing oncogenes.
Interestingly, activating (gain-of-function) mutations in the isocitrate dehydrogenase 1/2 (IDH) enzymes have been reported in glioma and other human tumors. Although these mutations may prove to have been clonally selected for their ability to alter energy metabolism, there is confounding data associating their activity with elevated oxidation and stability of the HIF-1 transcription factors, which could in turn affect genome stability and angiogenesis/invasion, respectively, thus blurring the lines of phenotypic demarcation. Currently, therefore, the designation of reprogrammed energy metabolism as an emerging hallmark seems most appropriate, to highlight both its evident importance as well as the unresolved issues surrounding its functional independence from the core hallmarks.
Figure 3. Emerging hallmarks and enabling characteristics. An increasing body of research suggests that two additional hallmarks of cancer are involved in the pathogenesis of some and perhaps all cancers. One involves the capability to modify, or reprogram, cellular metabolism in order to most effectively support neoplastic proliferation. The second allows cancer cells to evade immunological destruction, in particular by T and B lymphocytes, macrophages, and natural killer cells. Because neither capability is yet generalized and fully validated, they are labeled as emerging hallmarks. Additionally, two consequential characteristics of neoplasia facilitate acquisition of both core and emerging hallmarks. Genomic instability and thus mutability endow cancer cells with genetic alterations that drive tumor progression. Inflammation by innate immune cells designed to fight infections and heal wounds can instead result in their inadvertent support of multiple hallmark capabilities, thereby manifesting the now widely appreciated tumor-promoting consequences of inflammatory responses.