Causes and Consequences of Increased Glucose Metabolism of Cancers

Causes and Consequences of Increased Glucose Metabolism of Cancers Robert J. Gillies, Ian Robey, and Robert A. Gatenby University of Arizona, Tucson, Arizona does not appear to be a significant adaptive advantage of using In this review we examine the mechanisms (causes) underlying glycolysis when oxygen is present (the Warburg effect). Yet, the increased glucose consumption observed in tumors within its prevalence in the overwhelming majority of metastatic a teleological context (consequences). In other words, we will tumors is compelling evidence that aerobic glycolysis plays a ask not only ‘‘How do cancers have high glycolysis?’’ but also, very significant role in promoting tumor development. ‘‘Why?’’ We believe that the insights gained from answering the latter question support the conclusion that elevated glucose To address this, the evolutionary dynamics of carcinogen- consumption is a necessary component of carcinogenesis. esis have been modeled using several mathematic methods, Specifically we propose that glycolysis is elevated because it including information theory, evolutionary game theory, produces acid, which provides an evolutionary advantage to reaction–diffusion models, and modified cellular automata cancer cells vis-a-vis` normal parenchyma into which they invade. (2–12). Insights from these models combined with modern Key Words: cancer; glucose; metabolism; carcinogenesis; imaging, what we have termed ‘‘imag(in)ing,’’ have demon- acid-base; somatic evolution strated that hypoxia and acidosis develop inevitably in the J Nucl Med 2008; 49:24S–42S microenvironment of premalignant epithelial tumors, such as DOI: 10.2967/jnumed.107.047258 ductal carcinoma in situ (DCIS). This results from aberrant proliferation that carries cells away from their underlying blood supply, which remains on the opposite side of an in- tact basement membrane (BM). These conditions serve as In 1976, Sidney Weinhouse, a pioneer in the investigation microenvironmental selection forces that govern cellular of cancer metabolism (Fig. 1), stated that, ‘‘Since our per- adaptation during the later stages of somatic evolution. The spectives have broadened over the years, the burning issues of models demonstrate that, after this evolutionary pathway, glycolysis and respiration in cancer now flicker only dimly’’ aerobic glycolysis does in fact confer a significant growth (1). 18F-FDG PET imaging has rekindled interest in the advantage because it produces a toxic, acidic environment metabolic control of cancer by demonstrating a remarkable which is more toxic to adjacent tissue compared with the preponderance of metastatic cancers to trap far more glucose cancer cells themselves. In the process, corollaries have been than normal tissue. This observation has been the starting uncovered that explain other observed phenomena in cancers, point for Darwinian-based mathematic models to answer the namely the extreme variability in gene expression patterns. question: ‘‘Whydo metastatic cancers have such high rates of This review will discuss causes and consequences of in- glucose consumption’’? Driving this research is the assump- creased aerobic glycolysis by connecting mechanistic information that all aspects of tumor biology including progression, tion to teleology. It will begin with an introduction to canonical invasion, and metastases are the result of a continuous op- views of carcinogenesis and its molecular controls. This will be timization process governed by Darwinian dynamics (Fig. 2). followed by a brief review of the evidence that 18F-FDG uptake This leads to a fundamental assumption that any common is elevated in metastatic cancers and a discussion of the phenotype (including aerobic glycolysis) must always con- molecular causes and consequences of this elevated glycolysis fer a selective advantage on the cells that possess such a in cancer. Evolutionary Game Theory models and their pre- phenotype. Within an evolutionary/bioenergetic context, aer- dictions will then be described and the subsequent imaging of obic glycolysis would appear to be a conundrum because cancer histopathology, tumor hypoxia, and tumor pH. These glycolytic metabolism is very inefficient (producing only 2 data have led to additional conceptual models, derived from mol of adenosine triphosphate [ATP] per mole of glucose vs. mathematic models, which attempt to describe carcinogenesis 36 mol of ATP per mole of glucose for the citric acid cycle) and as a series of adaptations to environmental selections. generates an acidic, potentially toxic environment. Thus, there CARCINOGENESIS AND MICROENVIRONMENT Received Jan. 30, 2008; revision accepted Mar. 19, 2008. For correspondence or reprints contact: Robert J. Gillies, H. Lee Moffitt Cancer Progression Cancer Center, Tampa, FL 33612-9416. E-mail: robert.gillies@moffitt.org Before we consider the pathophysiology of cancer, the COPYRIGHT ª 2008 by the Society of Nuclear Medicine, Inc. developmental origin of cancer cells and their normal phys- 24S THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 6 (Suppl) • June 2008 TABLE 1 Incidence of Cancers and Mortality in U.S. Adults and Children (All Races, per 100,000) Adults Children Death Death Cancer type Incidence (%) Incidence (%) Breast 130 19 NR NR Colorectal 58 31 NR NR FIGURE 1. Sidney Weinhouse. Lung 71 86 NR NR (Courtesy of the Office of Prostate 170 20 NR NR NIH History, National Insti- Stomach 10 40 NR NR tutes of Health.) Pancreatic 10 96 NR NR Urogenital (female) 47 36 NR NR Leukemia 11 64 4.2 27 iologic niches must be discussed. In adults, there are essen- Lymphoma 20 30 1.6 17 Central nervous system 6 68 2.8 36 tially 2 types of tissues: epithelia and stroma. These are Neuroblastoma NR NR 0.9 40 behaviorally distinct tissues in that epithelia are highly Soft-tissue sarcoma 2.9 37 0.8 36 polarized and will grow in monolayers along a single axis, Bone 0.8 46 0.6 39 whereas stromal cells are phenotypically plastic, highly motile, and can grow in response to morphogenetic gradients NR 5 not reported. in any direction. Neoplasia of epithelia gives rise to carci- Data are from Cancer Facts and Figures, 2007 (American Cancer nomas, such as breast, lung, pancreatic, prostate, or mela- Society). noma, which have a high prevalence in adults. Stromal cancers include sarcomas, gliomas, and liquid cancers, which are more prevalent in the young (Table 1). In mature organs, than their cell of origin (14). This plasticity has significance epithelia and stroma are physically separated by a BM made to cancer, as epithelial cells undergo a transition to a mesen- of laminin, collagen IV, proteoglycan, and various growth chymal phenotype (an epithelial-to-mesenchymal transition) factors and proteases (13). On one side of the BM, epithelial concomitant with their adoption of an invasive phenotype cells grow in a mono- or bilayer of polarized cells, forming (15). a duct that is contiguous with the outside world. On the other Development of carcinomas proceeds through distinct side of the BM lies a stroma of connective tissue containing stages, as shown for colorectal cancer in Figure 5. The initial fibroblasts, muscle, blood, and lymphatic vessels, which are genetic changes result in hyperplasia that progresses into constantly remodeling (Fig. 3). Epithelial and stromal com- dysplasia within the lumen of the ducts. The dysplastic ponents are established during embryogenesis from the condition, known as carcinoma in situ (CiS), or adenoma in 3 primordial germ cell layers of ectoderm, endoderm, and the case of colorectal cancer (CRC), progresses through mesoderm that give rise to skin and nervous system, epithe- early, middle, and late phases yet still remains separated from lia, and mesenchymal tissues, respectively (Fig. 4). Epithelia the stroma by the BM. Once the BM is breached, the cells are generally derived from endoderm and ectoderm (dermis), and stromal components are generally derived from mesoderm. However, there is significant plasticity, and cell fates are more dependent on spatial and conditional factors FIGURE 2. Charles Darwin, circa 1870, by Julia Margaret Cameron (1815–1879). FIGURE 3. Normal human breast duct. Bar 5 0.2 mm. INCREASED CANCER GLUCOSE METABOLISM • Gillies et al. 25S FIGURE 4. Developmental origins of tissues and cancers. make contact with the stroma to become a locally invasive proliferation barriers that evolving tumor populations en- cancer. Further evolution is then required to allow the counter during their progression through carcinogenesis. avascular microscopic disease to ‘‘partner’’ with the stromal cells to promote angiogenesis and extracellular matrix re- Early Carcinogenesis modeling. The invasive tumor cells, either directly or indi- The initial steps in carcinogenesis result in the transfor- rectly via lymphatics, enter the bloodstream (intravasation). mation of normal epithelium to epithelium that is hyperplas- A small fraction of these are able to extravasate and colonize tic, which results in cellular proliferation away from the BM, distant sites, forming metastatic cancer. forming multilayer growth. We argue that, whatever the Although significant differences among cancers exist, mechanism, these steps have to involve a deregulation of there are some phenotypic elements common to all cancers, cell–cell and cell–matrix growth inhibitory interactions that which are known as the ‘‘hallmarks of cancer’’: evading maintain the epithelia in a monolayer (17). Despite the apoptosis, self-sufficiency in growth signals, insensitivity to importance of this

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