The Need to Understand Glucose Metabolism in Normal and Aberrant Tissues for Diagnostic Considerations

A key hallmark of many cancers, at least the most aggressive ones, is the capacity to metabolize glucose at an elevated rate - a phenotype detected clinically using positron emission tomography (PET). This phenotype provides cancer cells that are invasive/or participate in metastasis formation a distinct competitive edge over normal cells. Adaptation to hypoxia and acidosis of tumor cells causes an upregulation of glucose transporter 1 and 3 (GLUT-1 and GLUT-3), which gives the cells an advantage of higher per-cell glucose consumption and higher per-cell lactate production compared to non-cancerous finite lifespan cells of the microenvironment. Concomitantly, this feature allows a more accurate diagnostic discrimination of non-cancerous and cancerous tissue using the highly sophisticated PET technique with the appropriate glucose markers.

Gatenby et al. [5] and Smallbone et al. [6] successfully established models which nicely demonstrate that adaptation of initiated cancer cells to hypoxia and acidosis represents key events in transition from in situ to invasive cancer. The models suggest three phases of somatic evolution from self-limited premalignant growth to invasive growth. The evolutionary modeling of cancer cell metabolism calls for novel strategies directed towards novel diagnostic tools and towards interrupting the hypoxia-glycolysis-acidosis cycle and thus delaying or preventing metastatic spread.

In good accordance with this modeling is the observation by Yeh et al. [7] that the glycolytic pathway and glycolysis-related genes my play an important role in the tumorigenesis/progression of disease of human colorectal cancers.

The metabolomics of cancer cells with respect to glucose utilization are represented by the same key enzymes, such as hexokinase II [8], and increased expression of a variety of enzymes involved in glycolysis, tricarboxylic acid (TCA) cycle, and oxidative phosphorylation, as shown for human breast cancer cells forming brain metastases [9]. Most interestingly, although these cells do not only increase the enzymes for conversion of glucose to lactic acid, but also activate enzymes involved in the Embden-Meyerhoff pathway, these cells concomitantly show enhanced activation of the pentose phosphate pathway (PPP) and the glutathione system, which can minimize production of ROS from enhanced oxidation metabolism without losing the capacity to produce enough macromolecules and chemical energy for rapid self-renewal. Within this context it can be hypothesized - as put forward in part by Lu [10] - that cancer cells developing an invasive phenotype show decreased levels of ROS.

The bioenergetic phenotype of two human cancer cell lines, H460 and A549, was investigated and both lines showed increased glycolysis and reduced mitochondrial respiration [11]. The swift from the Embden-Meyerhoff pathway to glycolysis and lactic acid production is mandatory for a decreased ROS production. Glycolytic breakdown of glucose is preceded by the transport of glucose across the cell membrane, a rate-limiting process mediated by glucose transporter proteins belonging to the facilitative glucose transporter/solute carrier GLUT/SLC2A family [also see A. Schurmann, this

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Fig. 1. a, b Consequences of alterations in carbohydrate metabolism at non-diabetic versus diabetic conditions in malignant cells - a network between tissues. The scheme compares the glucose metabolism of tumor cells growing under either non-diabetic or diabetic conditions - comparing in addition the influence of the expression of GLUT-1. In general there is the observation that malignant cells show an increased flux of glucose, which will be further stimulated by insulin. Additional stimuli are the cytokines, secreted from the adipose tissue. Adipocytes growing under hyperglycemic/diabetic conditions display an increased proliferation - and over time will become hypertrophic. These adipocytes will secrete large amounts of various cytokines, which will lead to an increased proliferation of tumor cells, in addition to the insulin stimulus. Under non-diabetic conditions a tumor will proliferate during times shortly after the uptake of nutrition, when blood glucose as well as insulin levels are increased. Under non-diabetic conditions this elevated level of glucose and insulin will appear several times per day for approximately 2h. Therefore the stimulus for the proliferation of volume, pp. 71-83]. Tumors frequently overexpress GLUTs, especially the hypoxia-responsive GLUT-1 and GLUT-3 proteins [12]. GLUT-1 antibodies alone or in combination with chemotherapy induce growth arrest and apoptosis in human cell lines [13].

On the road to discovering cancer's Achilles heel, the emergence of the metabolic switch from oxidative phosphorylation to glycolysis is not only of therapeutic interest but also of diagnostic importance. PET imaging with 18F-fluorodeoxyglucose (FDG), which reflects tumor glucose metabolism, provides relevant information regarding treatment response and assessment of novel drug distribution [14]. FDG uptake of a tumor correlates to the histopathological findings and the variable appearance of tracer uptake on the PET scan depends on distribution of different tissue components with different utilization of glucose in the tumor, thus reflecting intratumoral heterogeneity [15].

Cancer cells possess a unique phenotype which is characterized by high glucose uptake, increased glycolytic activity and lactic acid production, decreased mitochon-drial activity, low bioenergetic expenditure and increased phospholipid turnover. These features, when properly addressed, are a challenge to induce metabolic catastrophe as therapeutic approach to kill the ineradicable cells.

Undoubtedly there are existing molecular links and common denominators between cancer and diabetes mellitus type 2. Some are obvious. It appears evident that the abundance of glucose in extracellular fluids associated with diabetes mellitus type 2 will support cell proliferation and represent a selective advantage for growth of cancer cells. Moreover, during the course of diabetes mellitus type 2 relatively high concentrations of insulin will be found - either because of insulin resistance or due to iatrogenic application of insulin for the control of blood sugar - which will trigger PI3K/Akt/mTOR signaling [16, 17] and promote the metabolic reprogramming that is characteristic of proliferating cancer cells (see figs. 1, 2).

Yet, novel therapeutics of type 2 diabetes mellitus addresses the secretion of insulin via the incretin hormone glucagon-like peptide-1 (GLP-1) [see B. Gallwitz, this volume, pp. 30-43]. GLP-1 will be secreted into the bloodstream from intestinal L-cells stimulated by the uptake of nutrition. However, GLP-1 displays an extremely short biological half-life of less than 5min, due to degradation by the dipeptidyl peptidase IV (DPPIV). Therefore, DPPIV-stable GLP-1 analogues as well as inhibitors of DPPIV have been developed within antidiabetic strategies. But especially the DPPIV inhibitors, because of their possible adverse side effects, are coming increasingly into the focus of molecular and clinical research. DPPIV exhibit a broad spectrum of substrates, not only directed to the incretin hormones (GLP-1, GIP) but also to peptides (e.g. SDF-1, RANTES, eotaxin)

GLUT-1-negative tumors will be reserved only for postprandial periods. A GLUT-1-bearing tumor will proliferate mainly all over time. Because of the high affinity for glucose of the GLUT-1 transporter, those malignant cells will have a permanent supply of energy. Even under diabetic conditions the expression of GLUT-1 will be an advantage, since GLUT-1-expressing cancer cells will be able to proliferate longer than GLUT-1-negative tumors. Thereby the diffusion of glucose is the limiting factor for tumor growth. Therefore, GLUT-1-expressing tumors are able to proliferate even under hypoglycemic conditions, while GLUT-1-negative cells will face necrosis under the same conditions.

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Fig. 2. Normal cells versus high-proliferating tumor cells concerning the utilization of glucose. The high flux of glucose in malignant cells can be explained by the effect of aerobe glycolysis - known as the 'Warburg effect. At first sight, the energy yield of aerobe glycolysis in tumor cells seems to be ineffective when compared to non-proliferating healthy cells. The cells of normal tissues will use glucose mainly for ATP production with a maximal (theoretical) yield of 38 mol ATP/mol glucose. But besides the production of ATP, the intermediate products of glycolysis are the main components for many biosynthetic processes to support proliferation. Especially the tricarboxylic acid (TCA) cycle and the pentose phosphate pathway (PPP) will maintain proliferation by the generation of amino acids, lipids as well as nucleotides. Some of the malignant cells acquired various (additional) mutations responsible for an increase in glucose uptake (GLUT-1) or glycolysis (LDH), resulting in dramatically elevated levels of glucose conversion to pyruvate and finally lactate. This surplus of lactate will be secreted into the surrounding tissue and thereby significantly decreasing the pH, making the direct neighborhood with immunologically functions [18]. All these substrates display a very short half-life due to DPPIV-mediated cleavage, the result of which is the deactivation of these signal molecules. Moreover, there are no known naturally occurring inhibitors of DPPIV, implying the importance of a rapid turn-off of those signals. This broad spectrum of DPPIV substrates suggests a certain likelihood that inhibition of DPPIV also affects other biological systems and organ functions like the immune system.

Most interestingly, Boonacker and van Noorden [18] reviewed in 2003 that the level of soluble CD26 equals serum DPPIV activity in respect to various physiological and pathophysiological processes (e.g. aging, colon cancer, diabetes, hypertension and immunosuppression). Within the above conditions, serum CD26 levels are already downregulated. This is an indication that low DPPIV activity is associated with different diseases. Therefore, a further inhibition of DPPIV activity seems to be doubtful or even contraindicative when e.g. diabetes is associated with cancer or immunological disorders. In addition, a prolonged GLP-1 activity induced by the treatment with DPPIV inhibitors for the treatment of diabetes will result in increased insulin secretion, a hormone which promotes the metabolic reprogramming of proliferation and enhanced glucose utilization of cancer cells.

Increased ROS formation has also been found associated with diabetes mellitus type 2 [19], which may contribute to its pathogenesis [20, 21] and/or to progression of the disease: 'glucolipotoxicity of diabetes mellitus type 2' [22].

Another hallmark of type 2 diabetes mellitus is the formation of advanced glycation end products (AGEs), which are the result of a chain of chemical reactions after an initial glycation reaction. The receptor for AGEs (RAGE) is a multifunctional receptor with multiple ligands that is known to play a key role in several diseases, including diabetes, arthritis, and Alzheimer's disease. Recent evidence indicates that this receptor also has an important role in cancer. RAGE ligands, which include the S100/calgran-ulins and high-mobility group box 1 (HMGB1) ligands, are expressed and secreted by of the tumor inheritable for normal cells without an increased H+ transporter activity (e.g. N+/H + exchanger), so that healthy tissue will be eliminated by acidosis. Because GLUT-1's high affinity for glucose a GLUT-1-positive tumor will be able to grow for longer periods, since the supply with the main source of energy and biosynthetic processes will not diminish. The worst case scenario will be a tumor growing under diabetic conditions - comparable to the metabolic syndrome. Glucose concentrations have been elevated on a 24-hour basis over a long period of time. As a consequence of the increased blood glucose levels, pancreatic p cells permanently secrete insulin. Caused by this plethora of glucose and insulin, the adipose tissue stored the energy in the form of fat, thereby an increase in visceral fat accumulation occurs. Mainly these visceral adipocytes will secret high amounts of cytokines - further stimulating tumor growth and additionally promoting a low systemic inflammation. Therefore, cytokines together with insulin as well as other growth hormones activate tumor cells via the 'growth hormone receptor', followed by PI3K activating the Akt pathway. Especially Akt promotes the increased glucose consumption and therefore supports aerobic glycolysis. Thus, even a GLUT-1-negative tumor will grow under diabetic conditions more extensively compared to non-diabetic circumstances. At very late stages such tumors will develop areas of necrosis in the center of the cluster. Because of the high affinity of GLUT-1 these tumors will have a further advantage since glucose diffusion rates may be high enough for a tumor growth without a necrotic core.

cancer cells and are associated with increased metastasis and poorer outcomes in a wide variety of tumors. These ligands can interact in an autocrine manner to directly activate cancer cells and stimulate proliferation, invasion, chemoresistance, and metastasis [23].

As described above, ROS impair HIF-1a degradation [24, 25], allowing it to trans-activate an array of genes that increase both glucose utilization and lactate production. In addition, lack-of-function mutations and polymorphisms in genes that regulate mitochondrial oxidative phosphorylation have also been linked to development of diabetes mellitus type 2 [26]. ROS may also trigger mitochondrial dysfunction resulting in decreased oxidative phosphorylation [27]. Hence the metabolic condition encountered in diabetes mellitus type 2 associated with mitochondrial dysfunction could provide an adequate basis to favor the metabolic reprogramming that is characteristic of the Warburg effect. Therefore, comorbidity of cancer and diabetes mellitus type 2 may produce additive or even potentiating effects on the molecular processes underlying both diseases as well as their pathology.

There are lines of evidence suggesting that cancer is a largely preventable disease, as is diabetes mellitus type 2. Patterns of cancer and diabetes mellitus type 2 are altered by environmental factors that show a genetic predisposition but are not necessarily genetically determined. The pattern of food and drinks, of physical activity, and of body composition has changed remarkably throughout human history. With urbanization and industrialization, food supplies usually become more secure, and more food is available for consumption. In general, diets become more energy-rich, as they contain fewer starchy foods but more fats and oils, sugars and additives. Populations become increasingly sedentary, their drain of energy from food drops, and the incidence of overweight and obesity increase, which are major risk factors for cancer and diabetes mellitus type 2. The spectrum of liver diseases in diabetes mellitus type 2 ranges from non-alcoholic fatty liver disease to cirrhosis and hepatocellular carcinoma (HCC). The incidence of HCC is increasing in the Western world, but the temporal changes of risk factors remain unclear. A significant proportion of HCC develops in cryptogenic cirrhosis, and may represent the most worrisome complication of non-alcoholic steato-hepatitis. Non-alcoholic steatohepatitis is tightly related to insulin resistance and several features of the metabolic syndrome. HCC is the result of a multifactorial process in which insulin resistance seems to play a major role in the initial accumulation of fat in the liver, whereas multiple causes of mitochondria dysfunction and oxidative stress can induce the secondary occurrence of necroinflammatory lesions and fibrosis [28]. A case of lipid-rich clear cell HCC arising in non-alcoholic steatohepatitis in a patient with diabetes mellitus type 2 was described immunohistochemically and ultrastructurally [29]. Tumor cells had lipid droplets, glycogen, swollen mitochondria, rough endoplasmatic reticulum, Mallory bodies, small bile canaliculi, desmo-somes and gap junction. Surrounding non-tumoral hepatocytes had a largely normal ultrastructure with prominent glycogen and lipid droplets. Similar histological features to the patients of human non-alcoholic steatohepatitis were found in hepatocyte-specific tumor suppressor gene PTEN-deficient mice [29]. These hepatocytes showed enhanced lipid accumulation, inflammatory change, and hyperoxidation; moreover, they developed into HCC. Thus, impairment of the PI3K/PTEN signaling may possibly be involved in a part of non-alcoholic steatohepatitis/HCC cases in human.

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