Cancer as a Metabolic Disease and Diabetes as a Cancer Risk?
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Cancer as a Metabolic Disease and Diabetes
as a Cancer Risk?
Nádory jako metabolická onemocnění a diabetes jako riziko
nádorů?
Kankova K.1,2, Hrstka R.2
1
Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
2
Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
Summary
The prevailing aerobic glycolysis (so called Warburg effect) in cancer cells is according to cur This study was supported by the European
Regional Development Fund and the State
rent understanding the consequence of reprogramming of cellular metabolism during the
Budget of the Czech Republic (RECAMO,
process of malignant transformation. Metabolic regulation is inseparable component of cell CZ.1.05/2.1.00/03.0101).
proliferation machinery and has a tight link with activities of oncogenes and suppressor genes.
Práce byla podpořena Evropským fondem
The purpose of metabolic reprogramming of cancer (but also normal intensively proliferating
pro regionální rozvoj a státním rozpočtem
cells) is to incorporate greater fraction of glucose metabolites into newly synthesised macro České republiky (OP VaVpI – RECAMO,
molecules. Apart from that, aerobic glycolysis confers several other selective advantages to CZ.1.05/2.1.00/03.0101).
cancer cells. Epidemiological data indicate that type 2 diabetes mellitus is associated with in The authors declare they have no potential
creased incidence of several types of cancer and that cancer mortality can be influenced by conflicts of interest concerning drugs,
certain types of anti-diabetic treatment, however future research is needed to explain whether products, or services used in the study.
this relationship might be causal. Deeper knowledge about metabolic properties of rapidly Autoři deklarují, že v souvislosti s předmětem
proliferating cells can be exploited for further improvement of anti-cancer, immunosuppres studie nemají žádné komerční zájmy.
sive or anti-inflammatory therapies. The Editorial Board declares that the manuscript
met the ICMJE “uniform requirements” for
biomedical papers.
Key words
diabetes – cancer – obesity – metabolism – glyoxalase – transketolase – p53 – metformin Redakční rada potvrzuje, že rukopis práce
splnil ICMJE kritéria pro publikace zasílané do
bi omedicínských časopisů.
Souhrn
Převažující aerobní glykolýza v nádorových buňkách (tzv. Warburgův efekt) je na základě sou
časných poznatků důsledkem přeprogramování buněčného metabolizmu během procesu ma Katerina Kankova, Prof. M.D., Ph.D.
ligní transformace. Regulace metabolizmu je neoddělitelnou komponentou procesu buněčné
Department of Pathophysiology
proliferace a je těsně svázána s aktivitami onkogenů a supresorových genů. Smyslem metabo
Faculty of Medicine
lické transformace nádorových buněk (a rovněž normálních intenzivně proliferujících buněk) je
inkorporovat větší podíl metabolitů glukózy do nově syntetizovaných makromolekul. Mimo to Masaryk University
aerobní glykolýza poskytuje nádorovým buňkám několik dalších selektivních výhod. Epidemio Kamenice 5/A18
logická data naznačují, že diabetes mellitus 2. typu je asociován s rostoucí incidencí několika 625 00 Brno
typů nádorů a že mortalita v důsledku nádorových onemocnění může být ovlivněna léčbou Czech Republic
určitými druhy antidiabetik, nicméně další výzkum je nutný k vysvětlení toho, zda je tento vztah e-mail: kankov@med.muni.cz
kauzální. Hlubší pochopení metabolizmu rychle proliferujících buněk může vést k dalšímu zlep
šení protinádorové, imunosupresivní a protizánětové léčby. Submitted/Obdrženo: 30. 9. 2012
Accepted/Přijato: 25. 10. 2012
Klíčová slova
diabetes – nádory – obezita – metabolizmus– glyoxaláza – transketoláza – p53 – metformin
2S26 Klin Onkol 2012; 25(Suppl 2): 2S26– 2S31Cancer as a Metabolic Disease and Diabetes as a Cancer Risk Introduction Cellular Metabolism and the been termed “aerobic glycolysis” or “the Research in oncology has traditionally Interplay with Cell Signalling and Warburg effect”. In cancer cells pyru focused on genetic and more recently Proliferation vate is not transported to mitochond epigenetic alterations of oncogenes In order to maintain viability cells need ria to be converted to acetyl-CoA and and tumour suppressor genes as cau to produce (i) energy in the form of ATP subsequently processed in the TCA sal factors responsible for the mul and (ii) precursors for synthesis of pro cycle. Instead it is converted into lactate. tistage process of malignant transfor teins, nucleic acids and membrane li Warburg originally assumed aerobic gly mation. Recently, attention has also pids. The main sources of energy in ani colysis as an epiphenomenon, a conse been paid to the tumour microenvi mal cells are glucose, glutamine and quence of a defect in the mitochondrial ronment and systemic factors. Me fatty acids. Most of the ATP is used by ac respiration and he proposed primary mi tabolic properties of cancer cells – tive membrane transport (ionic pumps). tochondrial dysfunction as a fundamen aerob ic glycolysis and impairment of Cells can obtain energy from oxygen-de tal cause of cancer (the so called Warburg mitochondrial function – were origi pendent (OXPHOS) or oxygen-indepen hypothesis) [3]. Naturally his hypothe nally considered to be a driving force dent processes (anaerobic glycolysis). sis was quickly dismissed as too sim of tumourigenesis, later a merely pas Since fatty acids in the form of triglyce plistic, not explaining the progressive sive consequence or rather an essen rides are the most abundant form of sto nature of disease, the formation of me tial compensation to hypoxia within red energy and OXPHOS is much more tastases etc. [1] and cancer has become the cancer mass. Nowadays we know efficient in generating ATP, adult diffe considered as a genetic rather than me that sustained aerobic glycolysis in rentiated cells convert glucose to lactate tabolic disease. However, the fact that cancer cells is linked to the activa (lactic acid fermentation) only in the ab most cancer cells predominantly pro tion of oncogenes and/or loss of func sence of oxygen (so called Pasteur ef duce energy by a high rate of glycoly tion of tumour suppressor genes and fect). In a normal cell with functioning sis followed by lactic acid fermentation represents a conditional phenotypic mitochondria approximately 88% of ATP in the cytosol even if oxygen is plentiful feature enabling all biological proper is produced by OXPHOS and the remai instead of low rate of glycolysis followed ties ascribed to cancer cells. However, ning 12% by glycolysis and TCA cycle [1]. by oxidation of pyruvate in mitochond unlike extensive genetic heterogene Cell fate and metabolism are closely ria as in most normal cells (although the ity among cancer types, impairment intertwined – information about nu total amount of energy produced rema of cancer cell metabolism represents trient and energy availability influen ins equal) has periodically regained at a unifying characteristic of nearly all ces self-renewal, growth and division. tention and could be considered one of types of cancer regardless of tissue In situations of energy depletion, cells the hallmarks of cancer. origin. Not the total amount of energy can undergo autophagy, apoptosis or The asymmetry in the yield of ATP in produced, but its’ source, is the most in most severe cases, necrosis. On the OXPHOS compared to glycolysis (36 mo striking difference of cancer cells from other hand, the activities of metabo lecules of ATP per molecule of glucose vs normal cells of the tissues they origi lic enzymes are under the strict control only 2 in the latter) plus loss of excreted nate from. The thorough knowledge of signalling pathways and transcrip lactate has often been regarded as a sign of the pathophysiology of impaired tion factors. The effect of cellular energy of metabolic insufficiency of cancer cells. cancer cell metabolism has an im (AMP/ATP ratio) and substrate status on But this would be a problem only when mense clinical potential since our ap the cell cycle is mediated by mTOR via resources are scarce. Proliferating mam proach to cancer management could either inhibitory AMPK/TSC2/mTOR or malian cells are however continuously radically shift in the light of its’ un opposing stimulatory insulin/PI3K/AKT/ supplied by glucose and other nu derstanding and further research into /mTOR pathway and others [2]. In fact, trients from blood [4]. Malignant, rapidly the metabolic properties of cancer al many other direct metabolic signals growing tumour cells typically have gly lowing therapeutic exploitation thus propagate the metabolic information colytic rates up to ten to hundred times represents a promising future anti into the cell cycle in a coordinated man higher than those of their normal tissues cancer strategy. The aims of this mini- ner – HIF-1 oxygen sensors, sensors of of origin. This phenomenon has a dia -review are to (A) summarise the cur NAD+/NADH ratio (such as sirtuins or gnostic value; the glycolytic phenotype rent findings explaining the metabolic PARP-1) and others [2]. of cancer cells is used clinically to dia phenotype of cancer cells and (B) the gnose and monitor treatment response intimate relationship with the process The History and Current by imaging uptake of glucose analogues of malignant transformation. Further Understanding of the “Warburg (FDG, a radioactive modified hexokinase more, (C) since epidemiological data Effect” substrate) with PET. suggest a relationship between dia It was shown by Otto Warburg some One proposed explanation for War betes and cancer, several hypothetical 90 years ago that tumour cells produce burg effect is tumour hypoxia and the links are presented to explain their co lactate despite the presence of oxy refore blockade of OXPHOS. Although incidence and the putative pathoge gen (which would otherwise favour tumour hypoxia plays an important role nic mechanisms. OXPHOS) and this phenomenon has in cancer development it is a relatively Klin Onkol 2012; 25(Suppl 2): 2S26– 2S31 2S27
Cancer as a Metabolic Disease and Diabetes as a Cancer Risk
late occurring event and could not ex out of the cell has in fact – as explained starvation). Key regulators of mTOR are
plain the early switch to aerobic glycoly above – a different purpose and is per AKT – stimulated by growth factors to ac
sis in cancer cells. There is another hypo fectly in place: glucose in cancer cells is tivate mTOR – and AMPK – activated by
thetical advantage in limiting OXPHOS used more for replication than for nor the lack of ATP to suppress mTOR [10]. In
in cancer cells – mitochondria are an ine mal cell metabolism. Owing to the large tuitively, every event autonomously sti
vitable source of ROS when oxidising nu body of evidence it is now clear that me mulating AKT and/or suppressing AMPK
trients. ROS might cause genotoxic oxi tabolic pathways in mammalian cells are could be considered tumourigenic. The
dative damage and induce apoptosis [4]. tightly regulated by signalling pathways activation of the cellular master switch
Although the original Warburg hypothe implicated in the regulation of cell pro AMPK (shutting-down mTOR and thus
sis of mitochondrial dysfunction as a pri liferation. This allows quick switches cell growth) is dependent on the tumour
mary cause of cancer has been rejected, between nutrient catabolism and their suppressor LKB1 [4]. Inactivating muta
evidence that mitochondrial function incorporation into biomass. Aerobic gly tions in LKB1 lead to impaired activation
and structure in tumour cells is not nor colysis is thus logically not limited to of AMPK (possibly restorable by metfor
mal is accumulating. There is a great cancer cells, it is found also in non-can min – see below) and unlimited growth.
controversy, though, on this subject re cerous rapidly proliferating cells such as Similarly, AKT is frequently activated in
garding causality. Experimental evi T-lymphocytes or endothelial cells [2]. Of human cancers [10]. Furthermore, Myc
dence supports the contribution of both special interest is the fact that many can (involved in glycolysis, mitochondrial
functional (down-regulation of ATPase cer cells (and stem cells) express a spe biogenesis and glutamine metabolism)
and mitochondrial uncoupling) and cific isoform of pyruvate kinase (PK-M2) was one of the first oncogenes linked to
structural (composition of membrane li slowing down the last step of glycolysis metabolism [11]. Other important pla
pids) defects of cancer cell mitochond and allowing the glucose intermediates yers are Ras, and tumour suppressors
ria to metabolic alterations (reviewed in to enter PPP for nucleotide and NADPH which in a wild-type form repress mTOR
detail elsewhere [1]). Nonetheless, mito production [6]. Nowadays we know that and once mutated activate glycolysis, in
chondria of cancer cells are functional sustained aerobic glycolysis in cancer cluding HIF-1 – PTEN, TSC 1 and2, VHL,
and capable of carrying out OXPHOS. cells is linked to the activation of onco p53 and others. Among them p53 plays
Indeed, they have to be since the con genes and loss of tumour suppressor a special role [10]. AMPK activation sti
tribution of glycolysis to the energy re genes. mulates p53 and subsequent p53-me
quirements of cancer cells seldom exce There are a few exceptions, howe diated inhibition of proliferation is a lo
eds 50–60% [5]. Mitochondrial OXPHOS ver, exemplifying reverse causality (pri gical response to nutrient deprivation.
in cancer cells utilizes predominantly mary metabolic derangements beha Conversely, wild-type p53 was found to
precursors produced by oxidation of ving like oncogenes and leading to activate AMPK (both directly and indi
glutamine. Substantial amounts of ATP cancer) such as germ-line mutations in rectly) and this way to oppose the pro
in cancer cells are produced by gluta TCA cycle enzymes (succinate dehyd liferation and anabolism of cancer cells.
minolysis which makes up for the lower rogenase, fumarate hydratase) leading Furthermore, p53 can also counteract
yield from glycolysis [4]. to familial cancer syndromes (paragan established metabolic transformation of
In summary, there is no evidence that gliomas, phaeochromocytomas, leiomy- cancer cell by suppressing glycolysis and
ATP production in cancer cells would be mas or renal carcinomas) [7,8]. Other promoting OXPHOS. However, involve
limited. In fact, the amount of ATP produ examples are mutations in isocitrate ment of p53 in normal metabolism and
ced in cancer cells is the same as in nor dehydrogenases 1 and 2 altering en metabolic transformation is much more
mal cells but the way the energy is pro zyme activities and producing an “on complex and some of its actions might
duced is different. The shift to glycolytic cometabolite” [9]. The pro-oncogenic seem counterintuitive (for comprehen
phenotype is not an adaptation but an mechanisms beyond these mutations sive review see [10]).
active process and serves a clear pur are HIF-1 stabilisation (with subsequent In spite of suggestive evidence of bio
pose – large requirements of cancer cells overexpression of glucose transporters energetic changes as a feature of malig
for synthesis of new macromolecules are and glycolytic enzymes and inhibition nant transformation we have to be cau
met by a high rate of glycolysis (and the of pyruvate dehydrogenase and thus tious to think of cancer cells in vivo as
pentose phosphate pathway – PPP). Ace down-regulation of OXPHOS) or epige a homogenous population (an in vitro
tyl-CoA, glycolytic intermediates and netic modifications. perspective). Not all cells in the tumour
NADPH (from PPP) are then used to pro There are multiple links between esta are identical in respect to their self-rene
duce nucleotides, amino acids and fatty blished oncogenes and tumour suppres wal potential, solid tumour stroma can
acids to support cell growth and division. sors and metabolic regulation, however contribute to some extent too as well
detailed description is beyond the focus as variable proximity of cells to tumour
Oncogenes and Tumour of this mini review. The majority of impu vessels [5]. There are still many gaps
Suppressors Regulate Metabolism tes converge on the level of mTOR whose to be fulfilled in our understanding to
Seemingly wasteful glucose consump activation promotes protein synthe what extent the Warburg effect can be
tion followed by excretion of lactate sis and inhibits autophagy (response to generalised.
2S28 Klin Onkol 2012; 25(Suppl 2): 2S26– 2S31Cancer as a Metabolic Disease and Diabetes as a Cancer Risk Epidemiologic and Pathogenic genous pathogenic mechanisms. In ad dent effects of metformin explaining its Overlap of Diabetes and Cancer dition, food is an important source of documented anti-cancer effects (for sys People with diabetes (namely T2DM) dietary carcinogens and inevitable pro tematic review see [22,23]) targeting cell have increased cancer incidence com ducer of mutagenic ROS as a by-product growth, cell cycle regulation, cell survi pared to non-diabetics [12] and mor of metabolism of nutrients. Other emer val and epithelial mesenchymal transi tality from cancer is increased in pe ging environmental risks include impai tion (EMT). ople with pre-existing diabetes [13]. red sleeping patterns and disturbed cir Once diabetes reaches its manifest Recently, numerous studies have been cadian rhythmicity in general [11]. stage, the prevention of development undertaken to try to investigate the pre Similar to previous issues concerning and progression of its late complications viously under-recognised relationship the exact mechanisms linking diabetes (diabetic micro- and macroangiopathy) between these two co-morbidities and and cancer, studies reporting that glu becomes the urgent therapeutic aim in this task is proving to be quite difficult. cose-lowering treatment might modu order to prevent the devastating outco Current uncertainty rises from several late cancer risk have considerable me mes (such as fatal cardiovascular events, reasons: (i) epidemiologic evidence lin thodological limitations. Metformin, an renal failure, blindness, limb amputa king diabetes and cancer is site-specific old known biguanide derivative com tions etc.). There are multiple pathways (observed validly for breast, endomet monly prescribed for the management contributing to the development of dia rial, colorectal, bladder and kidney can of T2DM (and in some trials for its pre betic complications but they are all rela cer and non-Hodgkin lymphoma where vention or for the treatment of polycys ted to dysregulated intracellular glucose risk in people with T2DM appears to tic ovary syndrome), has recently attrac metabolism marked by overproduction be 20–50% higher) [14]. Furthermore, ted new attention due to its therapeutic of an array of harmful metabolites. Va (ii) there are methodological problems potential in oncology. While meta-analy riable degree of fasting and/or postpran with the studies, these were not prima ses of prospective observational studies dial hyperglycaemia provides substrates rily designed to provide such evidence suggest that metformin lowers the over for several intracellular pathways (such (data were mostly obtained from on- all cancer risk by about one third [19,20], as polyol and hexosamine pathways, di -going cohort studies or by secondary the meta-analysis of available RCTs with carbonyl production and non-enzyma analyses of RCTs) and could thus be bia metformin did not confirm the reduced tic glycation leading to the production sed [14]. Finally, (iii) the effect of glucose- risk [21]. Nevertheless, there are trials in of Advanced Glycation End products -lowering therapies (mainly metformin) progress already of metformin as an ad (AGEs) etc.) that are believed to be lar seems to modulate the risk of cancer in juvant therapy in various cancer treat gely responsible for the hyperglycae cidence and cancer-associated mortality ments. Studies in vitro and in animal mia-induced cell damage [24]. There are, and this further raises controversy in the models are on-going to explore poten however, other metabolic pathways – clinical community [14]. tial anti-cancer mechanisms of metfor such as PPP, glyoxalase system and fruc The relationship between diabetes min. The classical anti-diabetic effects of tosamine-3-kinase pathway – poten and cancer can be principally direct (one metformin comprise stimulation of glu tially conferring protection from the causing or helping to develop the other) cose uptake by peripheral tissues (ske hyperglycaemia-induced damage since or indirect (through shared risk factors). letal muscle and adipose tissue), inhibi they metabolise glycolytic intermedia There are several plausible pathoge tion of hepatic glucose production and tes (especially triosephosphates) into nic mechanisms that can hypothetically decrease of intestinal absorption of glu harmless metabolites [25,26]. There is explain the association of diabetes and cose. Importantly, metformin does not obvious interest to augment their prote cancer: (1) hyperglycaemia (favouring stimulate insulin secretion (it improves ctive activity therapeutically in order to aerobic glycolysis [15]), (2) hyperinsuli insulin sensitivity but does not lower prevent development of complications, naemia compensating insulin resistance glycaemia) and is thus safe in non-dia even more so since their activity appears (promoting cell proliferation and survi betic persons. On the molecular level, to be insufficient or directly failing in val via insulin or IGF-1 receptors [16,17]), metformin largely exerts its effect via hyperglycaemia. Our group documen (3) decreased sex-hormone binding glo activation of the cellular energy sensor ted impaired activity of transketolase bulins (leading to excess of free oestro AMPK (dependent on upstream kinase (TKT) – the key enzyme of the non-oxi gens and development of oestrogen- LKB1). Upon activation, AMPK acts on its dative branch of PPP – and deficient cel -dependent tumours [18]) and (4) others down-stream targets – inhibiting mTOR lular availability of its co-factor thiamine such as aberrant activity of PPP or glyo pathway – and generally speaking sup diphosphate in human diabetics [27]. xalase. The most consistent common risk presses anabolic energy-conserving re Evidence from experimental and clini factors of diabetes and cancer comprise actions (gluconeogenesis, protein, fatty cal studies suggests that PPP activation poor dietary habits and physical inacti acid and cholesterol synthesis) and ac by supplementation of the TKT co-factor vity. They both contribute to the deve tivates catabolic energy producing re thiamine may prevent and reverse early- lopment of obesity (inevitably aggrava actions (fatty acid beta oxidation and -stage diabetic complications [28]. ting insulin resistance) and therefore glycolysis). There are numerous insu However, PPP and namely one of the constitute a vicious cycle feeding endo lin-dependent and insulin-indepen human TKT homologues, TKTL1, were Klin Onkol 2012; 25(Suppl 2): 2S26– 2S31 2S29
Cancer as a Metabolic Disease and Diabetes as a Cancer Risk
shown to play a role in aerobic glycolysis. ctive – quite unfortunate in the case of PARP-1 poly ADP ribose polymerase
PET positron emission tomography
While TKTL1 is overexpressed in a wide cancer. PI3K phosphatidylinositol 3 kinase
variety of solid cancers and its’ activity PPP pentose phosphate pathway
positively correlates with the aggressi Conclusions and Future RCT randomised controlled trial
ROS reactive oxygen species
veness of cancer, its’ inhibition media Directions T2DM type-2 diabetes mellitus
tes cell cycle arrest and apoptosis [29]. This mini-review aims to convince the TCA tricarboxylic acid cycle
Moreover, apart from TKT there are two reader that the switch to aerobic glyco TKT transketolase
TSC tuberous sclerosis
more enzymes utilising thiamine as a co- lysis in cancer cells is an active process VHL von Hippel-Lindau
-factor and involved in utilising glucose directed by oncogenes and tumour sup
into biomass. Another reason for cau pressor genes. Aerobic glycolysis confers
References
tion when considering recommenda many selective advantages for rapidly 1. Seyfried TN, Shelton LM. Cancer as a metabolic disease.
tion to thiamine supplementation arises proliferating cells – a greater fraction of Nutr Metab (Lond) 2010; 7: 7.
from observations that hypoxia induces glucose metabolites is incorporated into 2. Krejci A. Metabolic sensors and their interplay with cell
signalling and transcription. Biochem Soc Trans 2012;
up-regulation of the thiamine transpor newly synthesised macromolecules, it 40(2): 311–323.
ters in tumour cells in vitro [30]. Since creates local acidosis suiting the cancer 3. Warburg O. On the origin of cancer cells. Science 1956;
conflicting reports in regard to thia but not normal cells and it protects can 123(3191): 309–314.
4. Vander Heiden MG, Cantley LC, Thompson CB. Un-
mine transport in cancer cells exist, fur cer cells from ROS-mediated cell death.
derstanding the Warburg effect: the metabolic requi-
ther research is needed to resolve this The production of ATP by aerobic glyco rements of cell proliferation. Science 2009; 324(5930):
issue [31]. Similarly activity of the glyo lysis is not lower when glucose supply is 1029–1033.
5. Berridge MV, Herst PM, Tan AS. Metabolic flexibility and
xalase system was found to be disturbed affluent, on the contrary ATP production
cell hierarchy in metastatic cancer. Mitochondrion 2010;
under conditions of hyperglycaemia in is very fast. Suppression of the glycoly 10(6): 584–588.
experimental diabetes [32] and again re tic phenotype – by substrate limitation, 6. Christofk HR, Vander Heiden MG, Harris MH et al. The
storing its activity would be an alluring pharmacological intervention or gene M2 splice isoform of pyruvate kinase is important for
cancer metabolism and tumour growth. Nature 2008;
idea in diabetology. The glyoxalase sys tic manipulation – confers significant 452(7184): 230–233.
tem, consisting of two enzymes, GLO1 anti-tumour effects. The link between 7. Pollard PJ, Wortham NC, Tomlinson IP. The TCA cycle
and 2, catalyses the conversion of reac cancer and diabetes has been sugges and tumorigenesis: the examples of fumarate hydra-
tase and succinate dehydrogenase. Ann Med 2003; 35(8):
tive dicarbonyl methylglyoxal (produ ted for a long time by epidemiological 632–639.
ced excessively under hyperglycaemia studies. Currently, multiple pathogenic 8. King A, Selak MA, Gottlieb E. Succinate dehydro-
and contributing predominantly to the overlaps between diabetes and cancer genase and fumarate hydratase: linking mitochond-
rial dysfunction and cancer. Oncogene 2006; 25(34):
formation of AGEs) to D-lactate [33]. Wi are suggested by experimental findings 4675–4682.
thout efficient degradation methylgly advocating for causality of the associa 9. Mullen AR, Deberardinis RJ. Genetically-defined meta-
oxal would accumulate to levels inhibi tion. Considering the globally rising pre bolic reprogramming in cancer. Trends Endocrinol Metab
2012.
ting cell cycle and inducing apoptosis valence of diabetes and cancer, unders 10. Vousden KH, Ryan KM. p53 and metabolism. Nat Rev
(as observed for example in endothelial tanding the exact relationship between Cancer 2009; 9(10): 691–700.
cells or β-cells in diabetes). This is espe the two diseases is probably one of the 11. Dang CV. Links between metabolism and cancer.
Genes Dev 2012; 26(9): 877–890.
cially relevant for tissues with high rates biggest challenges for the research and 12. Giovannucci E, Harlan DM, Archer MC et al. Diabetes
of glycolysis, such as cancer. Indeed, clinical community in the near future. and cancer: a consensus report. Diabetes Care 2010; 33(7):
overexpression of GLO1 and GLO1 gene Targeting cellular metabolism more ef 1674–1685.
13. Renehan AG, Yeh HC, Johnson JA et al. Diabetes and
amplification was recently described in ficiently might offer a completely novel cancer (2): evaluating the impact of diabetes on mor-
many tumours and was also associated approach to the treatment of both di tality in patients with cancer. Diabetologia 2012; 55(6):
with tumour multidrug resistance [33]. seases in parallel and can represent 1619–1632.
14. Johnson JA, Carstensen B, Witte D et al. Diabetes and
In conclusion while T2DM and cancer a new line of treatment synergistic with cancer (1): evaluating the temporal relationship between
are probably interlinked not only epi conventional chemotherapies. Metfor type 2 diabetes and cancer incidence. Diabetologia 2012;
demiologically but pathogenically and min, a safe drug with minimal toxicity 55(6): 1607–1618.
15. Johnson JA, Pollak M. Insulin, glucose and the increa-
successful prevention of DM or its early and side effects, cheap and accessible, sed risk of cancer in patients with type 2 diabetes. Diabe-
stabilisation (for example by metfor appears to be one of the first candidates tologia 2010; 53(10): 2086–2088.
min) might target both diseases at the potentially suited for this task. 16. Pollak M. Insulin and insulin-like growth factor signal-
ling in neoplasia. Nat Rev Cancer 2008; 8(12): 915–928.
same time, the management of establis
17. Pisani P. Hyper-insulinaemia and cancer, meta-ana-
hed disease with the aim to prevent late Abbreviations lyses of epidemiological studies. Arch Physiol Biochem
complications by targeting pathways re AKT protein kinase B 2008; 114(1): 63–70.
AMPK AMP dependent protein kinase 18. van Kruijsdijk RC, van der Wall E, Visseren FL. Obe-
sponsible for their development may
ATP adenosine triphosphate sity and cancer: the role of dysfunctional adipose tis-
possess risks when considering cancer FDG 2-[18F] fluoro-2-deoxyglucose sue. Cancer Epidemiol Biomarkers Prev 2009; 18(10):
as an eventual co-morbidity. Preserving GLO1 glyoxalase 1 2569–2578.
HIF-1 hypoxia-inducible factor 1 19. Decensi A, Puntoni M, Goodwin P et al. Metformin
cell viability and inhibition of apoptosis
IGF-1 insulin growth factor 1 and cancer risk in diabetic patients: a systematic review
in target tissues affected by diabetes is mTORC1 mammalian target of rapamycin complex 1 and meta-analysis. Cancer Prev Res (Phila) 2010; 3(11):
a desirable effect, however – if not sele OXPHOS oxidative phosphorylation 1451–1461.
2S30 Klin Onkol 2012; 25(Suppl 2): 2S26– 2S31Cancer as a Metabolic Disease and Diabetes as a Cancer Risk 20. Noto H, Goto A, Tsujimoto T et al. Cancer risk in diabe- 25. Kankova K. Diabetic threesome (hyperglycaemia, 29. Wittig R, Coy JF. The role of glucose metabolism and tic patients treated with metformin: a systematic review renal function and nutrition) and advanced glycation end glucose-associated signalling in cancer. Perspect Medicin and meta-analysis. PLoS One 2012; 7(3): e33411. products: evidence for the multiple-hit agent? Proc Nutr Chem 2008; 1: 64–82. 21. Stevens RJ, Ali R, Bankhead CR et al. Cancer outco- Soc 2008; 67(1): 60–74. 30. Sweet R, Paul A, Zastre J. Hypoxia induced upregulation mes and all-cause mortality in adults allocated to met- 26. Rabbani N, Thornalley PJ. Glyoxalase in diabetes, obe- and function of the thiamine transporter, SLC19A3 in a bre- formin: systematic review and collaborative meta-analy- sity and related disorders. Semin Cell Dev Biol 2011; 22(3): ast cancer cell line. Cancer Biol Ther 2010; 10(11): 1101–1111. sis of randomised clinical trials. Diabetologia 2012; 55(10): 309–317. 31. Richardson AD, Moscow JA. Can an enzyme cofac- 2593–2603. 27. Pacal L, Tomandl J, Svojanovsky J et al. Role of thia- tor be a factor in malignant progression? Cancer Biol Ther 22. Del Barco S, Vazquez-Martin A, Cufi S et al. Metfor- mine status and genetic variability in transketolase and 2010; 10(11): 1112–1114. min: multi-faceted protection against cancer. Oncotarget other pentose phosphate cycle enzymes in the progres- 32. Skapare E, Konrade I, Liepinsh E et al. Glyoxalase 1 and 2011; 2(12): 896–917. sion of diabetic nephropathy. Nephrol Dial Transplant glyoxalase 2 activities in blood and neuronal tissue sam- 23. Barriere G, Tartary M, Rigaud M. Metformin: a Rising 2011; 26(4): 1229–1236. ples from experimental animal models of obesity and Star to Fight The Epithelial Mesenchymal Transition in On- 28. Rabbani N, Thornalley PJ. Emerging role of thiamine type 2 diabetes mellitus. J Physiol Sci 2012. cology. Anticancer Agents Med Chem 2012. therapy for prevention and treatment of early-stage di- 33. Thornalley PJ, Rabbani N. Glyoxalase in tumourigene- 24. Brownlee M. Biochemistry and molecular cell biology of abetic nephropathy. Diabetes Obes Metab 2011; 13(7): sis and multidrug resistance. Semin Cell Dev Biol 2011; diabetic complications. Nature 2001; 414(6865): 813–820. 577–583. 22(3): 318–325. Klin Onkol 2012; 25(Suppl 2): 2S26– 2S31 2S31
You can also read
