Energy metabolic dysfunction as a carcinogenic factor in cancer cells
© Sun et al. 2016
Received: 28 November 2015
Accepted: 29 March 2016
Published: 6 April 2016
Cancer, as a leading cause of death, has attracted enormous public attention. Reprogramming of cellular energy metabolism is deemed to be one of the principal hallmarks of cancer. In this article, we reviewed the mutual relationships among environmental pollution factors, energy metabolic dysfunction, and various cancers. We found that most environmental pollution factors could induce cancers mainly by disturbing the energy metabolism. By triggering microenvironment alteration, energy metabolic dysfunction can be treated as a factor in carcinogenesis. Thus, we put forward that energy metabolism might be as a key point for studying carcinogenesis and tumor development to propose new methods for cancer prevention and therapy.
To date, cancer has become a major public health problem and has caused global-scale morbidity and mortality in modern society. With approximately 14 million new cases and 8 million cancer-related deaths in 2012, cancer affects populations in all countries and all regions . One of the main characteristics of cancer cells is limitless replication potential , which results in high energy requirement. Cancer cells also deregulate energy homeostasis . Thus we cannot ignore the strong connection between cancers and energy metabolism, Accordingly, seeking new effective therapeutic methods for cancers from the perspective of energy metabolic dysfunction as a carcinogenesis factor could be possible.
Energy metabolism is one of the most basic characteristics of living organisms. It is associated with the progress of metabolic reactions catalyzed by a variety of enzymes. The mitochondria are crucial in energy metabolism . Most of the cellular energy required for various biological functions is provided by the mitochondria through oxidative phosphorylation .
Carcinogenesis and energy metabolism can be both influenced by the environment. Growing evidence has demonstrated that several environmental factors, including physical, chemical, and biological environmental factors, can disturb cellular energy metabolism. When energy metabolic dysfunction occurs, the living cell microenvironment and surroundings encounter alterations, which may become conducive to cancer cell proliferation. Leading alterations include acidity  and interstitial fluid pressure  in the microenvironment, such alterations can promote risks of carcinogenesis. Besides this, hypoxic microenvironment is tightly correlated with cancer progression as well . Therefore, environmental pollution factors can disturb energy homeostasis by triggering microenvironment alteration, thereby increasing carcinogenic risks.
In general, we briefly review the relationships among energy metabolism, cancers, tumor microenvironment, and environmental factors, to attempt to provide new perspectives on cancer prevention and treatment.
Energy metabolism disorders in cancer cells
Since Warburg reported that tumor cells in living organisms were associated with abnormal energy utilization , this phenomenon has continuously attracted research attention. Warburg first noted the increased intake of glucose and lactate production even in the presence of oxygen (aerobic glycolysis) in tumor cells, subsequently this phenomenon was named the “Warburg effect”. The Warburg effect has been implicated in cell transformation, immortalization, and proliferation during tumorigenesis . At present, most studies have demonstrated that energy metabolic dysfunction is one of the major features of cancer cells, and it can be driven by multiple factors, such as the effect of oncogenes, tumor suppressors, mitochondrial DNA (mtDNA) mutations, and signal pathways, etc. .
Several researches suggested that the altered metabolism with aerobic glycolysis was a feature of cancers rather than a cause . In malignant melanoma cells, the oncogene BRAF upholds the activity of glycolysis and therefore the addiction to glycolysis becomes an addiction to BRAF . Furthermore, tumor suppressor p53 has been proven to be related to several energy metabolic pathways in cancer cells, such as the tricarboxylic acid cycle (TCA cycle), glucose transportation, and glycolysis . Growing evidence also indicated that mtDNA mutations can increase the reactive oxygen species (ROS) production and contribute to tumorigenesis through the inhibition of oxidative phosphorylation . What’s more, several signal pathways involved in energy metabolism in cancer cells show abnormal conditions in compared with those in normal cells. The Akt-signal pathway mediates multiple cell activities, including cell cycle, apoptosis, and glycogen synthesis, which are all perturbed in cancer cells. The Akt-signal pathway has well been reported to be involved in the regulation of intracellular glucose levels favoring hexokinase-mitochondria interaction [16, 17]. In particular, PI3 K–Akt–mTOR signaling, plays an important role in coordinating metabolism and promoting cell survival, and the specific contributions of Akt hyperactivation to oncogenes have been attributed to its fundamental roles in cellular energy metabolism of inhibiting apoptosis, increasing cell proliferation, and accelerating oncogenic mutation rates .
Aside from the Warburg effect found in cancer cells, other abnormal energy metabolic alterations have been studied in recent years. The lower ATP generating efficiency of glycolysis in comparison with oxidative phosphorylation makes the cancer cells with more glucose uptake. Therefore, glucose transporters, which are transmembrane proteins in a series, were reported to be upregulated in various cancers [19, 20]. Glutaminolysis alteration also occurs in cancer cells . Increasing evidence indicated that elevated expression of glutaminase enhanced glucose utilization by glutaminolysis in prostate cancer , and the function of glutaminolysis regulation has been discussed by scientists . Several reports have asserted that glutamine can be involved in multiple energy metabolism-related processes, including TCA cycle, gluconeogenic precursor, and lipogenic precursor, etc. therefore cancer cells benefit from the activation of glutaminolysis, which can also promote the pentose phosphate pathway to generate more NADPH. Consequently, NADPH can generate reduced glutathione (GSH) and decrease the ROS levels to protect the cancer cells from excessive oxidative stress .
However, a recent scientific report has proposed an evolutionary theory that challenges the current understanding on cancers, suggesting that cancers are the generated products of tissue microenvironment alteration . Microenvironment alteration can be tightly linked with cell energy metabolic dysfunction. Some oncogenic mutations gain the upper hand and develop into malignant tumors because the ‘ecosystem’ of a tissue is altered in abnormal situations . The said report provides new perspectives on the mechanisms of carninogenesis and for better therapetic methods for cancers. Given the potential relationship between microenvironment and cancers, we first summarize the driving environmental factors of cancer-linked energy metabolic dysfunction.
Environmental factors contributing to energy metabolism dysfunction
Carcinogenic environmental factors are divided into three types according to their properties, namely, physical, chemical, and biological factors. Among the physical factors, the most familiar factor is light, especially ultraviolet, which promotes risks of cancer generation by inducing gene mutations and disturbing glycolysis . Thus, energy metabolism might be altered through the exposure to ultraviolet, and such alteration might be relate to cancer generation. Electricity is another physical environmental factor linked to energy dysfunction. Ionizing radiation can induce endogenously generated ROS. High intra-mitochondrial ROS levels damage the mt DNA and those mutations can affect the epigenetic control mechanisms of the nuclear DNA by decreasing the activity of methyltransferases, thus causing global DNA hypomethylation . These changes might increase the risks of mutation among energy metabolism-related genes and activate the epigenetic regulation of cellular energy homeostasis. Our recent study on the effect of electromagnetic field on energy metabolism of Caenorhabditis elegans has shown an upregulation of the gene expression of glycolysis-related enzymes at mRNA levels , suggesting that the relationships between this alteration and carcinogenic risks should be further investigated.
With regard to the diversified effective mechanisms of chemical factors on energy metabolism, one of the traditional perspectives implied that cancers are associated with genetic toxicity. Several chemicals can directly or indirectly result in DNA damage (mtDNA or nuclear DNA damage) [28, 29]. For example, chemicals may bind to DNA to initiate a complexity or disorder in DNA repair; as such, energy-related cell activities, such as cell proliferation, cannot be controlled. Moreover, growing evidence has shown that the mutation of ALDH2 involved in the oxidative pathway of alcohol metabolism can promote hepatocarcinogenesis in murine . Polychlorinated biphenyls, which are potent inducers of toxic ROS, have been reported to be capable of inducing DNA damage and activating oxidative stress responses . Besides the mutational events in chemical carcinogenesis, epigenetic alterations also affect the metabolism of cells and may be crucial for the development of cancer cells [32, 33]. Chemicals can also cause tumors by mechanisms other than directly damaging DNA. Mounting evidence indicates that the disruption of epigenetic balance can lead to diseases, including cancers. The contributions of various environmental, non-genotoxic carcinogens, such as polycyclic aromatic hydrocarbons, benzene, and N-nitrosamines, to induce methylome changes associated with oncogenic progression have been shown in lung, colorectal, and liver oncogenesis, as well as leukemogenesis [34, 35]. Metals such as lead, nickel, cobalt, and mercury have been reported to disrupt DNA repair, with nickel affecting epigenetic histone modification and causing defective telomere maintenance [36, 37]. A number of key metabolites, including SAM, acetyl-CoA, NAD(+), and ATP, serve as essential co-factors for many, perhaps most, epigenetic enzymes that regulate DNA methylation, post-translational histone modifications, and nucleosome position . Thus, chemical factors inducing the abnormal levels of energy metabolites can increase the carcinogenic risks. For instance, benzene poisoning increased the content level of lipid peroxidation products and mitochondrial energetic activities , and high peroxidation products level was reported to induce epigenetic alterations in human carcinogenesis .
For the biological factors that can affect the mentioned energy metabolic levels, we mainly focused on the influence of microorganisms. Viral, bacterial and fungal infections can all affect the energy utilization of the body and perturb the balance of cell metabolic activities [41–43]. The relationship between infection and cancers is a perennial object of study. Among these researches and clinical cases, Rous et al. first reported the biological and chemical pathogenic effects on cancers, and demonstrated the connection between cancer susceptibility and body alteration induced by infection . From the in-depth study on Helicobacter pylori (HP) infection, several findings have suggested that HP infection is linked to the pathogenesis of gastric cancer to some extent, and a key energy-metabolism related enzyme has been investigated simultaneously . HP infection can induce instability in mtDNA , and mutations in mtDNA can activate the mitochondrial oxidative phosphorylation pathway , further influencing energy generation and utilization. Additionally, human papillomavirus (HPV) infection has been proven correlated with colorectal cancer , cervical cancer , and head and neck cancer . Biological environmental factors, including hepatitis B and hepatitis C viruses (HBV and HCV), are considered among the main causes of hepatocellular carcinoma, which should not be ignored as well . Hence, the potential of energy metabolic dysfunction to increase carcinogenic risks induced by biological factors need to be examined further.
Environmental factors contributing to carcinogenesis and cancer progression by microenvironment disruption
In carcinogenesis and cancer development, carcinogenic factors and co-carcinogenic factors are highly correlated with the human living environment and activities. Complex multi-functional environmental factors can alter the concentration and constituents of tissue metabolites. The microenvironment of living cells can be a potential driving factor of carcinogenesis.
Numerous researchers have concluded that tissue microenvironment is an important determinant of carcinogenesis. One of the contributing factors to cancer cell adaptation is a hypoxic environment . Hypoxia is associated with increased metastatic potential, development of resistance to therapies, and poor prognosis . Hypoxic stress can activate the HIF-signal pathway, which presents a strong relationship with the energy metabolic process, especially in regulating the triosephosphate isomerase expression . Energy metabolic dysfunction can promote the establishment of a hypoxic microenvironment, particularly through abnormal mitochondrial aerobic respiration and increased rate of glycolysis. An acidic tissue microenvironment is also correlated with energy metabolic dysfunction, mainly because a high rate of glycolysis generates a large amount of lactic acid, which promotes the generation of acidic tissue microenvironment . Another contributing factor is elevated interstitial fluid pressure (IFP). The mechanism for elevated IFP was reported to be the dysfunction of the lymphatic system ; such dysfunction can help cancer cells escape from the attack of functional lymphatics and create conducive conditions for various metabolites and cell growth factors and cytokines .
To emphasize the importance and complexity of the microenvironment to cancers, we discuss how environmental factors, such as physical, chemical and biological factors, alter the microenvironment. For physical factors, several scientists have reported that radiation can induce aerobic glycolysis through ROS generation . Extracellular acidification of the microenvironment has been ascribed to lactate secretion from glycolysis . Therefore, radiation can act on the tumor microenvironment by regulating glycolysis. Chemical environmental factors, including various natural chemical metabolites and synthetic chemicals, affect cellular microenvironments in different ways. One of the approaches disruptive chemicals contribute to the tumor microenvironment is perturbing energy homeostasis. For example, chemicals affect the gene expression of enzymes involved in energy metabolism, thereby promoting the rapid growth and proliferation of cells . The persistently high level of energy utilization can establish a hypoxia microenvironment for the initiation and development of cancers .
YS, ZS, HL and PC contributed to the writing of this paper. All authors read and approved the final manuscript.
We are grateful for the support from Scientific Equipment Development Project of Chinese Academy of Sciences (CAS) (YZ201104 and YZ201205), Xiamen Science and Technology Plans Project (3502Z20126012), National Natural Science Foundation of China (31270888) and Natural Science Foundation of Fujian Province (2012J01157).
The authors declare that they have no competing interests.
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- Cancer IAfRo (2014) World cancer report 2014. WHO, Geneva
- Marahatta SB, Sharma N, Koju R, Makaju RK, Petmitr P, Petmitr S (2005) Cancer: determinants and progression. Nepal Med Coll J 7:65–71PubMedGoogle Scholar
- Ashrafian H, Ahmed K, Rowland SP, Patel VM, Gooderham NJ, Holmes E et al (2011) Metabolic surgery and cancer: protective effects of bariatric procedures. Cancer 117:1788–1799View ArticlePubMedGoogle Scholar
- Wallace DC (2012) Mitochondria and cancer. Nat Rev Cancer 12:685–698View ArticlePubMedPubMed CentralGoogle Scholar
- Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS (2004) Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol 287:C817–C833View ArticlePubMedGoogle Scholar
- Navratilova J, Hankeova T, Benes P, Smarda J (2013) Acidic pH of tumor microenvironment enhances cytotoxicity of the disulfiram/Cu2+ complex to breast and colon cancer cells. Chemotherapy 59:112–120View ArticlePubMedGoogle Scholar
- Milosevic MF, Pintilie M, Hedley DW, Bristow RG, Wouters BG, Oza AM et al (2014) High tumor interstitial fluid pressure identifies cervical cancer patients with improved survival from radiotherapy plus cisplatin versus radiotherapy alone. Int J Cancer 135:1692–1699View ArticlePubMedGoogle Scholar
- Semenza GL (2015) The hypoxic tumor microenvironment: a driving force for breast cancer progression. Biochim Biophys Acta 1863:382–391View ArticlePubMedGoogle Scholar
- Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8:519–530View ArticlePubMedPubMed CentralGoogle Scholar
- Oliveira PF, Martins AD, Moreira AC, Cheng CY, Alves MG (2015) The Warburg effect revisited–lesson from the Sertoli cell. Med Res Rev 35:126–151View ArticlePubMedGoogle Scholar
- Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13:472–482View ArticlePubMedGoogle Scholar
- Harris AL (2002) Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47View ArticlePubMedGoogle Scholar
- Hall A, Meyle KD, Lange MK, Klima M, Sanderhoff M, Dahl C et al (2013) Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the (V600E)BRAF oncogene. Oncotarget 4:584–599View ArticlePubMedPubMed CentralGoogle Scholar
- Chen JQ, Russo J (2012) Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells. Biochim Biophys Acta 1826:370–384PubMedGoogle Scholar
- Petros JA, Baumann AK, Ruiz-Pesini E, Amin MB, Sun CQ, Hall J et al (2005) mtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci USA 102:719–724View ArticlePubMedPubMed CentralGoogle Scholar
- Robey RB, Hay N (2006) Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene 25:4683–4696View ArticlePubMedGoogle Scholar
- Robey RB, Weisz J, Kuemmerle NB, Salzberg AC, Berg A, Brown DG et al (2015) Metabolic reprogramming and dysregulated metabolism: cause, consequence and/or enabler of environmental carcinogenesis? Carcinogenesis 36(Suppl 1):S203–S231View ArticlePubMedGoogle Scholar
- Lim HJ, Crowe P, Yang JL (2015) Current clinical regulation of PI3 K/PTEN/Akt/mTOR signalling in treatment of human cancer. J Cancer Res Clin Oncol 141:671–689View ArticlePubMedGoogle Scholar
- Krzeslak A, Wojcik-Krowiranda K, Forma E, Jozwiak P, Romanowicz H, Bienkiewicz A et al (2012) Expression of GLUT1 and GLUT3 glucose transporters in endometrial and breast cancers. Pathol Oncol Res: POR 18:721–728View ArticlePubMedPubMed CentralGoogle Scholar
- Szablewski L (2013) Expression of glucose transporters in cancers. Biochim Biophys Acta 1835:164–169PubMedGoogle Scholar
- Friday E, Oliver R 3rd, Welbourne T, Turturro F (2011) Glutaminolysis and glycolysis regulation by troglitazone in breast cancer cells: relationship to mitochondrial membrane potential. J Cell Physiol 226:511–519View ArticlePubMedGoogle Scholar
- Pan T, Gao L, Wu G, Shen G, Xie S, Wen H et al (2015) Elevated expression of glutaminase confers glucose utilization via glutaminolysis in prostate cancer. Biochem Biophys Res Commun 456:452–458View ArticlePubMedGoogle Scholar
- Dang CV (2010) Glutaminolysis: supplying carbon or nitrogen or both for cancer cells? Cell Cycle 9:3884–3886View ArticlePubMedGoogle Scholar
- Rozhok AI, DeGregori J (2015) Toward an evolutionary model of cancer: considering the mechanisms that govern the fate of somatic mutations. Proc Natl Acad Sci USA 112:8914–8921View ArticlePubMedPubMed CentralGoogle Scholar
- Kricker A, Armstrong BK, McMichael AJ (1994) Skin cancer and ultraviolet. Nature 368:594View ArticlePubMedGoogle Scholar
- Szumiel I (2015) Ionizing radiation-induced oxidative stress, epigenetic changes and genomic instability: the pivotal role of mitochondria. Int J Radiat Biol 91:1–12View ArticlePubMedGoogle Scholar
- Shi Z, Yu H, Sun Y, Yang C, Lian H, Cai P (2015) The energy metabolism in caenorhabditis elegans under the extremely low-frequency electromagnetic field exposure. Sci Rep 5:8471View ArticlePubMedPubMed CentralGoogle Scholar
- Teitelbaum SL, Belpoggi F, Reinlib L (2015) Advancing research on endocrine disrupting chemicals in breast cancer: expert panel recommendations. Reprod Toxicol 54:141–147View ArticlePubMedPubMed CentralGoogle Scholar
- Antwi SO, Eckert EC, Sabaque CV, Leof ER, Hawthorne KM, Bamlet WR et al (2015) Exposure to environmental chemicals and heavy metals, and risk of pancreatic cancer. Cancer Causes Control 26:1583–1591View ArticlePubMedGoogle Scholar
- Jin S, Chen J, Chen L, Histen G, Lin Z, Gross S et al (2015) ALDH2(E487 K) mutation increases protein turnover and promotes murine hepatocarcinogenesis. Proc Natl Acad Sci USA 112:9088–9093View ArticlePubMedPubMed CentralGoogle Scholar
- Li R, Cao S, Dai J, Wang L, Li L, Wang Y et al (2014) Effect of caffeic acid derivatives on polychlorinated biphenyls induced hepatotoxicity in male mice. J Biomed Res 28:423–428PubMedPubMed CentralGoogle Scholar
- Tabish AM, Poels K, Hoet P, Godderis L (2012) Epigenetic factors in cancer risk: effect of chemical carcinogens on global DNA methylation pattern in human TK6 cells. PLoS ONE 7:e34674View ArticlePubMedPubMed CentralGoogle Scholar
- Koturbash I, Beland FA, Pogribny IP (2011) Role of epigenetic events in chemical carcinogenesis–a justification for incorporating epigenetic evaluations in cancer risk assessment. Toxicol Mech Methods 21:289–297View ArticlePubMedGoogle Scholar
- Casey SC, Vaccari M, Al-Mulla F, Al-Temaimi R, Amedei A, Barcellos-Hoff MH et al (2015) The effect of environmental chemicals on the tumor microenvironment. Carcinogenesis 36(Suppl 1):S160–S183View ArticlePubMedGoogle Scholar
- Pogribny IP, Beland FA (2013) DNA methylome alterations in chemical carcinogenesis. Cancer Lett 334:39–45View ArticlePubMedGoogle Scholar
- Arita A, Niu J, Qu Q, Zhao N, Ruan Y, Nadas A et al (2012) Global levels of histone modifications in peripheral blood mononuclear cells of subjects with exposure to nickel. Environ Health Perspect 120:198–203View ArticlePubMedPubMed CentralGoogle Scholar
- Chervona Y, Arita A, Costa M (2012) Carcinogenic metals and the epigenome: understanding the effect of nickel, arsenic, and chromium. Metallomics 4:619–627View ArticlePubMedPubMed CentralGoogle Scholar
- Donohoe DR, Bultman SJ (2012) Metaboloepigenetics: interrelationships between energy metabolism and epigenetic control of gene expression. J Cell Physiol 227:3169–3177View ArticlePubMedPubMed CentralGoogle Scholar
- Trifonov Iu A, Turdyev AA, Tiunov LA, Ivanov VI, Voloshin SV (1989) Oxidative phosphorylation and lipid peroxidation of the liver mitochondria in rats after acute benzene poisoning. Gig Sanit 3:32–34PubMedGoogle Scholar
- Ziech D, Franco R, Pappa A, Panayiotidis MI (2011) Reactive oxygen species (ROS)–induced genetic and epigenetic alterations in human carcinogenesis. Mutat Res 711:167–173View ArticlePubMedGoogle Scholar
- Decsi T, Koletzko B (2000) Effects of protein-energy malnutrition and human immunodeficiency virus-1 infection on essential fatty acid metabolism in children. Nutrition 16:447–453View ArticlePubMedGoogle Scholar
- Paton NI, Angus B, Chaowagul W, Simpson AJ, Suputtamongkol Y, Elia M et al (2001) Protein and energy metabolism in chronic bacterial infection: studies in melioidosis. Clin Sci (Lond) 100:101–110View ArticleGoogle Scholar
- Staats CC, Kmetzsch L, Schrank A, Vainstein MH (2013) Fungal zinc metabolism and its connections to virulence. Front Cell Infect Microbiol 3:65View ArticlePubMedPubMed CentralGoogle Scholar
- MacKenzie I, Rous P (1941) The experimental disclosure of latent neoplastic changes in tarred skin. J Exp Med 73:391View ArticlePubMedPubMed CentralGoogle Scholar
- Guo XL, Wang LE, Du SY, Fan CL, Li L, Wang P et al (2003) Association of cyclooxygenase-2 expression with Hp-cagA infection in gastric cancer. World J Gastroenterol 9:246–249View ArticlePubMedPubMed CentralGoogle Scholar
- Machado AM, Figueiredo C, Touati E, Maximo V, Sousa S, Michel V et al (2009) Helicobacter pylori infection induces genetic instability of nuclear and mitochondrial DNA in gastric cells. Clin Cancer Res 15:2995–3002View ArticlePubMedGoogle Scholar
- CarewJS HP (2002) Mitochondrial defects in cancer. Mol Cancer 1:9View ArticleGoogle Scholar
- Li YX, Zhang L, Simayi D, Zhang N, Tao L, Yang L et al (2015) Human papillomavirus infection correlates with inflammatory Stat3 signaling activity and IL-17 level in patients with colorectal cancer. PLoS ONE 10:e0118391View ArticlePubMedPubMed CentralGoogle Scholar
- Asih TS, Lenhart S, Wise S, Aryati L, Adi-Kusumo F, Hardianti MS et al (2015) The dynamics of HPV infection and cervical cancer cells. Bull Math Biol 16:1–7Google Scholar
- Field N, Lechner M (2015) Exploring the implications of HPV infection for head and neck cancer. Sex Transm Infect 91:229–230View ArticlePubMedPubMed CentralGoogle Scholar
- Chuang SC, La Vecchia C, Boffetta P (2009) Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection. Cancer Lett 286:9–14View ArticlePubMedGoogle Scholar
- Beck KR, Tan SM, Lum SS, Lim LE, Krishna LK (2014) Validation of the emotion thermometers and hospital anxiety and depression scales in Singapore: screening cancer patients for distress, anxiety and depression. Asia Pac J Clin Oncol. doi:10.1111/ajco.12180 PubMedGoogle Scholar
- Muirhead L (2014) Cancer risk factors among adults with serious mental illness. Am J Prev Med 46:S98–S103View ArticlePubMedGoogle Scholar
- Zou C, Yu S, Xu Z, Wu D, Ng CF, Yao X et al (2014) ERRalpha augments HIF-1 signalling by directly interacting with HIF-1alpha in normoxic and hypoxic prostate cancer cells. J Pathol 233:61–73View ArticlePubMedGoogle Scholar
- Gess B, Hofbauer KH, Deutzmann R, Kurtz A (2004) Hypoxia up-regulates triosephosphate isomerase expression via a HIF-dependent pathway. Pflugers Arch 448:175–180View ArticlePubMedGoogle Scholar
- Rotin D, Robinson B, Tannock IF (1986) Influence of hypoxia and an acidic environment on the metabolism and viability of cultured cells: potential implications for cell death in tumors. Cancer Res 46:2821–2826PubMedGoogle Scholar
- DiResta GR, Lee J, Healey JH, Levchenko A, Larson SM, Arbit E (2000) Artificial lymphatic system: a new approach to reduce interstitial hypertension and increase blood flow, pH and pO2 in solid tumors. Ann Biomed Eng 28:543–555View ArticlePubMedGoogle Scholar
- Rofstad EK, Galappathi K, Mathiesen BS (2014) Tumor interstitial fluid pressure-a link between tumor hypoxia, microvascular density, and lymph node metastasis. Neoplasia 16:586–594View ArticlePubMedPubMed CentralGoogle Scholar
- Zhong J, Rajaram N, Brizel DM, Frees AE, Ramanujam N, Batinic-Haberle I et al (2013) Radiation induces aerobic glycolysis through reactive oxygen species. Radiother Oncol 106:390–396View ArticlePubMedPubMed CentralGoogle Scholar
- Kato Y, Ozawa S, Miyamoto C, Maehata Y, Suzuki A, Maeda T et al (2013) Acidic extracellular microenvironment and cancer. Cancer Cell Int 13:89View ArticlePubMedPubMed CentralGoogle Scholar
- Kakehashi A, Wei M, Fukushima S, Wanibuchi H (2013) Oxidative stress in the carcinogenicity of chemical carcinogens. Cancers (Basel) 5:1332–1354View ArticlePubMed CentralGoogle Scholar
- Yin C, Qie S, Sang N (2012) Carbon source metabolism and its regulation in cancer cells. Crit Rev Eukaryot Gene Expr 22:17–35View ArticlePubMedPubMed CentralGoogle Scholar