Abstract
Oxidative stress (OS) is a state of excessive free radicals and reactive metabolites among which the most important class is reactive oxygen species (ROS) – radicals derived from oxygen – as represented by the superoxide anion radical (
Introduction
In recent years, many studies have linked oxidative stress (OS) to thyroid cancer (e.g. Senthil & Manoharan 2004, Akinci et al. 2008, Lassoued et al. 2010). These studies investigated the relationship of various individual oxidative or antioxidative molecules with thyroid cancer and provided evidence suggesting an association of OS with this cancer. In the study reported by Wang et al. (2011) in the December 2011 issue of Endocrine-Related Cancer, the authors took a further step to look at this issue and provided additional strong evidence to support an association of OS with thyroid cancer. A particularly important aspect of this study was the examination of total oxidant status and also OS index and demonstration of their strong association with thyroid cancer. These parameters likely fully reflect OS status in the body of a patient, and thus could more accurately reflect the significance of OS in relation to thyroid cancer. Moreover, a unique strength of the Wang et al. study was also the inclusion of a group of patients with autoimmune thyroid diseases for comparison. Patients with autoimmune thyroid diseases have been shown to be associated with an increased OS (e.g. Andryskowski & Owczarek 2007, Erdamar et al. 2008, Torun et al. 2009, Aslan et al. 2011). Interestingly, the Wang et al. study found a much stronger association of OS with thyroid cancer in comparison with autoimmune thyroid diseases, consistent with previous similar studies on individual oxidative or antioxidative molecules (Lassoued et al. 2010), suggesting a more important role of OS in thyroid cancer. Although the mechanism for the link between OS and thyroid cancer and whether there is a causal relationship between the two have not been directly investigated, the report of Wang et al., together with the previous studies, seems to have now firmly established the association of the two.
Oxidative stress (OS) and reactive oxygen species (ROS)
The concept of OS has developed and evolved from the original free radical theory of oxygen toxicity nearly three scores of years ago (Commoner et al. 1954, Gerschman et al. 1954). OS represents a biochemical state of excessive presence of free radicals and reactive metabolites that exhibit harmful biological effects potentially damaging the organism (Valko et al. 2007, Durackova 2010). Free radicals are molecules or molecular fragments containing one or more unpaired electrons in atomic or molecular orbitals that confer the molecules considerable reactivity. Reactive oxygen species (ROS) – radicals derived from oxygen – are the most important class of radical species generated in organisms. Thus, OS represents an imbalance between the production of oxidants – ROS – and their elimination by the protective antioxidative systems in the body. A well-known basic radical ROS molecule is superoxide anion radical (
Possible mechanisms of OS and ROS in thyroid tumorigenesis
As with thyroid cancer, OS has also been known to be associated with other cancers (Lu et al. 2006, Valko et al. 2007, Durackova 2010). Although it is not clear mechanistically how OS can play a role in the pathogenesis of thyroid cancer, it seems that excessive ROS as a consequence of imbalanced intracellular redox systems may be an important event in the molecular pathogenesis of thyroid cancer, as implicated by cancers induced by certain chemicals, such as asbestos-induced lung cancer (Stayner et al. 1996) and iron-induced colorectal cancer (Valko et al. 2001). One potential consequence of this event may be DNA damage by ROS, resulting in mutagenic genetic alterations that can initiate carcinogenesis and development of cancer. Perhaps such genetic alterations could include those that can constitutively activate major signaling pathways, such as the MAP kinase and PI3K/Akt pathways. In fact, previous studies have demonstrated that ROS, particularly H2O2, can activate the MAP kinase pathway signaling and consequent cellular proliferation (Rao & Berk 1992, Guyton et al. 1996, Aikawa et al. 1997). There are also studies showing that the PI3K/Akt and nuclear factor κB (NFκB) pathways can be activated by ROS (Poli et al. 2004, Spencer 2005, Durackova 2010). Thus, these studies demonstrate a direct role of ROS in affecting the major intracellular signaling pathways that are widely involved in human tumorigenesis.
Over activation of the MAP kinase and PI3K/Akt pathways is a fundamental mechanism in the tumorigenesis of thyroid cancer (Xing 2007, 2010). NFκB pathway also plays a role in thyroid tumorigenesis (Liu & Xing 2008, Pacifico & Leonardi 2010). It is thus plausible to propose that ROS may play a role in the pathogenesis of thyroid cancer through affecting these signaling pathways. Consequently, this may represent a mechanistic link of OS with thyroid cancer and make ROS a novel contributing factor to the pathogenesis of thyroid cancer – an interesting hypothesis that is tempting to test. As genetic alterations of the MAP kinase and PI3K/Akt pathways, such as the mutations in the BRAF, Ras, PIK3CA, and PTEN genes, are a dominant driving force for the activation of these pathways (Xing 2007, 2010), it would be interesting to see how ROS could interact or cooperate with these genetic alterations in promoting the pathogenesis and progression of thyroid cancer. Perhaps a similar clinical approach as used in the Wang et al. study could be employed to see how OS levels might be specifically linked to the aggressiveness of thyroid cancer with respect to various genetic backgrounds.
ROS can stimulate the production of matrix metalloproteinase and various cytokines such as transforming growth factor β1 (TGFβ1; Poli et al. 2004, Valko et al. 2007, Durackova 2010). This may potentially be another mechanism for the role of ROS in the pathogenesis of thyroid cancer. Recent studies have established that alterations in extracellular matrix microenvironments involving abnormal production of matrix metalloproteinases and inflammatory cytokines are a major molecular mechanism in BRAF mutant-promoted pathogenesis and progression of thyroid cancer (Nucera et al. 2011). In this process, cytokine TGFβ1 has been shown to play a particularly important role (Riesco-Eizaguirre et al. 2009, Knauf et al. 2011). Interestingly, not only expression of TGFβ1 is increased under the state of increased OS but also ROS can be downstream intermediates of TGFβ1 (Poli et al. 2004). On the other hand, one study showed that under in vitro conditions, certain ROS-enhancing agents could somehow paradoxically induce degradation of the BRAF mutant (Fukuyo et al. 2008). Thus, BRAF mutant, TGFβ1, and ROS may have a complex relationship and role in the pathogenesis of thyroid cancer.
Sources of OS and ROS in thyroid cancer
If the mechanism in the link of OS with thyroid cancer involves an active role of ROS in promoting the pathogenesis of thyroid cancer as discussed above, there needs to be a source that persistently supplies ROS in the condition of thyroid cancer. In other words, a fundamental question is how excessive ROS is produced in patients with thyroid cancer. One answer may lie in the fact that thyroid cancer, like many other cancers (Lu et al. 2006), is, in many ways, an inflammatory disease. It has become well known in recent years that thyroid cancer is often abundantly infiltrated with inflammatory cells and various important inflammatory cytokines are actively produced in thyroid cancer (Nucera et al. 2011). Some of these inflammatory cytokines have an established important role in thyroid tumorigenesis, such as TGFβ1, as discussed above (Riesco-Eizaguirre et al. 2009, Knauf et al. 2011), and thrombospondin-1 (Nucera et al. 2010). Thus, inflammatory process in thyroid cancer and the ensuing development of inflammatory microenvironments seem to be an integral part of the pathogenesis of thyroid cancer. BRAF mutation, which is the most common activating mutation in thyroid cancer and is associated with tumor progression and aggressiveness (Xing et al. 2005), could elicit strong inflammatory responses of this cancer (Nucera et al. 2011). This inflammatory environment of thyroid cancer is conceivably a significant source of ROS since inflammation is a well-established classical condition that produces high OS (Poli et al. 2004, Lu et al. 2006). It is also possible that the common oncogenic mutants in thyroid cancer, such as the BRAF mutant, could increase the production of ROS through a yet-to-be-defined non-inflammatory mechanism. Thus, an interesting mechanism could be that oncogene-promoted production of ROS in turn promotes the pathogenesis and progression of thyroid cancer by enhancing the activation of major signaling pathways initiated by oncogenes, forming a vicious cycle that propels the pathogenesis of thyroid cancer.
There may be other mechanisms by which ROS can be produced in thyroid cancer, causing a high OS state. In fact, the thyroid gland itself is a site where reactive radical molecular species are actively generated through the process of iodide metabolism and thyroid hormone synthesis. In this process, signaling of thyrotropin (TSH) acting on the TSH receptor (TSHR) on thyroid cells stimulates the synthesis of H2O2, which is the substrate of thyroperoxidase in thyroglobulin iodination and thyroid hormone synthesis (Corvilain et al. 1991). ROS is therefore generated actively in the process of TSH stimulation of thyroid cells. Differentiated thyroid cancer cells usually express functional TSHR. It is thus conceivable that such thyroid cancer cells, upon stimulation by TSH secreted by the pituitary gland, could actively produce H2O2, thus contributing to the high OS state in thyroid cancer patients.
Interestingly, several studies in recent years have demonstrated a strong association of high TSH levels with an increased malignancy risk of thyroid nodules (Boelaert et al. 2006, Haymart et al. 2009). The mechanism of this association has been unclear. Given the link of OS with thyroid cancer and the possible mechanism involving ROS in promoting thyroid tumorigenesis discussed above, stimulation of H2O2 production by TSH acting on TSHR may represent one explanation. Such a mechanism is well consistent with the previous demonstrations that ROS can activate the thyroid cancer-promoting MAP kinase, PI3K/Akt, and NFκB pathways, as discussed above.
Clinical implications of OS in thyroid cancer
Whether OS-generating conditions other than the source of thyroid cancer itself tend to exist in patients with thyroid cancer remains to be investigated. Regardless of the source, the high OS state in thyroid cancer patients may also have important non-thyroid cancer health implications in these patients. For example, since OS is associated with cardiovascular disease, diabetes mellitus, neurodegenerative disorders, and other cancers, it remains an important question whether thyroid cancer patients are predisposed to these diseases, and may therefore warrant appropriate surveillance and special prevention for such diseases. Further biological and epidemiological studies are needed to address this important issue. Whether interference in the metabolism of ROS to reduce OS by targeting the potential mechanisms discussed above or by taking antioxidative measures can be preventative and therapeutic for such diseases in thyroid cancer patients and for thyroid cancer itself remains to be an interesting question to answer.
Regardless of the source of high OS in thyroid cancer, the strong association of OS with thyroid cancer demonstrated by Wang et al. (2011) and other investigators in recent years and the plausible molecular mechanisms discussed above strongly suggest that high OS is a risk factor associated with thyroid tumorigenesis and likely a risk factor for the progression of thyroid cancer as well. There are very few known thyroid cancer risk factors, among which the best established are radiation exposure and family history of thyroid cancer, which are currently clinically used in the risk assessment of thyroid nodules (Cooper et al. 2009). Although most of the mechanistic aspects or hypotheses discussed above regarding the role of OS in thyroid cancer remain to be directly tested, it seems to be convincing that high OS represents a new risk factor for thyroid cancer. It is thus tempting to propose that testing of OS, particularly in the form of total oxidant status and OS index as proposed by Wang et al. (2011), may be clinically useful in the risk assessment of thyroid nodules.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
M Xing was supported by the National Institutes of Health R0-1 grant R01CA134225.
References
Aikawa R, Komuro I, Yamazaki T, Zou Y, Kudoh S, Tanaka M, Shiojima I, Hiroi Y & Yazaki Y 1997 Oxidative stress activates extracellular signal-regulated kinases through Src and Ras in cultured cardiac myocytes of neonatal rats. Journal of Clinical Investigation 100 1813–1821. doi:10.1172/JCI119709.
Akinci M, Kosova F, Cetin B, Sepici A, Altan N, Aslan S & Cetin A 2008 Oxidant/antioxidant balance in patients with thyroid cancer. Acta Cirúrgica Brasileira 23 551–554. doi:10.1590/S0102-86502008000600013.
Andryskowski G & Owczarek T 2007 The evaluation of selected oxidative stress parameters in patients with hyperthyroidism. Polish Archives of Internal Medicine 117 285–289.
Aslan M, Cosar N, Celik H, Aksoy N, Dulger AC, Begenik H, Soyoral YU, Kucukoglu ME & Selek S 2011 Evaluation of oxidative status in patients with hyperthyroidism. Endocrine 40 285–289. doi:10.1007/s12020-011-9472-3.
Boelaert K, Horacek J, Holder RL, Watkinson JC, Sheppard MC & Franklyn JA 2006 Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. Journal of Clinical Endocrinology and Metabolism 91 4295–4301. doi:10.1210/jc.2006-0527.
Commoner B, Townsend J & Pake GE 1954 Free radicals in biological materials. Nature 174 689–691. doi:10.1038/174689a0.
Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F & Schlumberger M et al. 2009 Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 11 1167–1214.
Corvilain B, van Sande J, Laurent E & Dumont JE 1991 The H2O2-generating system modulates protein iodination and the activity of the pentose phosphate pathway in dog thyroid. Endocrinology 128 779–785. doi:10.1210/endo-128-2-779.
Dröge W 2002 Free radicals in the physiological control of cell function. Physiological Reviews 82 47–95.
Durackova Z 2010 Some current insights into oxidative stress. Physiological Research 59 459–469.
Erdamar H, Demirci H, Yaman H, Erbil MK, Yakar T, Sancak B, Elbeg S, Biberoğlu G & Yetkin I 2008 The effect of hypothyroidism, hyperthyroidism, and their treatment on parameters of oxidative stress and antioxidant status. Clinical Chemistry and Laboratory Medicine 46 1004–1010. doi:10.1515/CCLM.2008.183.
Fukuyo Y, Inoue M, Nakajima T, Higashikubo R, Horikoshi NT, Hunt C, Usheva A, Freeman ML & Horikoshi N 2008 Oxidative stress plays a critical role in inactivating mutant BRAF by geldanamycin derivatives. Cancer Research 68 6324–6330. doi:10.1158/0008-5472.CAN-07-6602.
Gerschman R, Gilbert DL, Nye SW, Dwyer P & Fenn WO 1954 Oxygen poisoning and X-irradiation – a mechanism in common. Science 119 623–626. doi:10.1126/science.119.3097.623.
Guyton KZ, Liu Y, Gorospe M, Xu Q & Holbrook NJ 1996 Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury. Journal of Biological Chemistry 271 4138–4142. doi:10.1074/jbc.271.7.3604.
Haymart MR, Glinberg SL, Liu J, Sippel RS, Jaume JC & Chen H 2009 Higher serum TSH in thyroid cancer patients occurs independent of age and correlates with extrathyroidal extension. Clinical Endocrinology 71 434–439. doi:10.1111/j.1365-2265.2008.03489.x.
Knauf JA, Sartor MA, Medvedovic M, Lundsmith E, Ryder M, Salzano M, Nikiforov YE, Giordano TJ, Ghossein RA & Fagin JA 2011 Progression of BRAF-induced thyroid cancer is associated with epithelial–mesenchymal transition requiring concomitant MAP kinase and TGFβ signaling. Oncogene 30 3153–3162. doi:10.1038/onc.2011.44.
Lassoued S, Mseddi M, Mnif F, Abid M, Guermazi F, Masmoudi H, El Feki A & Attia H 2010 A comparative study of the oxidative profile in Graves' disease, Hashimoto's thyroiditis, and papillary thyroid cancer. Biological Trace Element Research 138 107–115. doi:10.1007/s12011-010-8625-1.
Liu D & Xing M 2008 Potent inhibition of thyroid cancer cells by the MEK inhibitor PD0325901 and its potentiation by suppression of the PI3K and NF-kappaB pathways. Thyroid 18 853–864. doi:10.1089/thy.2007.0357.
Lu H, Ouyang W & Huang C 2006 Inflammation, a key event in cancer development. Molecular Cancer Research 4 221–233. doi:10.1158/1541-7786.MCR-05-0261.
Nucera C, Porrello A, Antonello ZA, Mekel M, Nehs MA, Giordano TJ, Gerald D, Benjamin LE, Priolo C & Puxeddu E et al. 2010 B-Raf(V600E) and thrombospondin-1 promote thyroid cancer progression. PNAS 107 10649–10654. doi:10.1073/pnas.1004934107.
Nucera C, Lawler J & Parangi S 2011 BRAF(V600E) and microenvironment in thyroid cancer: a functional link to drive cancer progression. Cancer Research 71 2417–2422. doi:10.1158/0008-5472.CAN-10-3844.
Pacifico F & Leonardi A 2010 Role of NF-kappaB in thyroid cancer. Molecular and Cellular Endocrinology 321 29–35. doi:10.1016/j.mce.2009.10.010.
Poli G, Leonarduzzi G, Biasi F & Chiarpotto E 2004 Oxidative stress and cell signalling. Current Medicinal Chemistry 11 1163–1182.
Rao GN & Berk BC 1992 Active oxygen species stimulate vascular smooth muscle cell growth and proto-oncogene expression. Circulation Research 70 593–599.
Riesco-Eizaguirre G, Rodríguez I, De la Vieja A, Costamagna E, Carrasco N, Nistal M & Santisteban P 2009 The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. Cancer Research 69 8317–8325. doi:10.1158/0008-5472.CAN-09-1248.
Senthil N & Manoharan S 2004 Lipid peroxidation and antioxidants status in patients with papillary thyroid carcinoma in India. Asia Pacific Journal of Clinical Nutrition 13 391–395.
Spencer JPE 2005 Interactions of flavonoids and their metabolites with cell signaling cascades. In Nutrigenomics, pp 353–377. Eds G Rimbach, J Fuchs & L Packer. Boca Raton: Taylor & Francis Publishing
Stayner LT, Dankovic DA & Lemen RA 1996 Occupational exposure to chrysotile asbestos and cancer risk: A review of the amphibole hypothesis. American Journal of Public Health 86 179–186. doi:10.2105/AJPH.86.2.179.
Torun AN, Kulaksizoglu S, Kulaksizoglu M, Pamuk BO, Isbilen E & Tutuncu NB 2009 Serum total antioxidant status and lipid peroxidation marker malondialdehyde levels in overt and subclinical hypothyroidism. Clinical Endocrinology 70 469–474. doi:10.1111/j.1365-2265.2008.03348.x.
Valko M, Morris H, Mazur M, Rapta P & Bilton RF 2001 Oxygen free radical generating mechanisms in the colon: do the semiquinones of vitamin K play a role in the etiology of colon cancer? Biochimica et Biophysica Acta 1527 161–166. doi:10.1016/S0304-4165(01)00163-5.
Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M & Telser J 2007 Free radicals and antioxidants in normal physiological functions and human disease. International Journal of Biochemistry & Cell Biology 39 44–84. doi:10.1016/j.biocel.2006.07.001.
Wang D, Feng J, Zeng P, Yang Y, Luo J & Yang Y 2011 Total oxidant/antioxidant status in sera of patients with thyroid cancers. Endocrine-Related Cancer 18 773–782. doi:10.1530/ERC-11-0230.
Xing M 2007 BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocrine Reviews 28 742–762. doi:10.1210/er.2007-0007.
Xing M 2010 Genetic alterations in the phosphatidylinositol-3 kinase/Akt pathway in thyroid cancer. Thyroid 20 697–706. doi:10.1089/thy.2010.1646.
Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, Carson KA, Vasko V, Larin A & Tallini G et al. 2005 BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. Journal of Clinical Endocrinology and Metabolism 90 6373–6379. doi:10.1210/jc.2005-0987.
