Sitagliptina e proteção em ca diferenciado da tireóide.x


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Câncer diferenciado da tireóide pode ter efeito protetor da sitagliptina.

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Sitagliptina e proteção em ca diferenciado da tireóide.x

  1. 1. Do anti-diabetic medications play a specific role in differentiated thyroid cancercompared to other cancer types?Eleonore Fröhlich1,2 and Richard Wahl11 Internal Medicine, Dept. of Endocrinology, M etabolism, Nephrology, Angiology andClinical Chemistry, University of Tuebingen, Otfried-Muellerstrasse 10, D-72076 Tuebingen,Germany; 2 Center for Medical Research, Medical University Graz, Stiftingtalstr. 24, A-8010GrazAbstractThe risk for differentiated thyroid cancer, like for many other types of cancer, is increased inobese individuals and people with intermediate hyperglycaemia. The incidence of all cancers,with the exception of thyroid cancer, is also increased in type 2 diabetes mellitus patients. Thereview compares the prevalence of thyroid carcinoma and other cancers in obese, people withintermediate hyperglycaemia and diabetic patients and summarizes mode of action and anti-tumorigenic effect of common anti-diabetic medications. The over-expression of dipeptidylpeptidase IV in the tumors, not seen in the other cancer types, is suggested as a potentialreason for the unique situation in thyroid cancer.Keywords:Thyroid carcinoma, diabetes, sulfonylureas, thiazolidinediones, biguanides, dipeptidylpeptidase IVAbbreviationsABL tyrosine kinase: Abelson leukemia virus tyrosine kinase; AKT: protein kinase B;AMPK: adenosine monophosphate-activated protein kinase; bFGF: basic fibroblast growthfactor; BGs: biguanides; CDK: cyclin dependent kinase; CREB: cAMP response element-binding protein; DM: diabetes mellitus; DPP IV: dipeptidyl peptidase IV; 4E-BP1: 4E-binding protein-1, GLP-1: Glucagon-like peptide 1; HDAC: histone deacetylase; IGF-1:Insulin-like growth factor 1; IGF1R: IGF-1 receptor; IR: Insulin receptor; IR-A: Insulinreceptor isoform A; IRS-1: insulin receptor substrate 1; LKB1: serine/threonine kinase 11;This is an Accepted Article that has been peer-reviewed and approved for publication in the Diabetes,Obesity and Metabolism, but has yet to undergo copy-editing and proof correction. Please cite thisarticle as an "Accepted Article"; doi: 10.1111/j.1463-1326.2011.01491.x
  2. 2. MAPK: Mitogen-activated protein kinase; MIG: monokine induced by interferon γ, mTOR:mammalian target of rapamycin; PI3K: phosphatidylinositol 3-kinase; SUs: sulfonylureas;SDF-1alpha: stromal-cell-derived factor 1α, S6K: ribosomal S6 kinase; TNF-α: tumornecrosis factor alpha; TZDs: thiazolidinediones; X-Pro: dipeptide X-proline
  3. 3. Thyroid neoplasms are within the top twenty most common cancers, although compared tocommon cancers such as breast (194,280 cases), lung (219,440 cases), colon (106,100 cases)and prostate (192,280 cases) cancer, the incidence per year of thyroid cancer (37,200) is ratherlow ([1]). Mortality rates from thyroid cancer compared to common cancers are even lower.Thyroid carcinomas are mainly of the differentiated type consisting of papillary and follicular(95%) and of the medullary (5%) type ([2]). The highly aggressive anaplastic thyroidcarcinoma is rare (<1%). The low mortality rate is in part due to relatively good therapeuticoptions.Current treatment of metastasized differentiated thyroid carcinoma includes surgery as the keyaction followed by postoperative remnant ablation with radioiodine. Radioiodine therapy is amajor element within the therapeutic procedure and makes an important contribution to thefavourable prognosis of metastasising differentiated thyroid cancers. This treatment acts morespecifically than general cytostatic drugs and consequently causes fewer adverse reactions inthe patient. At least 30% of patients with differentiated thyroid carcinoma, however, showinsufficient iodide uptake ([3]), caused by transcriptional and post-translational changes insodium-/iodide transporter (NIS) expression. To restore iodide uptake and thereby improvethe efficacy of radioiodine therapy, differentiating agents are being screened for efficacy.Data from cell cultures suggest that the histone deacetylase (HDAC) inhibitors valproic acidand depsipeptide ([4-7]), the retinoids all-trans and 13-cis retinoic acid, betaroxane and retinol([8-11]), and the thiazolidinediones (TZDs) troglitazone, rosiglitazone and pioglitazone ([12-14]) increase differentiation, as assessed by increased expression and physiological locationof thyroid-specific proteins such as the sodium-iodide symporter, or increased iodide uptakein addition to decreased proliferation and induction of apoptosis. In-vivo data from recentphase II clinical trials evaluating the efficacy of differentiating agents such as retinoic acidand rosiglitazone report increases in radioiodine uptake in about one third of the patients ([15-20]). These studies, however, included only relatively few patients with short follow-up timesand the metabolic pathways of the effects of TZD on patients with advanced thyroid cancerare still unknown.The fact that the anti-diabetic TZDs are more effective in thyroid carcinoma than in mostother tumors tested (see overview Table III) prompted us to look for differences in therelationship between thyroid cancer and diabetes compared to this relationship in other cancertypes. Specifically, we reviewed information on the incidence of thyroid carcinoma in obese,
  4. 4. people with intermediate hyperglycaemia and diabetic patients compared to other carcinomas.Here, the tumor-promoting role of glucose and insulin and the mechanism of the anti-canceraction of anti-diabetic drugs will be briefly addressed. Dipeptidyl peptidase IV, which on theone hand is a target of anti-diabetic medication but on the other hand possesses different rolesin thyroid cancer compared to other types of cancer, is discussed. Based on the reviewedinformation ([21]) it is suggested that this enzyme may be involved in the lower incidence ofthyroid carcinomas in diabetes patients but not in people with intermediate hyperglycaemia.Due to the relatively low incidence of thyroid carcinoma and to limitations of cohort studiesin general, this hypothesis presently remains speculative.Prevalence of cancer in obese, people with intermediate hyperglycaemia and diabetic patientsThe information given in the following paragraphs is limited to cancers in patients with type 2diabetes mellitus (DM). The incidence of cancer types with regard to obesity and tohyperglycaemic episodes (prediabetes with impaired glucose tolerance and /or impairedfasting glucose according to American Diabetes Association (ADA) guidance) is presented.Obesity is not only a risk factor for metabolic diseases like hypertension, diabetes andatherosclerosis, but obese people are also at higher risk of developing endometrial, thyroidand colon cancer ([22]). There is, by contrast, no increased relative risk for ovarian or prostatecancer. The link between obesity and the increased risk of differentiated thyroid carcinomamay be a result of dys-regulated thyroid hormone levels ([21]). Correlations between highglycaemic load and high glycaemic index and development of breast, endometrial, colon,stomach and thyroid cancer have also been reported ([23-32]). Hazard ratios for thyroidcancer are increased in individuals with fasting blood glucose levels both in the lower andupper normoglycaemic range and in the hyperglycaemic range ([33]). Similar to other cancertypes insulin resistance is seen frequently in patients with thyroid cancer ([34]). Apart fromthyroid cancer, insulin resistance is also common in other pathologies of the thyroid such asincreased size of the gland and nodules ([35]) and thyroid hormone levels influence half-lifeof circulating insulin and gut absorption of glucose ([36]). A positive correlation with DMwas identified for some types of cancers (Table I). According to meta-analyses, DM patientspresent with a higher prevalence of primary liver cancer, colorectal cancer and carcinoma ofthe pancreas, bladder, endometrium, and breast, as well as non-Hodgkin lymphoma ([37-43]).An association of DM and renal cancer has also been reported ([44]). Individual studies showcorrelations of DM with cancer of the pancreas, bladder, colon and with melanoma ([45]), aswell as endometrial, gall bladder, pancreas, oesophagus, bladder and renal cancer, and non-
  5. 5. Hodgkin lymphoma and leukemias ([46]). In one study the incidence of thyroid carcinomawas associated with high glycaemic indices ([31]) but was not found to be increased inanother study in DM patients ([47]). In this study, however, also other common cancers types,which showed a significantly increased risk in other studies (e.g. breast cancer), were reportedto be decreased. A recently published study compared the incidence of 24 types of cancers inpatients who had been hospitalized for DM. Incidence of all carcinomas except for melanomaand prostate cancer was increased. Standardized incidence ratios for liver, pancreas,colorectal and various gynecologic cancers but not for thyroid cancer were significantlyincreased relative to the normal population ([48]).We are well aware that the causal nature of the association between DM and cancer iscomplex, and that it remains unclear whether it is a direct association or whether diabetes is amarker of underlying biologic factors that alter cancer risk (for example insulin resistance), orwhether the association between cancer and diabetes is indirect and due to common riskfactors such as obesity. Well-organized prospective observational studies in which diabetes-related biomarkers and a better characterization of specific aspects of diabetes (for examplediabetes duration and the variety of drug therapy during disease progression) in relation tocancer risk are still lacking but are crucially important ([49]).Despite these limitations, we propose that there is a specific reaction of differentiated thyroidcancer to anti-diabetic medications. By limiting our comparison to tumors with increasedincidence in obese individuals and people with intermediate hyperglycaemia we are hoping toevaluate a more homogeneous group concerning the role of insulin and/or glucose in tumordevelopment and progression. In these tumors, the expression of the enzyme dipeptidylpeptidase IV in normal and in transformed cells is compared.Role of insulin-like growth factor 1 signaling in thyroid cancerAccording to epidemiologic and experimental data, activation of the insulin/insulin-likegrowth factor 1 (IGF-1) pathway is an important promoter of tumor development inindividuals with impaired carbohydrate metabolism, including people with intermediatehyperglycaemia and patients with DM ([50]). Activation of the insulin receptor or IGF-1receptor activates MAPK and PI3K pathways; in contrast inhibition of IGF-1 signalling by theneutralizing monoclonal antibody, SCH 717454, specific for the IGF-1 receptor, has potentantitumor effects in vitro and in vivo ([51]). Epidemiologic studies document associationsbetween insulin-like growth factor 1 levels and breast, prostate and colorectal cancerincidence ([52]). In acromegaly, where IGF-1 protein is produced in higher amounts due to
  6. 6. increased growth hormone levels, higher standardized incidence ratios have been reported forneoplasms of thyroid, kidney, small and large intestine and brain ([53]). A closer relation ofthyroid pathology to increased IGF-1 levels is also suggested by the high occurrence ofnodular goiter in 39-75% of patients with acromegaly ([54]). IGF-1 protein is also over-expressed in thyroid carcinoma and linked to tumor progression ([55]). Additionally, IGF-2,IGF-2 receptor and insulin receptor (IR) are involved in thyroid tumorigenesis. IGF-2 ishighly over-expressed in thyroid carcinoma and binds to the insulin receptor isoform IR-A([56]), which, in addition to the IGF-1 receptor, is also over-expressed in well-differentiatedthyroid carcinoma ([57]). Inactivation of the anti-proliferative IGF-2 receptor plays a role inthe metabolism of tumor cells in general ([58]). Impaired IRS-1 signaling, which leads toinappropriately high MAP kinase pathway activity, is especially important for thedevelopment of breast cancer ([59]). Because insulin and glucose levels are not dysregulatedto the same degree in people with intermediate hyperglycaemia and in diabetic patients andare not consistently higher in DM patients than in healthy individuals, other factors may alsobe involved in the link between DM and cancer. Firstly, increased fatty acid synthase activityappears to act as an additional factor. Involvement of this enzyme in cancer cell metabolismwas corroborated by the cytostatic action of specific inhibitors in xenograft models ofdifferent cancers (e.g ovarian cancer, ref. [60]). Secondly, inflammation and oxidative stressare important factors. Especially TNF-α, produced by adipose tissue, induces developmentand progression of many tumors ([61]). For the (negative) correlation of DM and prostatecancer, decreased testosterone levels, and for non-Hodgkin lymphoma abnormalities ofcellular and humoral immunity are thought to be important. Interpretation of cancer mortalitydata in DM is difficult because of the lack of data, lack of stratification in the studies andindications of confounding factors like menopausal status.Studies on complete datasets suggest a positive correlation of DM with mortality fromcolorectal and endometrial cancer and – despite a reduced incidence- from prostate cancer([50]). One long-term all-cause mortality study identified an increased risk of death for DMpatients from breast, endometrial and colorectal cancer ([62]) but the heterogeneity of thestudies analyzed and changes in treatment during the long observation time from 1969 to2008 decrease the significance of the data. A more recent analysis reported a higher risk fordeath from liver, pancreas and colorectal cancer and a lower mortality from prostate andendocrine cancer in DM patients ([63]). The low mortality rate of thyroid cancer may lead toan underestimation of incidence of thyroid cancer in DM. It is also obvious that the
  7. 7. heterogeneity of the patient population regarding type of treatment also hampers theinterpretation of the observed effects. All studies show that DM patients have an increasedincidence for some but not all cancer types and similar findings were also applicable tomortality. Breast, endometrial and colon cancer have an increased incidence in DM patientsand in obese individuals or subjects with intermediate hyperglycaemia. The question whythese cancers but not other types of cancers like lung and thyroid cancer are also seen morefrequently in DM patients cannot yet be answered. If an effect in all patients irrespective ofthe type of treatment was observed, the decreased incidence of cancer in DM patients couldbe explained by a decreased frequency of hyperglycaemic episodes. The fact that the decreaseis seen for some but not for all cancers with increased incidence in people with intermediatehyperglycaemia may have several reasons. For example, the incidence of the respectivecancer is low and not enough cases for a statistical evaluation have been studies, or othermetabolic changes are caused by diabetes therapy or possibly some anti-diabetic drugs mayactually directly prevent transformation of these cells.Action of anti-diabetic drugs on cancer cells in vitro and on cancer incidence in DM patientsunder medicationFor the systemic treatment of type 2 diabetes, five main classes of drugs are used in additionto insulin substitution. Sulfonylureas (SUs), biguanides (BGs) and thiazolidinediones (TZDs)are well-established whereas Glucagon-like peptide 1 (GLP-1) analogues and dipeptidylpeptidase IV inhibitors are relatively new and long-term data are lacking. These drugs displayanti-diabetic action by diverse in part overlapping mechanisms, which have been reviewedmany times. SUs, BGs and TZDs, in addition, possess anti-tumor activity to different extent(Table II).Anti-diabetic SUs, do not show prominent anti-tumor activity. Although inhibiton ofpotassium channels is a cytostatic target, few data demonstrate strong anti-tumor effects of theKATP channel blocker glibenclamide. Induction of apoptosis in gastric cancer and in prostatecancer cell lines ([64, 65]) and reduced proliferation in liver cell lines ([66, 67]) and in abladder cell line have been reported. In other studies, however, glibenclamide did not reduceproliferation of ovarian cancer cell lines ([68]). Glibenclamide is suspected to act mainly bygeneration of oxidative stress and alteration in the mitochondrial membrane potential ([65]).In DM patients, moderate effects, such as a slight non-significant reduction in the incidence ofgastrointestinal, lung, prostate and breast cancer ([69]), were observed. Another study showed
  8. 8. a decrease of prostate cancer incidence in SU-treated and insulin-treated diabetes patients([70]).Biguanides, with the main representative being metformin, showed anti-tumor action inovarian-, endometrial-, breast-, prostate cancer and glioblastoma cell lines ([71-74]). Mainmodes of anti-tumor action include activation of AMPK, reduction of mammalian target ofrapamycin (mTOR) signalling resulting in decrease of protein synthesis through decrease ofribosomal protein S6 kinase (S6K) and increase of eukaryotic initiation factor 4E-bindingprotein-1 (4E-BP1). For a more detailed description of the pleiotopic mode of action ofmetformin, the reader is referred to one of the more recent reviews (e.g. [75, 76]). In mousexenografts and transgenic mice, reduction of growth and suppressed development was seen,respectively ([77-80]). The protection against chemically induced tumor formation in animalmodels and against progression of preneoplastic lesions in humans suggests achemopreventive action of metformin ([81, 82]).Slight but not significant reduction in cancer risk in general was seen in diabetes patientstreated with Metformin ([83-88]). In particular, the incidence of colon and pancreas cancertended to be reduced ([89]). The protective effect against cancer increased with greatermetformin exposure ([90]). In addition to a lower cancer risk also a lower cancer-relatedmortality, was reported ([91]). Metformin may also act in combination with chemostaticcompounds: higher pathologic complete response rates were shown in breast cancer ([92]).Concentrations of metformin as used for anti-diabetes treatment, however, may not besufficiently high to achieve maximal anti-tumor effects because neither in the study withbreast cancer nor in another study with prostate cancer a clear benefit in terms of improved 3-year relapse-free survival rates or 5-year risk of biochemical recurrence was obtained ([93]).A first trial evaluating metformin in breast cancer patients is under way ([94]). Although itsaction on thyroid carcinoma cells was not investigated, metformin was proposed as a potentialdrug for thyroid carcinoma therapy because of its ability to decrease TSH levels withoutchanges in free thyroid hormone levels ([95]).TZDs (troglitazone, rosiglitazone, pioglitazone and ciglitazone) possess anti-tumor activity oncancer cell lines derived from colon-, breast-, prostate-, lung-, ovarian-, thyroid cancer andmelanoma ([96]). Reduced tumor growth of xenografts from lung, colon, neuroblastoma,osteosarcoma, melanoma and adrenocortical carcinoma cell lines upon treatment with TZDswas reported (e.g. [97]). Chemoprevention by TZDs was demonstrated for lung
  9. 9. carcinogenesis, endometrial hyperplasia and hepatocarcinogenesis ([98-100]). Animal datahave to be interpreted with caution because mouse and human endothelial cell, and possiblyalso other cell types, react differently to TZDs ([101]).TZDs act via activation of PPAR-γ but also exert PPAR-γ independent effects; often anti-tumor efficacy is not correlated with expression of PPAR-γ ([102]). The role of PPAR-γ incancer development, in general, is not clear: on the one hand activation of PPAR-γ inducesdifferentiation and apoptosis ([103, 104]), on the other hand PPAR-γ may act as a tumorpromoter ([105]). The induction of apoptosis in tumor cells appears to be one important modeof action of TZDs but the pathway, by which apoptosis is induced, is cancer cell-type specific([106]). Other mechanisms of the anti-tumor action, such as proposed mechanisms for cellcycle arrest, for cellular differentiation, induction of cellular acidosis, anti-angiogenesis,action on pro-inflammatory cytokines, etc. of TZDs are described in more detail byBlanquicett ([107]).Studies on TZD medication in DM patients reported decreased incidence of gastrointestinaland lung neoplasms, slightly increased incidence for breast and no changes in prostate cancerincidence ([69]); another study showed a significant decrease in the incidence of lung cancerand slight reductions in the incidence of prostate and colorectal cancer ([108]). No changes inthe incidence of the common cancers of breast, colon and prostate in TZD-treated DMpatients or in colorectal, bladder, liver, pancreatic cancer and melanoma compared to DMpatients receiving other medication was noted ([45, 109]). Recent studies report an increasedincidence of bladder cancer in patients under medication with pioglitazone ([110, 111]),suggesting that TZDs may not have a general favourable effect on cancer development and/orprogression.For TZDs, data from cancer trials are also available: limited clinical data support the efficacyof TZDs in lung cancer ([108]). Clinical trials with TZDs in common cancers, namely breast,colon and prostate did not convincingly show effectiveness ([112]). The effect of TZDs onchemoprevention for breast, colon and prostate carcinoma was neutral ([109]). TZDs did,however, cause increased radio-iodine uptake in a small study ([20]) and were effective in apilot and a phase II trial with thyroid carcinoma patients ([19]). A larger phase II trial is nowongoing ([113]).After screening the literature for common targets for the anti-tumor action of TZDs and BGsin combination with specific characteristics of the tumors where TZDs were most successful,we focussed on DPP IV as a potential target. TZDs and BGs but not SUs significantly inhibit
  10. 10. the proteolytic activity of DPP IV ([114]). This protease is expressed in differentiated thyroidcarcinoma cells but not in normal human thyrocytes. In other cancer types no systematicincrease in DPP IV is seen but a grade-dependent or variable effect was noted (Table III). Itmay be speculated that DPP IV is an additional target of anti-diabetic drugs, especially ofTZDs, for their anti-tumor action, which explains the better efficacy of TZDs in thyroidcarcinoma patients.Role of DPP IV in cancerDPP IV has a more important role in thyroid cancer than in other cancer types because theabsence of activity in normal cells is unusual and DPP IV activity, therefore, serves asdiagnostic marker for differentiated thyroid carcinoma. The relationship of DPP IV to thebiological behaviour of cancer cells is not trivial: it acts in a pro- or anti-oncogenic mannerdepending on the tumor-specific local microenvironment. DPP IV cleaves X-Pro dipeptidesfrom their substrates. Of the peptides controlling cell growth, many possess a proline residueat the second position of the amino-terminus and represent substrates for DPP IV. Amongthese peptides, neuropeptide Y, peptide YY, growth hormone-releasing hormone, substance P,glucagon-like peptide 1,2, gastrin-releasing peptides, the chemokines eotaxin, stromal-cell-derived factor 1α ( SDF-1alpha/ CXCL12), monokine induced by interferon γ (MIG/CXCL9)and the interleukins IL-2 and IL-6 are thought to act in cancer growth regulation ([115]). DPPIV may change the extracellular matrix by degrading these growth factors. Animal studies onbreast carcinoma suggest an additional role for DPP IV independent of its proteolytic activity:its expression on endothelial cells may facilitate adhesion of tumor cells and supportmetastasis ([116]). The identification of the role of DPP IV in cancer is complicated by thefact that most normal cell types possess DPP IV activity and that this protease has multiplefunctions in cell physiology. Neither the protease domain nor the cytoplasmic domain of theprotein appears to be essential for the action of DPP IV in tumor cells ([117]).In accordance with the tumor-specific role of DPP IV, its activity is not consistently elevatedor decreased in cancer tissue and some cancers show stage-dependent changes. Activity ofDPP IV in normal cells and cancer cells is compared in Table III and related to the effect ofTZDs in tumor trials. Increased DPP IV activity in the initial stage of tumor formation is seenfor endometrial, ovarian, prostate and thyroid cancer ([118-121]). DPP IV activity is increasedin all stages of lung cancer ([122]). Over-expression of DPP IV without correlation to thegrade or stage of cancer was reported for colorectal carcinoma ([123]). Data on breast cancershow no consistent increase in DPP IV activity ([124]). Increased DPP IV activity in cancers
  11. 11. is seen more frequently than decreased activity. Only in malignant cutaneous melanoma isDPP IV lost during transformation ([125]). Few data are available on the effects of inhibitionof DPP IV; the study by Wesley et al. ([126]) showed that inhibition of DPP IV activity inprostate cells has a tumor-promoting effect. Based on these data, the authors concluded thatDPP IV inhibits the malignant phenotype of prostate cancer cells by blocking the bFGFsignaling pathway. The different role of DPP IV for the development and propagation oftumors is unusual for proteases; most proteases, for instance cathepsin B, have a tumor-promoting role independent of the cell of origin (e.g.[127]). Animal studies can mimic theeffects on DPP IV only to a limited extent because normal porcine, which are frequently usedas models for human thyrocytes, express DPP IV, while normal human thyrocytes do not([128]).DPP IV-inhibitors and GLP-1 analogues in diabetesGlucagon-like peptide 1 (GLP-1) is a new target for DM therapy. Relevant effects of thepeptide include increased insulin release and decreased glucagon secretion from the pancreas,and increased insulin sensitivity. Three classes of drugs have been developed to increase theeffect of GLP-1: GLP-1 receptor agonists like exenatide, a synthetic version of the venomouslizard hormone exendine-4, GLP-1 analogues like liraglutide, an acylated human GLP-1, andthe inhibitors of degradation of endogeneous GLP-1 (DPP IV- inhibitors) such as sitagliptin,vildagliptin and saxagliptin. In contrast to exenatide and liraglutide DPP-IV inhibitors onlyprevent degradation of GLP-1. The GLP-1 analogue liraglutide induced medullary thyroidcarcinomas in rodents. This tumor-promoting effect appeared to be linked to the high GLP-1receptor expression in rodents, which is not seen in humans ([129, 130]). Studies by the FDAon the effects of liraglutide on C-cell carcinomas did not find an increased incidencecompared to the control group ([131]). In this study of short duration also no reduction in theincidence of differentiated thyroid carcinoma was seen but the incidence of papillarymicrocarcinoma is relatively high in the population. Elashoff et al. ([132]) reportedsignificantly higher odds ratio vs. control drug for thyroid cancer (without discriminationbetween cancer types) in the exenatide group but not in the sitagliptin group. The potentialtumor-promoting effect of this GLP-1 analogue and of this DPP IV inhibitor for thyroidcarcinoma, most likely is caused by long-term GLP-1 receptor activation. It cannot beexcluded that inhibition of DPP IV on the one hand promotes the development of medullarythyroid cancer by increasing GLP-1 levels and, on the other, prevents differentiated thyroidcancer by other mechanisms. The relevance of the increased incidence of pancreas carcinoma
  12. 12. upon therapy with GLP-1 analogues and DPP IV inhibitors, reported in the same study, iscurrently not clear. None of the pre-clinical studies required by drug regulating authoritiesreported an increased frequency of malignancies upon exenatide or sitagliptin treatment and,therefore, Spranger et al. ([133]) advised to interpret the findings of this study with caution.ConclusionsDifferentiated thyroid cancer cells and lung cancer cells differ from most common cancers intheir over-expression of DPP IV and an increased efficacy of TZDs in clinical anti-tumortrials. It is speculated that anti-tumorigenic effects of DM medication are seen only in DPP IVover-expressing cancers. DPP IV inhibition, however, appears to be inappropriate as a targetfor cancer therapy in general because DDP IV is not increased in all cancer types, andinhibition may even promote the growth of some. Potential adverse effects of increased GLP-1 levels must also be taken into account. It remains to be determined whether DM patientswith thyroid cancer profit from therapy with DPP IV inhibitors.AcknowledgementsWe are grateful to Prof. H. Staiger and Prof. G. Pawelec for critical reading and constructivecomments on the manuscript.Author Disclosure StatementThe authors declare that there is no conflict of interest.
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  22. 22. Table I: Correlation of obesity, intermediate hyperglycaemia (high glycemic index) and ofdiabetes mellitus to different types of cancers. References given in parenthesis.Type of Correlation to obesity Correlation to high Correlation to diabetescancer glycemic indexLung RR= 0.6/0.9 (men, OR= 1.55 ([136]) HR= 0.98 ([137]) black/white), [134]) RR= 0.74 (women) ([135])Breast Postmenopausal OR= Pre-menopausal HR= 1.61 ([62]) 2.67 ([138]) RR= 1.62, RR= 1.4 ([135, 139]) postmenopausal RR= 2.18 ([24])Endometrial RR=1.59 ([22]) RR= 1.36 ([140]) HR= 1.76 ([62])Colon RR= 1.24 ([22]) RR= 1.32 ([23]) RR= 1.33 ([27]) RR= 1.4 ([134]) RR= 1.26 ([140]) RR= 1.61 ([135, 139])Thyroid RR= 1.33 ([22]) Papillary OR= 2.17, ∅, ([47]) RR= 1.9 ([134]) Follicular OR= 3.3 ([31])∅: no correlation, RR (relativ risk): probability that a member of an exposed group willdevelop the disease relative to the probability that a member of an unexposed group willdevelop the same disease. OR (odds ratio): odds of disease among exposed individualsdivided by the odds of disease among unexposed. HR (hazard ratio): the rate at which theevent happens in one group by the rate at which the event happens in the other.
  23. 23. Table II: Action of sulfonylureas, biguanides and thiazolidinediones on targets in anti-diabetes medication in normal cells and effect in cancer cellsNormal Target Sulfonylureas Biguanides Thiazolidinedionescells KATP- + ([141]) ∅ ([142]) + ([143]) channel (blockade ) AMPK ∅ ([144]) + ([145]) + ([146]) (activation) PPAR-γ + ([144]) - ([147]) + ([148]) (activation) DPP IV ∅ ([114]) + ([114, 149]) + ([114]) (inhibition)Cancer Anti-tumor + (gastric cancer; + (ovary, + (ovary, colon,cells effect in- [65]) endometrium, lung, breast, vitro breast, prostate, prostate, thyroid; glioblastoma; [71- [107, 151]) 74, 150])∅: no effect; -: inverse effect; +: effect present
  24. 24. Table III: DPP IV activity in normal and cancer tissue. References given in parenthesisOrgan DPP IV DPP IV (transformed Effect of TZD in clinical (normal cells) cells) trialsLung + ↑ ([122]) Positive effect ([112])Breast (+) ∅ ([124]) Negative effect ([107, 152, 153])Endometrium + ↑ (grade 1; [118]) Negative ([154])Colon + ↑ (variable; [123]) Positive and negative effect ([107, 108, 112])Thyroid - ↑ ([121, 155]) Positive effect in a small(differentiated) study ([19])-: absent; (+): low; +: strong activity; ∅: no effect;↑: increaseConflict of interest details: EF: Design, data collection, analysisand writing of manuscriptRW:Design, analysis and writing of manuscriptAuthorship details: EF: there is no competing interest.