Do anti-diabetic medications play a specific role in differentiated thyroid cancer compared to other cancer types?

Eleonore Fröhlich1,2 and Richard Wahl1 1Internal Medicine, Dept. of Endocrinology, M etabolism, Nephrology, Angiology and

Clinical Chemistry, University of Tuebingen, Otfried-Muellerstrasse 10, D-72076 Tuebingen,

Germany; 2 Center for Medical Research, Medical University Graz, Stiftingtalstr. 24, A-8010

Graz

Abstract The risk for differentiated thyroid cancer, like for many other types of cancer, is increased in

obese 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. The

review compares the prevalence of thyroid carcinoma and other cancers in obese, people with

intermediate hyperglycaemia and diabetic patients and summarizes mode of action and anti-

tumorigenic effect of common anti-diabetic medications. The over-expression of dipeptidyl

peptidase IV in the tumors, not seen in the other cancer types, is suggested as a potential

reason for the unique situation in thyroid cancer.

Keywords: Thyroid carcinoma, diabetes, sulfonylureas, thiazolidinediones, biguanides, dipeptidyl

peptidase IV

Abbreviations ABL tyrosine kinase: Abelson leukemia virus tyrosine kinase; AKT: protein kinase B;

AMPK: adenosine monophosphate-activated protein kinase; bFGF: basic fibroblast growth

factor; 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: Insulin

receptor 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 this article as an "Accepted Article"; doi: 10.1111/j.1463-1326.2011.01491.x

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: tumor

necrosis factor alpha; TZDs: thiazolidinediones; X-Pro: dipeptide X-proline

Thyroid neoplasms are within the top twenty most common cancers, although compared to

common 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 rather

low ([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 thyroid

carcinoma is rare (<1%). The low mortality rate is in part due to relatively good therapeutic

options.

Current treatment of metastasized differentiated thyroid carcinoma includes surgery as the key

action followed by postoperative remnant ablation with radioiodine. Radioiodine therapy is a

major element within the therapeutic procedure and makes an important contribution to the

favourable prognosis of metastasising differentiated thyroid cancers. This treatment acts more

specifically than general cytostatic drugs and consequently causes fewer adverse reactions in

the patient. At least 30% of patients with differentiated thyroid carcinoma, however, show

insufficient iodide uptake ([3]), caused by transcriptional and post-translational changes in

sodium-/iodide transporter (NIS) expression. To restore iodide uptake and thereby improve

the efficacy of radioiodine therapy, differentiating agents are being screened for efficacy.

Data from cell cultures suggest that the histone deacetylase (HDAC) inhibitors valproic acid

and 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 location

of thyroid-specific proteins such as the sodium-iodide symporter, or increased iodide uptake

in addition to decreased proliferation and induction of apoptosis. In-vivo data from recent

phase II clinical trials evaluating the efficacy of differentiating agents such as retinoic acid

and 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 times

and the metabolic pathways of the effects of TZD on patients with advanced thyroid cancer

are still unknown.

The fact that the anti-diabetic TZDs are more effective in thyroid carcinoma than in most

other tumors tested (see overview Table III) prompted us to look for differences in the

relationship between thyroid cancer and diabetes compared to this relationship in other cancer

types. Specifically, we reviewed information on the incidence of thyroid carcinoma in obese,

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-cancer

action of anti-diabetic drugs will be briefly addressed. Dipeptidyl peptidase IV, which on the

one hand is a target of anti-diabetic medication but on the other hand possesses different roles

in thyroid cancer compared to other types of cancer, is discussed. Based on the reviewed

information ([21]) it is suggested that this enzyme may be involved in the lower incidence of

thyroid 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 studies

in general, this hypothesis presently remains speculative.

Prevalence of cancer in obese, people with intermediate hyperglycaemia and diabetic patients

The information given in the following paragraphs is limited to cancers in patients with type 2

diabetes mellitus (DM). The incidence of cancer types with regard to obesity and to

hyperglycaemic episodes (prediabetes with impaired glucose tolerance and /or impaired

fasting glucose according to American Diabetes Association (ADA) guidance) is presented.

Obesity is not only a risk factor for metabolic diseases like hypertension, diabetes and

atherosclerosis, but obese people are also at higher risk of developing endometrial, thyroid

and colon cancer ([22]). There is, by contrast, no increased relative risk for ovarian or prostate

cancer. The link between obesity and the increased risk of differentiated thyroid carcinoma

may be a result of dys-regulated thyroid hormone levels ([21]). Correlations between high

glycaemic load and high glycaemic index and development of breast, endometrial, colon,

stomach and thyroid cancer have also been reported ([23-32]). Hazard ratios for thyroid

cancer are increased in individuals with fasting blood glucose levels both in the lower and

upper normoglycaemic range and in the hyperglycaemic range ([33]). Similar to other cancer

types insulin resistance is seen frequently in patients with thyroid cancer ([34]). Apart from

thyroid cancer, insulin resistance is also common in other pathologies of the thyroid such as

increased size of the gland and nodules ([35]) and thyroid hormone levels influence half-life

of circulating insulin and gut absorption of glucose ([36]). A positive correlation with DM

was identified for some types of cancers (Table I). According to meta-analyses, DM patients

present with a higher prevalence of primary liver cancer, colorectal cancer and carcinoma of

the 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 show

correlations of DM with cancer of the pancreas, bladder, colon and with melanoma ([45]), as

well as endometrial, gall bladder, pancreas, oesophagus, bladder and renal cancer, and non-

Hodgkin lymphoma and leukemias ([46]). In one study the incidence of thyroid carcinoma

was associated with high glycaemic indices ([31]) but was not found to be increased in

another 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 reported

to be decreased. A recently published study compared the incidence of 24 types of cancers in

patients who had been hospitalized for DM. Incidence of all carcinomas except for melanoma

and prostate cancer was increased. Standardized incidence ratios for liver, pancreas,

colorectal and various gynecologic cancers but not for thyroid cancer were significantly

increased relative to the normal population ([48]).

We are well aware that the causal nature of the association between DM and cancer is

complex, and that it remains unclear whether it is a direct association or whether diabetes is a

marker of underlying biologic factors that alter cancer risk (for example insulin resistance), or

whether the association between cancer and diabetes is indirect and due to common risk

factors such as obesity. Well-organized prospective observational studies in which diabetes-

related biomarkers and a better characterization of specific aspects of diabetes (for example

diabetes duration and the variety of drug therapy during disease progression) in relation to

cancer risk are still lacking but are crucially important ([49]).

Despite these limitations, we propose that there is a specific reaction of differentiated thyroid

cancer to anti-diabetic medications. By limiting our comparison to tumors with increased

incidence in obese individuals and people with intermediate hyperglycaemia we are hoping to

evaluate a more homogeneous group concerning the role of insulin and/or glucose in tumor

development and progression. In these tumors, the expression of the enzyme dipeptidyl

peptidase IV in normal and in transformed cells is compared.

Role of insulin-like growth factor 1 signaling in thyroid cancer

According to epidemiologic and experimental data, activation of the insulin/insulin-like

growth factor 1 (IGF-1) pathway is an important promoter of tumor development in

individuals with impaired carbohydrate metabolism, including people with intermediate

hyperglycaemia and patients with DM ([50]). Activation of the insulin receptor or IGF-1

receptor activates MAPK and PI3K pathways; in contrast inhibition of IGF-1 signalling by the

neutralizing monoclonal antibody, SCH 717454, specific for the IGF-1 receptor, has potent

antitumor effects in vitro and in vivo ([51]). Epidemiologic studies document associations

between insulin-like growth factor 1 levels and breast, prostate and colorectal cancer

incidence ([52]). In acromegaly, where IGF-1 protein is produced in higher amounts due to

increased growth hormone levels, higher standardized incidence ratios have been reported for

neoplasms of thyroid, kidney, small and large intestine and brain ([53]). A closer relation of

thyroid pathology to increased IGF-1 levels is also suggested by the high occurrence of

nodular 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 is

highly 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-differentiated

thyroid carcinoma ([57]). Inactivation of the anti-proliferative IGF-2 receptor plays a role in

the metabolism of tumor cells in general ([58]). Impaired IRS-1 signaling, which leads to

inappropriately high MAP kinase pathway activity, is especially important for the

development of breast cancer ([59]). Because insulin and glucose levels are not dysregulated

to the same degree in people with intermediate hyperglycaemia and in diabetic patients and

are not consistently higher in DM patients than in healthy individuals, other factors may also

be involved in the link between DM and cancer. Firstly, increased fatty acid synthase activity

appears to act as an additional factor. Involvement of this enzyme in cancer cell metabolism

was corroborated by the cytostatic action of specific inhibitors in xenograft models of

different cancers (e.g ovarian cancer, ref. [60]). Secondly, inflammation and oxidative stress

are important factors. Especially TNF-α, produced by adipose tissue, induces development

and progression of many tumors ([61]). For the (negative) correlation of DM and prostate

cancer, decreased testosterone levels, and for non-Hodgkin lymphoma abnormalities of

cellular and humoral immunity are thought to be important. Interpretation of cancer mortality

data in DM is difficult because of the lack of data, lack of stratification in the studies and

indications of confounding factors like menopausal status.

Studies on complete datasets suggest a positive correlation of DM with mortality from

colorectal 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 DM

patients from breast, endometrial and colorectal cancer ([62]) but the heterogeneity of the

studies analyzed and changes in treatment during the long observation time from 1969 to

2008 decrease the significance of the data. A more recent analysis reported a higher risk for

death from liver, pancreas and colorectal cancer and a lower mortality from prostate and

endocrine cancer in DM patients ([63]). The low mortality rate of thyroid cancer may lead to

an underestimation of incidence of thyroid cancer in DM. It is also obvious that the

heterogeneity of the patient population regarding type of treatment also hampers the

interpretation of the observed effects. All studies show that DM patients have an increased

incidence for some but not all cancer types and similar findings were also applicable to

mortality. Breast, endometrial and colon cancer have an increased incidence in DM patients

and in obese individuals or subjects with intermediate hyperglycaemia. The question why

these cancers but not other types of cancers like lung and thyroid cancer are also seen more

frequently in DM patients cannot yet be answered. If an effect in all patients irrespective of

the type of treatment was observed, the decreased incidence of cancer in DM patients could

be explained by a decreased frequency of hyperglycaemic episodes. The fact that the decrease

is seen for some but not for all cancers with increased incidence in people with intermediate

hyperglycaemia may have several reasons. For example, the incidence of the respective

cancer is low and not enough cases for a statistical evaluation have been studies, or other

metabolic changes are caused by diabetes therapy or possibly some anti-diabetic drugs may

actually directly prevent transformation of these cells.

Action of anti-diabetic drugs on cancer cells in vitro and on cancer incidence in DM patients

under medication

For the systemic treatment of type 2 diabetes, five main classes of drugs are used in addition

to insulin substitution. Sulfonylureas (SUs), biguanides (BGs) and thiazolidinediones (TZDs)

are well-established whereas Glucagon-like peptide 1 (GLP-1) analogues and dipeptidyl

peptidase IV inhibitors are relatively new and long-term data are lacking. These drugs display

anti-diabetic action by diverse in part overlapping mechanisms, which have been reviewed

many 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 of

potassium channels is a cytostatic target, few data demonstrate strong anti-tumor effects of the

KATP channel blocker glibenclamide. Induction of apoptosis in gastric cancer and in prostate

cancer cell lines ([64, 65]) and reduced proliferation in liver cell lines ([66, 67]) and in a

bladder cell line have been reported. In other studies, however, glibenclamide did not reduce

proliferation of ovarian cancer cell lines ([68]). Glibenclamide is suspected to act mainly by

generation 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 of

gastrointestinal, lung, prostate and breast cancer ([69]), were observed. Another study showed

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 in

ovarian-, endometrial-, breast-, prostate cancer and glioblastoma cell lines ([71-74]). Main

modes of anti-tumor action include activation of AMPK, reduction of mammalian target of

rapamycin (mTOR) signalling resulting in decrease of protein synthesis through decrease of

ribosomal protein S6 kinase (S6K) and increase of eukaryotic initiation factor 4E-binding

protein-1 (4E-BP1). For a more detailed description of the pleiotopic mode of action of

metformin, the reader is referred to one of the more recent reviews (e.g. [75, 76]). In mouse

xenografts and transgenic mice, reduction of growth and suppressed development was seen,

respectively ([77-80]). The protection against chemically induced tumor formation in animal

models and against progression of preneoplastic lesions in humans suggests a

chemopreventive action of metformin ([81, 82]).

Slight but not significant reduction in cancer risk in general was seen in diabetes patients

treated with Metformin ([83-88]). In particular, the incidence of colon and pancreas cancer

tended to be reduced ([89]). The protective effect against cancer increased with greater

metformin exposure ([90]). In addition to a lower cancer risk also a lower cancer-related

mortality, was reported ([91]). Metformin may also act in combination with chemostatic

compounds: higher pathologic complete response rates were shown in breast cancer ([92]).

Concentrations of metformin as used for anti-diabetes treatment, however, may not be

sufficiently high to achieve maximal anti-tumor effects because neither in the study with

breast 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 its

action on thyroid carcinoma cells was not investigated, metformin was proposed as a potential

drug for thyroid carcinoma therapy because of its ability to decrease TSH levels without

changes in free thyroid hormone levels ([95]).

TZDs (troglitazone, rosiglitazone, pioglitazone and ciglitazone) possess anti-tumor activity on

cancer cell lines derived from colon-, breast-, prostate-, lung-, ovarian-, thyroid cancer and

melanoma ([96]). Reduced tumor growth of xenografts from lung, colon, neuroblastoma,

osteosarcoma, melanoma and adrenocortical carcinoma cell lines upon treatment with TZDs

was reported (e.g. [97]). Chemoprevention by TZDs was demonstrated for lung

carcinogenesis, endometrial hyperplasia and hepatocarcinogenesis ([98-100]). Animal data

have to be interpreted with caution because mouse and human endothelial cell, and possibly

also 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 in

cancer development, in general, is not clear: on the one hand activation of PPAR-γ induces

differentiation and apoptosis ([103, 104]), on the other hand PPAR-γ may act as a tumor

promoter ([105]). The induction of apoptosis in tumor cells appears to be one important mode

of 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 cell

cycle arrest, for cellular differentiation, induction of cellular acidosis, anti-angiogenesis,

action on pro-inflammatory cytokines, etc. of TZDs are described in more detail by

Blanquicett ([107]).

Studies on TZD medication in DM patients reported decreased incidence of gastrointestinal

and lung neoplasms, slightly increased incidence for breast and no changes in prostate cancer

incidence ([69]); another study showed a significant decrease in the incidence of lung cancer

and slight reductions in the incidence of prostate and colorectal cancer ([108]). No changes in

the incidence of the common cancers of breast, colon and prostate in TZD-treated DM

patients or in colorectal, bladder, liver, pancreatic cancer and melanoma compared to DM

patients receiving other medication was noted ([45, 109]). Recent studies report an increased

incidence 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/or

progression.

For TZDs, data from cancer trials are also available: limited clinical data support the efficacy

of 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 on

chemoprevention 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 a

pilot and a phase II trial with thyroid carcinoma patients ([19]). A larger phase II trial is now

ongoing ([113]).

After screening the literature for common targets for the anti-tumor action of TZDs and BGs

in 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

the proteolytic activity of DPP IV ([114]). This protease is expressed in differentiated thyroid

carcinoma cells but not in normal human thyrocytes. In other cancer types no systematic

increase in DPP IV is seen but a grade-dependent or variable effect was noted (Table III). It

may be speculated that DPP IV is an additional target of anti-diabetic drugs, especially of

TZDs, for their anti-tumor action, which explains the better efficacy of TZDs in thyroid

carcinoma patients.

Role of DPP IV in cancer

DPP IV has a more important role in thyroid cancer than in other cancer types because the

absence of activity in normal cells is unusual and DPP IV activity, therefore, serves as

diagnostic marker for differentiated thyroid carcinoma. The relationship of DPP IV to the

biological behaviour of cancer cells is not trivial: it acts in a pro- or anti-oncogenic manner

depending on the tumor-specific local microenvironment. DPP IV cleaves X-Pro dipeptides

from their substrates. Of the peptides controlling cell growth, many possess a proline residue

at the second position of the amino-terminus and represent substrates for DPP IV. Among

these 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]). DPP

IV may change the extracellular matrix by degrading these growth factors. Animal studies on

breast 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 support

metastasis ([116]). The identification of the role of DPP IV in cancer is complicated by the

fact that most normal cell types possess DPP IV activity and that this protease has multiple

functions in cell physiology. Neither the protease domain nor the cytoplasmic domain of the

protein 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 elevated

or decreased in cancer tissue and some cancers show stage-dependent changes. Activity of

DPP IV in normal cells and cancer cells is compared in Table III and related to the effect of

TZDs in tumor trials. Increased DPP IV activity in the initial stage of tumor formation is seen

for endometrial, ovarian, prostate and thyroid cancer ([118-121]). DPP IV activity is increased

in all stages of lung cancer ([122]). Over-expression of DPP IV without correlation to the

grade or stage of cancer was reported for colorectal carcinoma ([123]). Data on breast cancer

show no consistent increase in DPP IV activity ([124]). Increased DPP IV activity in cancers

is seen more frequently than decreased activity. Only in malignant cutaneous melanoma is

DPP IV lost during transformation ([125]). Few data are available on the effects of inhibition

of DPP IV; the study by Wesley et al. ([126]) showed that inhibition of DPP IV activity in

prostate cells has a tumor-promoting effect. Based on these data, the authors concluded that

DPP IV inhibits the malignant phenotype of prostate cancer cells by blocking the bFGF

signaling pathway. The different role of DPP IV for the development and propagation of

tumors 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 the

effects on DPP IV only to a limited extent because normal porcine, which are frequently used

as models for human thyrocytes, express DPP IV, while normal human thyrocytes do not

([128]).

DPP IV-inhibitors and GLP-1 analogues in diabetes

Glucagon-like peptide 1 (GLP-1) is a new target for DM therapy. Relevant effects of the

peptide include increased insulin release and decreased glucagon secretion from the pancreas,

and increased insulin sensitivity. Three classes of drugs have been developed to increase the

effect of GLP-1: GLP-1 receptor agonists like exenatide, a synthetic version of the venomous

lizard hormone exendine-4, GLP-1 analogues like liraglutide, an acylated human GLP-1, and

the 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 only

prevent degradation of GLP-1. The GLP-1 analogue liraglutide induced medullary thyroid

carcinomas in rodents. This tumor-promoting effect appeared to be linked to the high GLP-1

receptor expression in rodents, which is not seen in humans ([129, 130]). Studies by the FDA

on the effects of liraglutide on C-cell carcinomas did not find an increased incidence

compared to the control group ([131]). In this study of short duration also no reduction in the

incidence of differentiated thyroid carcinoma was seen but the incidence of papillary

microcarcinoma is relatively high in the population. Elashoff et al. ([132]) reported

significantly higher odds ratio vs. control drug for thyroid cancer (without discrimination

between cancer types) in the exenatide group but not in the sitagliptin group. The potential

tumor-promoting effect of this GLP-1 analogue and of this DPP IV inhibitor for thyroid

carcinoma, most likely is caused by long-term GLP-1 receptor activation. It cannot be

excluded that inhibition of DPP IV on the one hand promotes the development of medullary

thyroid cancer by increasing GLP-1 levels and, on the other, prevents differentiated thyroid

cancer by other mechanisms. The relevance of the increased incidence of pancreas carcinoma

upon therapy with GLP-1 analogues and DPP IV inhibitors, reported in the same study, is

currently not clear. None of the pre-clinical studies required by drug regulating authorities

reported 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.

Conclusions

Differentiated thyroid cancer cells and lung cancer cells differ from most common cancers in

their over-expression of DPP IV and an increased efficacy of TZDs in clinical anti-tumor

trials. It is speculated that anti-tumorigenic effects of DM medication are seen only in DPP IV

over-expressing cancers. DPP IV inhibition, however, appears to be inappropriate as a target

for cancer therapy in general because DDP IV is not increased in all cancer types, and

inhibition 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 patients

with thyroid cancer profit from therapy with DPP IV inhibitors.

Acknowledgements We are grateful to Prof. H. Staiger and Prof. G. Pawelec for critical reading and constructive

comments on the manuscript.

Author Disclosure Statement The authors declare that there is no conflict of interest.

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Table I: Correlation of obesity, intermediate hyperglycaemia (high glycemic index) and of

diabetes mellitus to different types of cancers. References given in parenthesis.

Type of

cancer

Correlation to obesity Correlation to high

glycemic index

Correlation to diabetes

Lung RR= 0.6/0.9 (men,

black/white), [134])

RR= 0.74 (women)

([135])

OR= 1.55 ([136]) HR= 0.98 ([137])

Breast Postmenopausal OR=

2.67 ([138])

RR= 1.4 ([135, 139])

Pre-menopausal

RR= 1.62,

postmenopausal RR=

2.18 ([24])

HR= 1.61 ([62])

Endometrial RR=1.59 ([22]) RR= 1.36 ([140]) HR= 1.76 ([62])

Colon RR= 1.24 ([22])

RR= 1.4 ([134])

RR= 1.61 ([135, 139])

RR= 1.32 ([23])

RR= 1.26 ([140])

RR= 1.33 ([27])

Thyroid RR= 1.33 ([22])

RR= 1.9 ([134])

Papillary OR= 2.17,

Follicular OR= 3.3

([31])

∅, ([47])

∅: no correlation, RR (relativ risk): probability that a member of an exposed group will

develop the disease relative to the probability that a member of an unexposed group will

develop the same disease. OR (odds ratio): odds of disease among exposed individuals

divided by the odds of disease among unexposed. HR (hazard ratio): the rate at which the

event happens in one group by the rate at which the event happens in the other.

Table II: Action of sulfonylureas, biguanides and thiazolidinediones on targets in anti-

diabetes medication in normal cells and effect in cancer cells

Target Sulfonylureas Biguanides Thiazolidinediones

KATP-

channel

(blockade )

+ ([141]) ∅ ([142]) + ([143])

AMPK

(activation)

∅ ([144]) + ([145]) + ([146])

PPAR-γ

(activation)

+ ([144]) - ([147]) + ([148])

Normal

cells

DPP IV

(inhibition)

∅ ([114]) + ([114, 149]) + ([114])

Cancer

cells

Anti-tumor

effect in-

vitro

+ (gastric cancer;

[65])

+ (ovary,

endometrium,

breast, prostate,

glioblastoma; [71-

74, 150])

+ (ovary, colon,

lung, breast,

prostate, thyroid;

[107, 151])

∅: no effect; -: inverse effect; +: effect present

Table III: DPP IV activity in normal and cancer tissue. References given in parenthesis

Organ DPP IV

(normal cells)

DPP IV (transformed

cells)

Effect of TZD in clinical

trials

Lung + ↑ ([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

(differentiated)

- ↑ ([121, 155]) Positive effect in a small

study ([19])

-: absent; (+): low; +: strong activity; ∅: no effect;↑: increase

Conflict of interest details: EF: Design, data collection, analysis

and writing of manuscript

RW:Design, analysis and writing of manuscript

Authorship details: EF: there is no competing interest.