Obesity and Cancer Exp Clin Endocrinol Diabetes

Obesity and Cancer Exp Clin Endocrinol Diabetes
2009; 117: 563 – 566


Authors R. Percik 1 , M. Stumvoll 2


1. Institute of Endocrinology, Sheba Medical Center, Tel-Hashomer, Israel

2.  Department of Medicine, University of Leipzig, Leipzig, Germany



Epidemiological studies have suggested that

obesity is associated with increased risk of several

cancer types including colon, esophagus, breast

(in postmenopausal women), endometrium, kidney,

liver, gallbladder and pancreas. Suggested

mechanisms include increased intake of potentially

carcinogenic food ingredients along with

excessive amount of calories, loss of cancer protective

eff ects due to reduced physical activity,

carcinogenic factors released from increased adipose

tissue mass and “ secondary ” associations

via “ precursor ” condition such as gallstones. The

increased cancer risk in patients with obesity is

a neglected topic which deserves more scientifi c

attention. Because of its extreme chronicity and

co-association with numerous other conditions

true causality and underlying mechanisms are

diffi cult to study. Nevertheless, a large body of

literature is already available which provides

concepts for future research.


“ Corpulence is not only a disease itself, but the

harbinger of others ” Hippocrates wrote 2,500

years ago, recognizing that obesity is both a medical

disorder and a cause for many other co morbidities.

Since the early 1960, when obesity was a

minor problem epidemiologically, with the accelerating

increase in its prevalence during the 80s

and 90s, the mean BMI increased by 3 BMI units

approximately in both genders. This translates

into an increase of 9 kg while average height only

increased by less than 2 cm. Alarmingly, the same

trend applies to children [1] . Excess bodyweight

is the sixth most important risk factor contributing

to the overall burden of disease worldwide.

1.1 billion adults and 10 % of children are now

classified as overweight or obese. Current epidemiologic

trends in obesity suggest that the steady

rise in life expectancy during the past two centuries

may soon come to an end [2] . In a 40-yearold

obese person the average life expectancy is

already diminished by 7 years. The relationship

between excess body weight and morbidity

including cardiovascular disease, type 2 diabetes

mellitus, hypertension and osteoarthritis has

been firmly established. Several forms of cancer,

including endometrium, colon, renal cell and

esophageal cancer are also associated with

obesity [3, 4] . The WHO International Agency for

Research on Cancer estimated that overweight

and inactivity account for a about a quarter of

these cancers [5] . The mechanisms that link

obesity and cancer have not been fully elucidated

and are being intensively investigated in many

fields of basic science. The topic has been covered

by a number of excellent reviews [6, 7] . While the

mechanism linking obesity with metabolic and

cardiovascular disease seem to be operative on a

more accessible time scale, those involved in cancer

are probably more subtle and slower. Clearly,

any individual cancer is far less prevalent than

coronary heart disease or type 2 diabetes, for

example. Therefore, establishing epidemiological

and mechanistic associations between obesity

and cancer is challenging.

Epidemiologic Evidence


Epidemiological studies have suggested that

overweight and obesity are related to increased

risk of several cancer types, including colon cancer,

adenocarcinoma of the esophagus, breast

cancer (in postmenopausal women), endometrial

cancer and kidney (renal-cell) cancer. Epidemiological

evidence also indicates that cancers of the

liver, gallbladder and pancreas are obesity related,

and that obesity might also increase the risk of

some hematopoietic cancers and aggressive forms of prostate cancer [8] . Data from other cancers have been

inconsistent [9] . Estimates suggest that 14 % of all cancer deaths

in men and 20 % of all cancer deaths in women are attributable

to overweight and obesity [10] .

Obesity has been consistently associated with higher risk of

colorectal cancer in both case – control and cohort studies [3] .

Similar relationships are seen for colonic adenomas which are

considered carcinoma precursors. Obese men are more prone to

develop colorectal cancer than obese women, a consistent observation

across studies and populations. Abdominal adiposity is

thought to account for this difference. Obese women have a 30 –

50 % higher risk of breast cancer in postmenopausal years

[11, 12] . There is convincing and consistent evidence from both

case – control and cohort studies that overweight and obesity are

strongly associated with endometrial cancer [10, 13] . Studies of

populations worldwide have revealed that the risk of kidney

cancer (specifically, renal-cell cancer) is 1.5 – 3 times higher in

overweight and obese individuals than in people of normal

weight [14, 15] .

The incidence of adenocarcinoma of the esophagus has been

rapidly increasing in western countries in recent decades [16] .

Independent of obesity, gastro-esophageal reflux disease

(GERD) has been associated with esophageal adenocarcinoma

and with its metaplastic precursor, Barrett’ s esophagus [17] .

Obesity has therefore been proposed to increase the risk of adenocarcinoma

of the esophagus indirectly, by increasing the risk

of GERD and Barrett ’ s esophagus [18] . Results from many

recent studies indicate that obesity is associated with an almost

twofold increased risk of pancreatic cancer [19, 20] . The majority

of studies on liver and gallbladder cancer found an increased

risk among obese individuals [21, 22] .

Suggested Mechanisms


Obesity is a state of increased body fat mass caused by a prolonged

positive energy balance. This is accompanied by a wide

range of physiological and biological alterations. The mechanisms

and pathways involved in obesity-related carcinogenicity

are multifaceted and difficult to extricate. We have defined four

groups of mechanisms: 1) increased energy intake, 2) decreased

energy output, 3) increased adipose tissue mass and 4) “ secondary

” associations. Intake includes both the amount of consumed

calories and the dietary composition. Energy output is equivalent

to energy expenditure and can be viewed as a cancer protective

mechanism. Increased adipose tissue as a potential

source of metabolic and endocrine modulators of oncogenic cascades

will be described in more detail and finally two examples

for indirect or secondary associations will be given ( ● ▶ Fig. 1 ).

Increased energy intake

Diet is one main determinant of body composition and dietary

factors are thought to account for about 30 % of cancers in Western

countries [1] . Thus, diet is second only to tobacco as a modifiable cause of cancer. Not only the quantitative caloric intake

but also the composition of consumed food has potential carcinogenic

effects. The majority of case control and prospective

studies imply a causal relationship between increased caloric

intake and breast, colon and prostate cancer [23] . Caloric restriction

has never prospectively examined as a preventive intervention

in humans. Obesity virtually by definition is a result of

overeating, not only of energy-rich compounds such as fat, but of pretty much everything contained in modern food including

complex proteins, toxins and artificial food additives whose

metabolic derivatives (e. g., toluols, nitrites) may contribute to

large bowel carcinogenesis and other malignancies [24] .

Decreased energy output

In addition to reduction of adipose tissue mass and its detrimental

metabolic and endocrine consequences, especially reduced

pro-inflammatory cytokine expression, physical activity is independently

associated with reduced mortality from cancer.

Potential mechanisms include the reduction of oxidative stress

and the increase of protective cytokines [25] .

Increased adipose tissue mass

The endocrine function of adipose tissue is altered when it

becomes hypertrophic or hyperplastic. Both conditions, but

more so the former, can result in significant changes in hormone

and growth factor secretion. This can have complex consequences

on intracellular pathways involved in inflammation, cell

proliferation, oxidative stress and carcinogenesis.

Insulin and IGF-1 pathways

Chronic hyperinsulinemia and insulin resistance increases risk for

several malignancies [6, 26– 28]. The mechanisms are not fully

understood but may involve direct growth promoting effects of

insulin or indirect eff ectsvia stimulation of the IGF-1 receptor or

modulation of the release of other hormones. Both insulin and

IGF-1 act in vitro as growth factors to promote cancer cell proliferation

and decrease apoptosis [26] . This topic will be covered in

more detail by a separate mini-review in this series.


Although difficult to separate from diabetes mellitus, hyperglycaemia

per se, including transient and mild forms such as in

obesity-related pre-diabetic states, is considered to possess carcinogenic

potential. Like in diabetic complications increased levels

of reactive oxygen species and accumulation of advanced

glycation end products (AGEs) may play a role. Bound to their

receptor, AGEs induce inflammation by activating the transcription

factor NF-kB and inducing the formation of intracellular

ROS [29] . This may adversely interfere with DNA-repair mechanisms,

for example. Inflammation

Hypertrophied adipose tissue has been shown to release inflammatory

adipocytokines including IL-1, TNF- α and plasminogen-

activator inhibitor – 1 (PAI-1) [30] which affect cell growth,

survival, proliferation and angiogenesis. The association between

chronic inflammation and cancer has been studied in greater

depth in other conditions such as inflammatory bowel disease

which carries an increased risk of colonic cancer [31] .


This hormone is secreted from adipocytes and links fat cells and

positive energy balance to satiety, fertility and other endocrine

and metabolic pathways. Obesity is associated with high circulating

levels of leptin, probably as a consequence of central leptin

resistance. Consistent findings link hyperleptinemia to colon

cancer [32] . In vitro, leptin stimulates proliferation of multiple

types of preneoplastic and neoplastic cells [33] . The Janus kinase

2 / signal transducer and activator of transcription 3 (JAK2 / STAT3)

pathway is the main downstream channel through which leptin

exerts its metabolic and proliferative effects, in addition to activation

of AMPK in muscle and liver [34] . There are increasing

data suggesting crosstalk between the JAK / STAT family of transcription

factors, the insulin / IGF-1 / Akt pathway and AMPK [35] .

Leptin also functions as an inflammatory cytokine and appears

to influence immune function, possibly by triggering release of

interleukin-6 and other cytokines [33] .

Sex hormones

Adipose tissue aromatase converts androgenic precursors produced

in adrenals and gonads to estrogens. Increased insulin

and bioactive IGF-1 levels that typically accompany obesity

down-regulate levels of sex hormone binding globulin (SHBG),

resulting in an increased fraction of bio available estradiol and

possibly testosterone. The epidemiologic literature suggests this

increased bioavailability of sex hormones, especially estrogen, is

strongly associated with risk of endometrial and postmenopausal

breast cancers [13] . This link is attributed to the direct proliferative

and anti-appoptotic effect of estrogen on its main target

organ: endometrium and breast and through an indirect effect

via induction of increased production of IGF-1 and consequently

increased growth promoting effects on these tissues.

“ Secondary ” associations.

In addition to the described systemic processes, some more indirect

or “ secondary ” associations between obesity and cancer

also need to be considered. Two such examples are cholelithiasis

and gall bladder carcinoma or gastroesophageal reflux and

esophageal carcinoma. Both precursor conditions are more common

among overweight and obese people than in normal weight

population due to stasis and disrupted balance of bile acids and

increased intra-abdominal pressure, respectively. Both pathologies

involve localized chronic inflammation which in turn may

lead to cancer through various pathways not necessarily specific

for obesity (see Table 1 ).



The increased cancer risk in patients with obesity is a neglected

topic which deserves more scientific attention. Because of its

extreme chronicity and co-association with numerous other

conditions true causality and underlying mechanisms are difficult to study. Nevertheless, a large body of literature is already

available which provides concepts for future research.


Conflict of interest: None.



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Obesity and Cancer Exp Clin Endocrinol Diabetes
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