obesity as a major risk for cancer

8/18/2019 Obesity as a Major Risk for Cancer

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Hindawi Publishing CorporationJournal o Obesity Volume , Article ID , pageshttp://dx.doi.org/.//

Review ArticleObesity as a Major Risk Factor for Cancer

Giovanni De Pergola and Franco Silvestris

Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Oncology,University of Bari “Aldo Moro”, School of Medicine, Policlinico, Piazza Giulio Cesare , Bari, Italy

Correspondence should be addressed to Giovanni De Pergola; [email protected]

Received December ; Revised July ; Accepted July

Academic Editor: Francesco Saverio Papadia

Copyright © G. De Pergola and F. Silvestris. Tis is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Te number o cancer cases caused by being obese is estimatedto be %with theincreased risko malignancies being inuencedby diet, weight change, and body at distribution together with physical activity. Reports rom the International Agency or Researchinto Cancer and the World Cancer Research Fund (WCRF) have shown that the strongest evidence exists or an association o obesity with the ollowing cancer types: endometrial, esophageal adenocarcinoma, colorectal, postmenopausal breast, prostate, andrenal, whereas the less common malignancies are leukemia, non-Hodgkin’s lymphoma, multiple myeloma, malignant melanoma,and thyroid tumours. o be able to develop novel methods in prevention and treatment, we rst must understand the underlyingprocesses which link cancer to obesity. Four main systems have been identied as potential producers o cancer in obesity:insulin, insulin-like growth actor-I, sex steroids, and adipokines. Various novel candidate mechanisms have been proposed:

chronic inammation, oxidative stress, crosstalk between tumour cells and surrounding adipocytes, migrating adipose stromalcells, obesity-induced hypoxia, shared genetic susceptibility, and the unctional deeat o immune unction. Herein, we review themajor pathogenic links between obesity and susceptibility to cancer.

1. Introduction

Obesity is a serious problem which heightens the risk o several chronic illnesses including cancer development [–].Current recommendations rom the Public Health Goals o the World Cancer Research Fund (WCRF) suggest thatthe median adult BMI should be maintained between and kg/m2, depending on the normal range or differentpopulations [].

2. Obesity and Cancer Risk

.. Epidemiology and General Factors. It has been estimatedthat about % o all cancers are caused by excess weight[], and the Million Women Study, the largest study o itskind on women, has shown that approximately hal canbe attributed to obesity in postmenopausal women [].Tere are many prospective epidemiological studies whichhave demonstrated a direct association between overweightand cancer, even though obesity alone does not apparently heighten cancer risk in all tissues by the same amount [ –].

A recent systematic review and meta-analysis o prospec-tive observational studies [], with , incident cancercases and a ollow-up greater than million person-years,has demonstrated that the obesity and cancer associationis sex specic over a wide range o malignancies, and thisremains mostly true or different geographic populations.However, cancer risk in obesity is different between ethnic

groups [] in that Arican Americans appear rather sus-ceptible to cancer, in contrast to Hispanics who appear tobe relatively protected while the association o increasedBMI with breast cancer is particularly strong in Asia-Pacicpopulations [].

Te International Agency or Research into Cancer(IARC) [] and the World Cancer Research Fund (WRCF)reports [] showed that common cancers in obese people arepredominantly endometrial, esophageal adenocarcinoma,colorectal, postmenopausal breast, prostate, and renal. Lesscommon malignancies associated with obesity are malignantmelanoma, thyroid cancers [], and leukemia, non-Hodgkin’slymphoma, and multiple myeloma [].


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Te role that obesity plays in carcinogenesis has beenbrought to the ore by data such as the rapid rise o oesophagus adenocarcinoma over the past years. In act,whether oesophageal reux is associated with adenocarci-noma [], or whether it is avoured by obesity [], thechange in oesophageal cancer morphology rom squamous to

adenocarcinoma has ollowed the worldwide rise in obesity.A urther example is provided by weight accumulation withage which is also linked to an increase in postmenopausalbreast cancer risk in women who do not ollow a menopausalhormone therapy regime [], while cohort studies haveshown that breast cancer risk was lowered by % in womenwho intentionally underwent weight loss higher than kgafermenopause[]. In addition,the Swedish Obese Subjects(SOS) study, a large prospective study which establishedthat bariatric surgery achieves an average o kg weight

reduction in obese patients with BMI higher than kg/m2

and that matched the surgery group with untreated morbidly obese women, reported a signicant reduction in cancer inci-

dence in association with substantial weight loss on a ollow-uplonger than years []. Concerning the role o childhoodobesity in adult cancer, a study perormed in a cohort o ,subjects retrospectively evaluated cancer risk related to ageand sex-specic BMI standard deviation scores (SDS) o sub-

jects aged – []. Among these subjects, the risk o cancerin adult lie was increasedby % perSD increase in childhoodBMI []. Also, an excess o weight in teenagers was linkedto doubling the mortality risk o colon cancer in adulthood[]. Because o the time lag in cancer development in thepresence o adiposity, the typical ollow-up is longer than years in cohorts assessing cancer risk, and it is thoughtthat this is an “average” lag period or obesity-related cancerdevelopment []. However, the lag period may be shorterwhen hyperoestrogenemia is a predominant mechanism, asit occurs in postmenopausal breast and endometrial cancer.

.. Relation with Body Fat Distribution. Apart rom BMI,other anthropometric measurements, such as waist-to-hipratio (WHR) or waist circumerence (WC), are currently being investigated as indicators o adiposity and cancer risk.It has been shown that cancers that are associated more withabdominal adiposity than with BMI predominantly includecolon, premenopausal breast, endometrium, and oesophagealadenocarcinoma, together with pancreas tumours [–]. Arecent longitudinal study (median o . years), perormed inparticipants rom the Framingham Heart Study, has shown

that visceral adiposity, measured by using multidetector com-puted tomography, is associated with cancer afer adjustmentor clinical risk actors and generalized adiposity []. As ormortality, a longitudinal study in US women has shown thatWC and WHR are strongly and positively associated withcancer mortality, independently o BMI [].

.. Effect of Weight Change. A Canadian case-control study has ound that those men whose weight increased by morethan kg afer reaching adulthood had a colorectal cancerrisk % higher than those with a weight increase o – kg,and the association was even stronger afer excluding thosepatients with rectal tumours []. Endometrial cancer has

also seemingly been shown to be directly correlated withweight gain during adulthood among Japanese women [].Additionally, diet-induced weight loss reduces colorectalinammation and cancer-related gene pathways in obeseindividuals [].

3. Obesity and Cancer Mortality Te American Cancer Society has urnished data which sug-gest that overweight and obesity are correlated to liver andpancreatic cancers death rates, as are both myeloma and non-Hodgkin’s lymphoma [].

Data published over the last years emphasize thatobesity is a cause o about % o deaths rom cancer inwomen while the rate is around % in men. Tese rates aresecond only to smoking or the number o avoidable cancers[]. However, these data are possibly underestimated, sinceaverage weight has continued to rise in the worldwidepopulation over the same time. Recently, Jaggers et al. ounda positive multivariable-adjusted association between cancermortality and abdominal obesity that increases the risk o cancer mortality up to % []. Epidemiological studieshave also shown that obesity is a contributing actor inboth increased incidence and mortality rom cancers o thecolon, the endometrium, the kidneys, and the breast (inpostmenopausal women) [, ]. In the European Union, it hasbeen calculated that not becoming overweight could reducethe annual incidence o colon cancer by up to , casesand breast cancer by up to , cases. Te higher cancerdeath rate in the obese also accounts or a decreased survivalrate, that may be due to the enhancing effects o obesity oncancer potency and progression. A study on invasive ductalbreast cancer in , women ound that those in the highest

quartile o BMI developed tumours with a higher histologicalgrade, mitotic cell count, and larger tumour size comparedto women in the lower quartiles []. Furthermore, by considering solely large tumours up to cm o diameter, thosein the group o the highest BMI quartile largely expressedmarkers o high prolieration, supporting their ast growth,as compared to those with similar-size tumours in nonobesewomen []. However, it has been reported that chemother-apy dosages are ofen not adequate in women o excessweightreceiving breast cancer treatments when compared to dosagesin lean women [], thus implying that an overall ull weight-based adjusted dose would allow better outcomes.

4. BMI-Cancer Associations andHistological Subtypes

Several data suggest that the BMI-cancer association is typicalo a number o histological subtypes within a site speciccancer. Tese examples include the ollowing.

(a) A dose-response meta-analysis ( cohorts: case-control studies) showed that the BMI-breast cancerassociation is stronger or oestrogen receptor posi-tive/progesterone receptor-positive (ER+PR+) tum-

ours (% increase per kg/m2 increment or post-menopausal breast cancer), while there were no


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signicant BMI-cancer associations or ER −PR- andER+PR-tumours.

(b) Detailed pathological examination o a Swedish pop-ulation-based prospective cohort (, postmeno-pausal women not using hormone therapy) showedthat the highest quartiles o BMI were associated with

ductal type tumours, grade II, low Ki index, HERnegativity, low-cyclin D expression, ERa, and PR immune-positivities, but not ERb tumours.

(c) For endometrial cancer, obesity is predominantly arisk actor or type I endometrioid tumours (account-ing or % o endometrial cancers) rather than typeII.

(d) BMI associations are stronger or the papillary sub-type o thyroid carcinoma.

(e) Positive associations exist between BMI and cardiasgastric adenocarcinomas, but not noncardia gastricmalignancies.

Te biological mechanisms responsible or stronger asso-ciation o BMI with some cancer subtypes are not known, butthese inormation might have implications in determiningthe patient’s risk and the subsequent recommendations.

5. Biological Mechanisms Linking AbdominalObesity to Cancer Susceptibility

In the obese, the mechanisms which may oster or promotecancer occurrence or progression are usually classied asbeing o two types. Tey may be universal and direct innature in that they apply to all or the majority o tumoursbecause they have to do with the hormonal and/or metabolic

abnormalities prevalent in obesity. Alternatively, they may be site specic, in which conditions can oster a particulartumour in a particular site because they have to do with theconsequential effects o obesity, so leading to complicationsinspecic tissues or organs. Tere is, or example, a heightenedrisk o cancer o the gallbladder when gallstones are presentand o oesophageal adenocarcinoma as a putative effect o aggravated gastrooesophageal reux. Also liver cancer can bea consequence o nonalcoholic steatohepatitis []. Certainly,

various syntheses o mechanisms can operate differently indifferent people.

.. Diet. Both epidemiological studies in people and exper-

iments in animals suggest that alterations in caloric intake orin quality o diet may signicantly inuence the risk o cancerdevelopment and progression. However, the separate effectso diet per se, as well as o positive energy balance, reducedphysical activity, and increased adiposity, are not easy todetermine. It is well known that caloric excess will lead toincreased cancer incidence and that positive energy balanceappears to promote cancer cell prolieration and tumourprogression. By the same token, limited long-term calorieintake has led to a decrease in cancer incidence and extendedlongevity in rodents []. Tere are many studies, not with-standing the symptomatic underreporting o surveys, whichdocument the health hazards related to diets typical o the

rst world, rich in calories, overabundant in alcohol andanimal ats, and/orlacking in plant products[]. By contrast,a dened association between low-cancer risk and a higherintake o ruit and vegetables has been proven. High-brecereal consumption has also been linked to a reduced risk o colorectal cancer, although large-scale studies do not demon-

strate such a benet []. Te negative energy balance may bean important actor in lowering the susceptibility to cancerbecause o direct or indirect effects on levels o insulin [],insulin-like growth actor-I (IGF-I) [], and inammatory biomarkers []. Interestingly, preliminary data demonstratethat a low carbohydrate insulin-inhibiting diet, associatedwith ketosis, is sae and correlated with stable disease orpartial remission in patients with advanced cancer []. It isnoteworthy that obesity is correlated with low-serum levelso - hydroxyvitamin D ( (OH)D), conrmed by a study showing that low vitamin D levelsmay be responsible or%o the cancer risk linked to increased BMI [].

.. Physical Activity. For the prevention o the onset o chronic diseases, including cancer, guidelines suggest exer-cise as part o the daily routine, a brisk walk or walkingto work instead o driving, and/or practicing more physicalactivity at home, such as using stairs or gardening []. Terehave been several studies which show that physical exercisecan lower breast cancer risk and that there are benets bothphysical and mental or cancer patients []. It has alsobeen correlated to a decrease in the risk o both colon andbreast cancer development, and probably with a lower risk o endometrial cancer [].

Regarding possible mechanisms responsible or can-cer prevention, regular physical activity helps maintain ahealthy body weight, regulates sex hormones, insulin, andprostaglandins and has various benecial effects on theimmune system []. Te specic dose o exercise needed tooptimize primary cancer prevention remains to be elucidated.

.. Insulin Resistance. Te most popular hypothesis explain-ing the association between obesity and cancer is that o lower insulin sensitivity. Excess body weight and adiposity are directly correlated with insulin resistance, compensatedor by the stimulation o pancreatic insulin secretion, andthis commonly results in hyperinsulinemia. Elevated insulinserum levels avour aster growth and increased aggressive-ness o colorectal [, ], pancreatic [], liver [], post-menopausal breast [, , ], and endometrial [, ] can-

cers. C-peptide is ofen used, preerably to insulin, as a serumbiomarker o pancreatic-cell secretory activity because o itslonger hal-lie due to the lack o hepatic extraction, its lowermetabolic clearance rate, and its lack o cross-reactivity withinsulin antibodies. Several epidemiological cohort studieshave indicated a direct correlation between circulating C-peptide levels and colorectal [, ], pancreatic [, ],liver [] endometrial [, ], and postmenopausal breast[] cancers. However, prospective cohort studies have notdemonstrated any association between prostate cancer risk and elevated C-peptide levels or high insulin levels, althougha more elevated risk o prostate cancer mortality or men withthe highest C-peptide levels has been recently reported afer


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adjustment or BMI []. Although insulin itsel does notinduce somatic cell mutations, it has anabolic and antiapop-totic effects, and it is thought that only supraphysiologicalconcentrations o insulin have mitogenic effects. Interest-ingly, cancer cells commonly have the ability to respond tothe activation effect o insulin on intracellular transduction

pathways, particularly when insulin is highly concentrated, asoccurs in obesity. Signalling by the insulin pathway is highly relevant in cancer development as both extracellular-signal-regulated kinase (ERK) and phosphatidylinositol- kinase(PI- K) pathways are triggered by activation o the insulinreceptor (IR). Te insulin receptor is highly expressed inadipose, muscle, and kidney tissues, while it is overexpressedin breast [] and prostate [] cancer cells as well as in mostnormal and neoplastic haematopoietic cells []. It has beenhypothesized that the IGF-I receptors are the mediators orthe main prolierative effects o insulin as the insulin receptor(IR) andthe receptor orIGF-I (IGF-IR) show more than %o overall sequence homology and even % o homology inthe tyrosine kinase domain o the -subunit [] while theirligands, insulin, and IGF-I share –% homology. Becauseo this, insulin and IGF-I can interact either with IR or withIGF-IR [], and both o these receptors have been associatedwith tumour development.

Regarding increased tumour invasion, biochemical andunctional analyses have demonstrated that ligand-inducedactivation o the IGF-IR kinase results in the loss o epithelialintegrity, at the same time promoting cell migration []. Inaddition to the specic receptors IR and IGF-IR, coexpressedin the same cell, a third receptor, a hybrid orm (IR-IGF-IR) between IR and IGF-IR, can mediate the effects o bothinsulin and IGF-I as a result o their high homology [].Interestingly, over-expression o both IR and IGF-IR in a

variety o cancer tissues leads to heterodimerization andthe ormation o this hybrid receptor in amounts that evenexceed IGF-IR content, especially in malignant breast andthyroid tissues []. Te hybrid receptor in malignant tissuespredominantly includes IGF-IR and IR isoorm A, which hasa higher affinity or binding IGF-I than insulin does andstimulates cell prolieration.

.. IGFs and IGF Binding Proteins (and Teir Interrelation-ship with Insulin and Insulin Resistance). Te indirect effectso hyperinsulinemia on carcinogenesis are attributable to theaction o insulin on circulating endogenous growth actorstogether with their binding proteins. In hyperinsulinemia,

the growth hormone receptor (GHR) is upregulated by theincrease o insulin concentrations in portal circulation thusincreasing GHR signalling and hepatic IGF-I synthesis [].Moreover, insulin decreases the hepatic expression o bindingproteins o IGF-I, such as insulin-like growth actor bindingproteins- and - (IGFBP-, IGFBP-) [], thus leading tohigher plasma levels and bioavailability o ree IGF-I [, ].In this context, IGFBP- inhibits the growth o breast cancercells in mice with MCF- breast cancer xenografs, as well ashepatocellular cancer growth in mice over-expressing IGF-Iand IGF-II []. IGF-I also exerts proangiogenic effectsand induces tumour-related lymphangiogenesis. In act,IGF-I induces the synthesis o hypoxia-inducible actor-a

(HIF-a), which together with vascular endothelial growthactor (VEGF) [] leads to neovascularization and metasta-ses, as shown in a colon cancer model []. Moreover,through the inhibition o p, IGF-I prevents apoptosis []and induces metastatic tumour spread, linked to integrinsmovement to the borders o migrating cells []. In addition

to insulin and IGF-I, over-expression o IGF-II, a hormoneproduced in the liver, is also associated with tumour develop-ment. IGF-II signalling takes place through IR (specically the mitogenic IR-A subtype) and IGF-IR. Another actorinuencing IGF-I ree levels is insulin-like growth actorbinding protein- (IGFBP-), which is the most prouse o the IGFBPs. Worthy o note is that visceral at accumulationleads to lower IGFBP- plasma levels [], and lowerIGFBP- concentrations lead to higher ree IGF-I levels.Moreover, IGFBP- exerts direct protective effects againstcancer development, by inducing apoptosis through bothp-dependent mechanisms and Bcl- amily proteins [].IGFBP- also interacts with the nuclear retinoid X receptor(RXR)-a, altering its binding to the transcription actor Nur and activating the apoptosis cascade [].

.. Sex Hormones. In women, BMI has been regularly cor-related with breast, endometrium, and other cancers linkedto hormones, since an increase in circulating sex steroidsrom weight excess is a well-known mechanism implicatedin cancer development. Data rom epidemiological studiesdemonstrate that the postmenopausal risk o breast cancerincreases in women with heightened levels o circulatingsex steroids, including dehydroepiandrosterone (DHEA), itssulate (DHEAS),Δ-androstenedione, testosterone, estrone,and total estradiol, and low levels o sex hormone bindingglobulin (SHBG). Endogenous sex hormones are active intumour cell growth and directly mediate the effect o obesity on cancer, in particular in tumours o the breast [–]and the endometrium []. Tere is evidence that estro-gens are mitogenic [], regulate the expression o insulinreceptor substrate- (IRS-) in the breast [], and induceree radical-mediated DNA damage, genetic instability, andgene mutations in cells. Te Million Women Study [] andprevious studies have shown that in premenopausal womenbreast cancer risk decreases with increasing BMI, while itincreases with BMI in postmenopausal women who do notpractice hormone replacement therapy, possibly owing toheightened levels emale sex hormones in circulation, causedby increased estradiol creation rom androgenic precursors

in adipose tissue through an increase in activity o thearomatase enzyme. In endometrial cancer, heightened con-centrations o plasma estradiol and estrone are correlatedwith increased cancer risk in postmenopausal obese women[] and elevations o estradiol increase endometrial cellprolieration while inhibiting apoptosis and at the same timeencouraging IGF-I synthesis in endometrial tissue []. At

variance with postmenopausal women, in premenopausalwomen a deciency o progesterone is likely to have moreinuence than any excess o estrogen. As ar the role o androgens is concerned, anthropometric parameters (BMIand waist circumerence) and testosterone levels are inversely correlated in men [] and directly associated in women [].


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Te EPIC and other epidemiological studies have demon-strated that heightened plasma levels o androgens are asso-ciated with a more elevated risk o breast cancer in womenboth pre- and postmenopausal, thereore suggesting thatandrogens may also be considered as links between obesity and breast cancer [–]. Elevated plasma androstenedione

and testosterone levels may also correlate with endometrialcancer risk in both pre- and postmenopausal women [].

.. Adipose issue and Adipokine Production. Much meta-bolic and endocrine activities take place in adipose tissue.In obesity, there is oversecretion o deleterious proinam-matory molecules like interleukin- (IL-), tumour necrosisactor- (NF-), leptin, resistin, retinol binding protein-, plasminogen activator inhibitor- (PAI-), hepatic growthactor (HGF), and so orth and hyposecretion o ben-ecial adipokines such as adiponectin and visatin [].Tese adipokines can be secreted rom both adipocytes andstromal-vascular cells, and most o these substances are

actually rom macrophages and other immune cells (-cells,etc.) that inltrate adipose tissues in obese patients [].Interestingly, human adipose tissue macrophages resem-ble human tumor-associated macrophages and increase theexpression o FAS in cancer cells, thus playing a critical rolein cancer cell survival [].

Adiponectin and leptin have been subject to much study in cancer development as they are the most abundant adipok-ines. Higher leptin levels can be a actor or ostering cancerdevelopment and progression since it is now known to bemitogenic, proinammatory, antiapoptotic, and proangio-genic []. Most experimental studies on leptin have been onbreast cancer, andthey have shown that: () leptin upregulatesoestrogen/ER signalling; () leptin intensies the expressiono aromatase and, thereore, oestrogen production []; and() leptin receptors are located in both normal and malignantbreast epithelial cells. However, while breast tumour cellsprolierate afer leptin stimulation [], transgenic mice withno leptin or its receptor have been shown to be resistantto tumour ormation []. Te idea has been put orwardthat leptin regulates hepatocellular carcinoma developmentthrough the modulation o human telomerase reverse tran-scriptase []. Tere are our splice variants o the leptinreceptor; however, only LRb has a long enough intracellulardomain to allow ull signal-transducing capabilities. LRbactivates the PI kinase, MAPK (mitogen-activated proteinkinase), and SA (signal transducer and activator transcrip-

tion) signalling pathways, which are vital or cell survival,prolieration and differentiation [], and c-os gene tran-scription. Interestingly, isoorms may also have differentialroles in ER-positive and ER-negative breast cancer cells [].

Blocking cancer-stromal cell communication may well bea strategy to target breast cancer therapy, and, interestingly,it has been shown that leptin drives tumour progressionby a bidirectional crosstalk between breast cancer cells andcancer-associated broblasts [].

Adiponectin, being the most abundant adipokine, isparticularly interesting because it enhances insulin sensitiv-ity, and its circulating levels are inversely related to canceroccurrence and cancer stage []. However, adiponectin

serum levels correlate negatively with BMI and even morenegatively with visceral adiposity [] while insulin andestrogens may suppress its secretion []. Adiponectin has aprotective role in carcinogenesis, indirectly by acting againstthe development o insulin resistance [] and directly, asin vitro and in vivo studies have shown, by activating the

AMPK pathway [] and inactivating MAPK kinases and and ERK and ERK []. Moreover, adiponectin stimulatesapoptosis through the induction o p and Bax expressionand the decrease o Bcl- expression [], inhibits angiogen-esis and cell migration [], exerts an anti-inammatory role,and induces downregulation o vascular adhesion molecules,thus reducing tumour spread []. Last, adiponectin preventsthe interaction o various growth actors with their receptors[]. Adiponectin levels have been studied in relation tothe risk o several cancer types. In breast cancer, two case-control studies showed inverse correlations, one study in pre-and postmenopausal women [] and the other one only in postmenopausal cases []. Breast cancer risk was muchlower in postmenopausal women with elevated adiponectinlevels in a large prospective case-control study in two NorthAmerican cohorts []. For endometrial cancer, two case-control studies have reported signicant inverse correlationswhich seem stronger in younger women [] while a prospec-tive case-control study, nested within the EPIC, ound alower risk or women in the highest versus lowest quartileso adiponectin afer adjustment or BMI []. Te HealthProessionals Follow-up Study reported that low adiponectinblood levelswas a risk actoror colorectal cancerin men [],but this nding has not been conrmed in other prospectivestudies. Tere are no clear-cut results available or other can-cers such as pancreas adenocarcinoma or prostate cancer innonsmoker populations. Several studies have suggested thatthe activation o peroxisomeprolierator-activated receptor-(PPAR-) may be involved in cancer development in obesity,since it inhibits cell prolieration and induces apoptosis in

vitro, possibly by antagonizing the activities o NF-B [].Obesity has several eatures or altered PPAR- unction,

which include an increased production o PAI-, and thereare diverse studies which show that PAI- promotes tumourgrowth through the inhibition o apoptosis. It is also anindicator o poor prognosis or several cancers such asbreast cancer []. PAI- also seems to be involved in angio-genesis, enhanced cell adhesion, and increased migration[]. Furthermore, in breast cancer, PAI- is implicated ininammatory response, neutrophil recruitment, and proli-

eration o smooth muscle cells. PPAR- dysregulation andPAI- overproduction in adipose tissue o obese womenmay change the breast microenvironment and acilitate localcancer development and/or metastasis []. Maury et al. haveidentied other adipokines that are oversecreted by omentaladipose tissue (A) in obesity and which positively correlatewith BMI, insulin resistance, and hypoadiponectinemia [].In particular, the circulating concentrations o adipokinessuch as growth-related oncogene actor (GRO-), tissueinhibitor o metalloproteinases- (IMP-), and thrombopoi-etin (PO) are increased in severely obese women [, ].Tereore, high levels o these molecules are suspected topromote cancerogenesis especially as GRO- is involved


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in inammation, angiogenesis, and tumorigenesis [], andhigh levels o GRO- and IMP- may play a role by enhancing cell prolieration, antiapoptotic activity, and/orangiogenesis [], while PO stimulates the prolieration anddifferentiation o megakaryocytes [].

.. Chronic Inammation and Nuclear Factor-B System.Obesity is correlated to chronic inammatory response, withabnormally high cytokine production and the activationo proinammatory signalling pathways. Te subclinicallow-grade chronic inammatory state in obesity might beimportant in the initiation and promotion o cancer cells [].Prospective studies have reported that an increase in circu-lating C-reactive protein (CRP) is associated with increasedrisk o colorectal cancer, and, in particular, it has been shownthat genetic variation in the CRP gene inuences risk o both colon and rectal cancer developments []. A case-control study has also provided epidemiological evidence thatendometrial carcinogenesis may be promoted by an inam-matory milieu []. O the two different pathways which link inammation with tumorigenesis, one is an extrinsic pathway mediated by chronic inammation (inammation-inducedcancer) and the other an intrinsic pathway where geneticalterations, without underlying inammation, originate atumor-driven host immune response creating a microen-

vironment made up o inammatory cells (cancer-inducedinammation) []. Both intrinsic and extrinsic pathwayslink inammation and cancer by a number o oncogenes(ras/ra, ReIB, nuclear oncogenes, oncosuppressors, etc.) [,]. Interestingly, abundant literature suggests that energy accumulation plays an important part in the origin o chronicinammation [], and, in act, caloric restriction induceslow inammation. Recent evidence gives support to theidea that the inammatory response is to increase energy expenditure through eedback to compensate or the excesso energy in obesity, andi this eedback system is not efficient(inammation resistance), energy expenditureis lowered andenergy is conserved which then leads to obesity [].

.. Crosstalk between umour Cells and Surrounding Adi- pocytes and Migrating Adipose Stromal Cells. umour pro-gression is now seen as resulting rom the crosstalk betweentumour cells and the “normal” cells which surround them.In breast cancer, mature adipocytes are part o the breastcancer tissue and thus contribute to cancer progression ashighlyspecialized endocrine cellscapable o modiying breast

cancer cell behaviour. It has been proposed that evolvingbidirectional crosstalk is unctional between breast can-cer cells and tumour-surrounding adipocytes, and that thetumour-modied adipocytes are actively involved in tumourprogression []. umour vasculogenesis is also essentialin cancer development, and a possible source o progenitorcells or new vessels could be mesenchymal stromal cells(MSCs) which differentiate into different phenotypes, andwhich, though at low plasma concentrations, can be attractedby pathological signals such as hypoxia or inammationto specic tumour sites where they promote angiogenesis,driving tumour progression, and become tumour stromalcells. Other than rom bone marrow, MSCs may arise rom

white adipose tissue (WA) and other sources []. It hasbeen suggested that a higher requency o MSCs in periph-eral blood may well be a diagnostic marker or colorectalcancer [], and changes in circulating MSCs dependent onBMI, possibly mobilized rom white adipose tissue, may beaddressed to tumors, representing a link between obesity and

cancer progression.

.. Adipose issue and Vascular Growth Factors. Not only doobese patients with different types o cancers have a worseprognosis but also they have an increased risk o metastaticdisease and a shorter remission period afer treatment, per-haps because angiogenesis may be exacerbated in obesity []. In angiogenesis, there is an equilibrium between angi-ogenic actors, which stimulate the prolieration and migra-tion o endothelial cells, and antiangiogenic actors, whichinhibit these activities. Endothelial cells abound in adiposetissue, and they secrete angiogenic actors, such as VEGF andHGF, which have autocrine/paracrine actions and endocrineeffects elsewhere. Antiangiogenic actors such as angiostatin,endostatin, and adiponectin are also expressed in adiposetissue []. An altered balance between vascular growthactors and inhibitors is typical o obesity, with expansion o the capillary bed in regional at depots [], thus possibly contributing to the increased risk o metastatic disease inobese subjects with cancer.

.. Obesity-Induced Hypoxia. Oxygen levels in the WA o obese mice are considerably lower than those o lean mice[], and adipose tissue hypoxia may contribute to cancerrisk. In particular, transcription actor HIF- is correlatedwith increased metastatic spread and poor prognosis [].Studies rom Bedogni et al. have previously demonstrated

the importance o mild hypoxia o the skin in melanocytetransormation and the development o melanoma [].

.. Oxidative Stress. Antioxidant activities may be indepen-dently decreased by obesity, thus increasing systemic oxida-tive stress, in part through the inammatory process andin part independently o other mechanisms []. Increasedoxidative damage to DNA may heighten cancer risk.

.. Shared Genetic Susceptibility. Genetic predispositionto obesity may predispose to the development o certaintumours, and it is now possible to identiy in associatedregions likely mutual candidate genes or cancer and obesity,

independently o diabetes. Recently, a study in Scotland[] reported that variants o common single nucleotidepolymorphism around the melanocortin receptor (MCR)gene are associated with both obesity and colorectal cancer.

.. EndocrineDisruptors. Exposure to endocrine disruptorssuch as stress and ood contaminants, which have an effecton the regular activity o estrogens, androgens, and insulinmay also affect the simultaneous development o obesity andcancer [].

.. Energy Homeostasis and Cancer. Coupled to insulinsignalling, nutrientsensing pathways havebeen hypothesized


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to play a role in carcinogenesis. Several studies are currently examining targets such as AMP-activated protein kinase(AMPK), mammalian target o rapamycin (mOR), atty acid synthase, deacetylase SIR (sirtuin ), and epigeneticmodulators [].

.. Obesity, Immune Function and Risk of Cancer. Immunesystem alterations may be important in the higher incidencerates o cancer in obese patients since obesity has been cor-related to a reduced immunocompetence in humans. Moulinet al. have recently shown that severely obese patients have asignicantly lower natural killer(NK) cell cytotoxic activity ascompared to normal individuals matched or age and gender,with lower deence against invaders such as precancerous andcancerous cells []. Interestingly, weight loss (% less o initial weight) is responsible or an increase in NK cytotoxicactivity afer months rom gastric bypass surgery [].Lynch et al. have recently shown that omental invariant NK(iNK) cell requencies were lower in patients with severe

obesity as compared to lean healthy subjects, thus suggestinga novel role or the omentum in immune regulation andtumor immunity [].

Te ollowing list shows the possible actors involved inthe development o cancer in obesity.

Anthropometric parameters:

body mass index (BMI) [],

weight increase [, ],

visceral at [–].

Liestyle actors:

hypercaloric diet [, ],

highintake o animal at, trans-attyacids, andrenedcarbohydrates and low intake o ber, vegetables,ruit, whole grain carbohydrates, and -hydroxyvi-tamin D ((OH)D) [, , ],

sedentary liestyle [, ].

Biological mechanisms:

hyperinsulinemia and insulin resistance [, –,, ],

IGF-I, IGF-II, and IGF binding proteins [],

sex hormones and sex hormone binding globulin[–],

chronic whole body low-grade inammation [–

],

adipose tissue inammation [],

adipose tissue adipokine production (leptin, adi-ponectin, resistin, PAI-, growth-related oncogenes,etc.) [–, –, , ],

adipose tissue vascular growth actors [, ],

shared genetic susceptibility [],

oxidative stress [],

endocrine disruptors [],

immune unction (NK cells and invariant NK cells)[, ].

6. Conclusions

Obesity is responsible or approximately % o all malignan-cies, although its inuence is gender and site specic. Teassociation between obesity anda higher cancerrisk is mainly due to anthropometric parameters and liestyle actors whichactivate different biological mechanisms. Anthropometricparameters areBMI, weight increase, andthe amount o body at,particularlyvisceral at.Liestyle actors include sedentary habits and diet parameters, such as a hypercaloric and/orlow-quality diet. Te most important biological mechanismsmediating the unavourable inuence o the above actorsare hyperinsulinemia and insulin resistance, the activities o IGFs and IGF binding proteins, sex hormones and SHBG,general and adipose tissue low-grade inammation, changesin adipose tissue production o adipokines and vasculargrowth actors, oxidative stress, endocrine disruptors, andalterations in immune unction. We do not yet have a clearscientic demonstration that avoiding increasing or reducingbody weight signicantly reduces the risk o cancer; however,

the data rom the surgical treatment o obese patients with aBMI higher than . are leading in this direction.

Acknowledgments

Tis work was supported by a Grant (IG, ) rom theItalian Association or Cancer Research (AIRC), the ItalianMinistry o University and Scientic Research (MIUR), PRIN, and local unds (e.g., % o University o Bari).

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