# Dietary Modulation of Inflammation-Induced Colorectal Cancer through PPARγ

Authors: Ashlee B. Carter; Sarah A. Misyak; Raquel Hontecillas; Josep Bassaganya-Riera
Journal: PPAR Research
 (2009)

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## Abstract

Mounting evidence suggests that the risk of developing colorectal cancer (CRC) is dramatically increased for patients with chronic inflammatory diseases. For instance, patients with Crohn's Disease (CD) or Ulcerative Colitis (UC) have a 12–20% increased risk for developing CRC. Preventive strategies utilizing nontoxic natural compounds that modulate immune responses could be successful in the suppression of inflammation-driven colorectal cancer in high-risk groups. The increase of peroxisome proliferator-activated receptor-γ (PPAR-γ) expression and its transcriptional activity has been identified as a target for anti-inflammatory efforts, and the suppression of inflammation-driven colon cancer. PPARγ down-modulates inflammation and elicits antiproliferative and proapoptotic actions in epithelial cells. All of which may decrease the risk for inflammation-induced CRC. This review will focus on the use of orally active, naturally occurring chemopreventive approaches against inflammation-induced CRC that target PPARγ and therefore down-modulate inflammation.


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## Body

## 1. Introduction

The molecular
basis for colorectal cancer (CRC) stems from genomic instability through
genetic mutations linked to oxidative damage from chronic inflammation [1, 2].
Dissecting the inflammatory networks in the gut and identifying novel
chemopreventive approaches are important because over 149 000 people will be
diagnosed with CRC in 2009 in the United States; although there is a trend to a
lower incidence that probably can be attributed to extensive screening and
prevention efforts, almost 50 000 people will die of colon cancer this year [3, 4].
Furthermore, CRC is still the second leading cause of cancer-related mortality.
The most common risk factors for CRC include genetic predispositions
(adenomatous polyposis coli, hereditary nonpolyposis colon cancer) and
exposure to radiation but intestinal inflammation (ulcerative colitis and
Crohn’s disease) also drastically increase the risk for developing colon cancer
especially at early ages (<30 years of age) [5]. For instance,
inflammatory bowel disease (IBD) and other types of chronic inflammation
increase the risk for developing more severe colorectal cancer by 2 or 3
fold [2, 6].
Thus, the role of the immune system in the development and pathology of cancer
is a large and growing area of research [1].
In addition, developing effective chemopreventive interventions is both timely
and urgently needed.The alimentary tract is a sterile organ at very early stages of
development (i.e., embryonic and fetal phases). However, after birth, the
gastrointestinal mucosa, particularly that lining the large intestine and
terminal ileum, evolves to become densely colonized by bacteria. Specifically,
from birth to weaning, successive waves of microorganisms will colonize the
mucosa with a final result of 500–1000 species, which amount to 100 trillion
discreet microorganisms, residing in the large intestine of adult humans [7]. The number of gut
microorganisms is 10 times greater than the total number of somatic and stem
cells [8].  In healthy individuals, these bacteria contribute
to the regulation of T cell responses [9]. With a few exceptions, the
lack of regulation leads to excessive polarization toward a T helper 1 (Th1)
phenotype and initiation of IBD. The cellular interactions between T cells and
antigen-presenting cells occurring in the gut mucosa and draining lymph nodes
are tightly regulated to prevent excessive immune responses to foods and the
gut microflora, whereas a defect in down-regulation of the immune responses
predominates in individuals with IBD. The distribution and function of lamina
proprial macrophages and T cells in the gut mucosa are important determinants
of the extent and severity of the inflammatory process, and thus, represent
targets for anti-inflammatory compounds. Bioactive
food ingredients such as n-3 polyunsaturated fatty acids (PUFAs) and conjugated
linoleic acid (CLA) are well recognized to suppress colonic inflammation and
decrease the risk of colorectal cancer [10]. However, the limited
understanding about their mechanisms of anti-inflammatory action has halted
further progress in the development of nutrition-based approaches for
preventing this devastating and widespread disease.Many of the anti-inflammatory bioactive food
ingredients and nutraceuticals elicit its actions through nuclear receptors, a
broad class of transcription factors which regulate the expression of genes [11].  The peroxisome proliferator-activated
receptors (PPARs), which make up a fatty acid binding subfamily of nuclear
receptors, are involved regulating immune responses and therefore are potential
therapeutic targets for CRC [12]. Nuclear receptors are common
pharmaceutical targets for diabetes, IBD, endotoxemia.  Of note, about 13% of all FDA-approved drugs
target nuclear receptors [13]. Thus, they offer a great
potential as targets for novel chemopreventive agents against both gut
inflammation and inflammation-induced CRC.


## 2. Significance of CRC

Colorectal cancer is one of the most
prevalent types of cancer, second only to lung cancer [14].  In
2004, over 35% of all men and women in the United States diagnosed with CRC
died.  The risk of colorectal cancer in
the general population is less than 7%, though chronic inflammation
including ulcerative colitis (UC) and Crohn’s disease (CD)—the two clinical
manifestations of IBD—can increase the risk of colorectal
cancer.  More specifically, the risk of
developing colorectal cancer for an ulcerative colitis patient is estimated to
be 2% after 10 years, 8% after 20 years, and 18% after 30 years of disease
onset [15].Demographics is another factor related to
CRC, although not as strong as inflammation.
Evidence suggests that ethnicity, gender, and geography all play a role.  For instance, African American males over 50
living in the Western world are statistically at the highest risk for CRC [16]. Overall, inflammation emerges as the major
factor for developing CRC. The consequences of CRC can be significant as the
main therapies include colon removal which can lower dramatically a patient’s
quality of life, or lifelong surveillance including regular colonoscopies and
medications, some of which have significant side effects [2]. In addition, in contrast to the more
limited cost of chemoprevention, the cost of palliative treatment can represent
a major burden for many CRC patients, with frequent hospital visits and
expensive medications.  Over 1.8 billion
dollars are spent in medical care for IBD patients per year [16]. All of which could be minimized with more
effective chemopreventive approaches.


## 3. The Role of the Mucosal Immune System in CRC

The mucosal immune system consists of cells and organs associated with body surfaces directly
exposed to the environment, including lymphoid tissues associated with the
lachrymal, salivary, gastrointestinal, respiratory and urogenital tracts as
well as the lactating breasts [17]. The mucosal immune system is divided into
inductive sites, where the immune responses are initiated or induced (antigen
presentation to T cells) and effector sites, where responses are elicited (e.g.,
cytokine production, pathogen destruction).Interestingly, about 70% of the immune system
is localized in the gastrointestinal tract. Thus, understanding its
architecture, functions, and how to favorable manipulate them is paramount for a
rational design of chemopreventive approaches against both gastrointestinal
inflammation and CRC. The gut associated lymphoid tissue (GALT) includes
tonsils (lingual tonsils or Waldeyer’s ring), adenoids (nasopharyngeal
tonsils), appendix and specialized structures called Peyer’s Patches, draining
lymph nodes (i.e., mesenteric lymph nodes) in inductive sites and diffuse
lymphoid tissue including intraepithelial lymphocytes and lamina propria cells
(i.e., T cells, B cells, plasma cells, macrophages, dendritic cells,
eosinophils, and mast cells) and isolated follicles in effector sites.
Alterations in the GALT are well recognized to be an important mechanism
underlying impaired host defense in CRC patients. Diet plays an important role
in shaping the GALT as the lack of enteral delivery of nutrients decreases the
numbers of T cells in the intraepithelial spaces and lamina propria of
colorectal cancer patients [18]. In addition, the
gastrointestinal tract is in very close proximity with the intraabdominal
white adipose tissue (WAT) which in obese and overweight individuals is
populated by large numbers of inflammatory macrophages [19]. Thus, the cross-talk between
the GALT and WAT may play a role in shaping inflammatory responses that lead to
CRC. In this regard, Crohn et al. in 1932 published
a landmark paper characterizing for the first time Crohn’s disease [20]. In this study, changes in
the appearance in mesenteric adipose tissue were reported to be a key
characteristic of the disease. In line with those early findings, we have
recently found that macrophage infiltration into the intra-abdominal fat
worsens the severity of experimental IBD [21]. Epidemiological evidence
suggests a link between obesity and human CRC [22]. While the specific
mechanisms underlying this link remain unknown, obesity-related inflammation
represents a plausible explanation for this increased risk. The better
understanding of the relationship between GALT and WAT may uncover some novel
insights on mechanisms of carcinogensis and shed new light on possible
preventive approaches.The immune
modulatory activities that aid in CRC chemoprevention by suppressing
inflammation differ from the type of immune modulation after carcinogenesis has
already occurred.  Different modulatory
agents should be sought for before and after carcinogenesis in order to
heighten antitumor immune responses (i.e., T helper 1 and CD8+ T
cell-mediated cytolytic responses) and to achieve optimal therapeutic efficacy.
The mucosal immune system will play a crucial role in both phases of the
disease. Interestingly, PPARγ is expressed by all cell types that play a major
role in the pathogenesis of CRC, including epithelial cells, T cells, and macrophages
[23]. Therefore their function
can theoretically be modulated by this nuclear receptor.


## 4. Inflammation-Induced CRC

It is estimated that approximately 15% of deaths in patients with
CD and UC can be attributed to inflammation-induced CRC.  The risk of developing CRC for CD and UC
patients increases yearly, eventually reaching 12–20% increased risk after
living with disease for 30 years [24]. Markers of inflammation like C reactive
protein (CRP) whose synthesis occurs in hepatocytes and is induced by IL-6 and
TNF-α in the serum have even been used as predictors of disease severity in
advanced stages of CRC [16, 25]. While the exact mechanism for this
elevated risk is still unknown, recent studies have been investigating whether
the marked reduction in levels of the nuclear receptor PPARγ  in colons of UC patients may play a role in
their increased susceptibility to developing colorectal cancer [26]. The exact mechanisms by which inflammation leads to CRC are slowly
being elucidated.The transcription factor nuclear factor
kappa B (NF-κB), which is found at the crossroads of many inflammatory
pathways, has also been linked to tissue repair [27].
Aberrant NF-κB signaling has been proposed to be one of the mechanisms
by which chronic inflammation leads to cancer [28].  In
a murine model of intestinal cancer, adenomatous polyposis coli (APC)min/+ mice, it was shown that
the TLRs and IL-1R, through the adaptor MyD88, control the signaling of many
genes which modify tumorigenesis in the intestine, including the NF-κB-mediated
genes IL-6 and IL-1β [29].
Loss-of-function studies demonstrated that MyD88-induced IL-6 was
necessary for colon carcinogenesis [30].Another upstream regulator of NF-κB, tumor
necrosis factor alpha (TNF-α), also plays a role in the development of IBD and
CRC. TNF-α is a pro-inflammatory cytokine which activates NF-κB as a positive
autocrine feedback signal.  Once
activated, NF-κB induces further production of TNF-α and other pro-inflammatory
mediators [31]. The positive feedback loop
between TNF-α and NF-κB may lead to the overactivation of the NF-κB tissue
repair pathways, which in turn leads to tumorigenesis.  Blockade of NF-κB dramatically reduced tumor
incidence by 75% in mice with DSS colitis [32].  Popivanova et al. more recently showed that
treatment of DSS-challenged mice with a TNF-α inhibitor also reduces tumor
incidence [33].  High levels of circulating TNF-α in plasma
are associated with colorectal
adenomas [34], further confirming the link between
systemic inflammation and CRC.One of the
hallmarks of cancer cells is an uncontrolled growth and supported by a
metabolic shift from aerobic to anaerobic metabolism [35]. This leads to an increased
production of reactive oxygen species (ROS) in the electron transport
chain.  A state of chronic inflammation
may also increase production of ROS as cytokines in inflammatory sites recruit
macrophages and neutrophils which produce ROS. The ROS damage DNA which leads
to mutations and the development of cancer [36].  ROS are also involved in pathways which
progress tumor growth by increasing the production of interleukin 8 (IL-8) and
inducible nitric oxide (iNOS), and inducing the secretion of matrix
metalloprotease-1 (MMP-1) [37].  This illustrates an interaction between
dysregulated host responses characterized by excessive inflammation resulting
in genotype changes (i.e., mutations) that will in turn lead to CRC.


## 5. Role of PPARγ in Regulating Inflammation-Induced CRC

The PPARs are a subfamily of nuclear hormone receptors which recognize a wide range of ligands,
then heterodimerize with retinoid X receptor (RXR), and regulate expression of
responsive genes. They also antagonize the activity of transcription factors,
involved in inflammation and immunity such as NF-κB, activator protein-1
(AP-1), nuclear factor of activated T cells (NFAT), and STATs [38].  Three different isotypes of PPARs, each of
which represents a therapeutic target, have so far been identified: PPARα,
PPARδ, and PPARγ [39].  Of the three subtypes, PPARγ, in particular,
represents a potential therapeutic target for CRC and IBD chemoprevention.
However, the apparent ability of PPARγ to promote differentiation and
maturation of epithelial cells has also led to studies of its potential role in
the cause of CRC. Animal studies suggest both pro- and anticancer properties in
the colon [40–42],
though the bulk of studies point to PPARγ ligands as chemopreventative agents [43].PPARγ is found in
monocytes, macrophages, T cells, dendritic cells, skeletal muscle, adipocytes,
and gastrointestinal epithelium and is involved in wide range of processes
including the regulation of lipid and glucose homeostasis, inflammation, and
adipocyte differentiation [38, 44].
One way by which PPARγ acts in an anti-inflammatory capacity is through the
inhibition of NF-κB activity. More specifically, PPARγ can interact directly
with the NF-κB subunits p50 and p65 [45].
In fact PPARγ   has been shown to antagonize the NF-κB
activities through several mechanisms. A nonpathogenic bacterium present in
the human gut, B. thetaiotaomicron, acts in an
anti-inflammatory capacity in Caco-2 cells by stimulating PPARγ to act as a
nuclear-cytoplasmic shuttle for the p65 subunit of NF-κB.  PPARγ binds to the p65 subunit and prevents
NF-κB transcriptional regulation by exporting it from the nucleus [46].
In macrophages, sumoylation of PPARγ ligand-binding domain prevents the removal
of the nuclear receptor corepressor (NCoR)/histone deacetylase-3 (HDAC3)
complex from the promoters of proinflammatory genes and, therefore, blocks
NF-κB [47, 48].  Stimulation of colonic epithelial cells with
PPARγ ligands prevents the immune-induced degradation of IκB, anchoring NF-κB
in the cytosol [49].
Overall, the inhibition of NF-κB in response to the activity of PPARγ ligands
attenuates the expression of various cytokines and inflammatory cells in
colonic epithelial cells such as IL-1beta, COX-2, IL-6 IL-8, TNF-α, IFN-γ, and
iNOS [48–51].Increased
expression of PPARγ in human colorectal cancer cell lines treated with
troglitazone, a PPARγ agonist, is associated with increased differentiation [52].  This effect may exert itself due to the
interaction of PPARγ with the coactivator protein, Hic5, expressed in colonic
epithelial cells. The expression of both Hic5 and PPARγ is down-regulated in
tumors. This interaction mediates induction of gut epithelial differentiation
markers such as keratin 20 in gastrointestinal cells [53].Pioglitazone, a
synthetic agonist for PPARγ, increases protein expression of caspase-3, a
pro-apoptotic protein, and decreases protein expression of apoptotic inhibitory
proteins Bcl-2, COX-2, and XIAP in retinoblastoma protein (RB)-deficient human
CRC cells (SNU-C4 and SNU-C2A) [54].  These results have been demonstrated with
several CRC cell lines using a number of PPARγ agonists [55–58].
However, a limited number of mechanistic studies in inflammation-induced CRC
are available using naturally occurring agonists of PPARγ.


## 6. Potential Use of Naturally Occurring Agonists of PPARγ for CRC Chemoprevention

A
number of studies have examined the use of naturally occurring compounds for
the prevention and treatment of inflammatory diseases and several types of
cancer (Table1).  These naturally
occurring compounds represent naturally occurring agonists of PPARγ  and/or potential therapies for inflammation
induced-CRC. However, only a few have shown efficacy in the prevention or
treatment of CRC. Among those are n-3 polyunsaturated fatty acids (PUFAs),
which are known ligands or activators for PPARs. An active role for protein
syndecan-1, which is regulated by PUFAs and a PPARγ molecular target, has
recently been identified in causing apoptosis in both prostate and breast
cancer cells [83].  There is also some evidence to suggests
docosahexaenoic acid (DHA), one of the PUFAs, is important in cellular
apoptosis and cell cycle arrest in colorectal cancer.  DHA and eicosapentaenoic acid (EPA) work at
the molecular level through signaling pathways putting stress on proliferating
cells and ultimately causing changes in gene expression of cancer cell lines [84]. DHA has generated promising results in animal studies with transplantable or
chemically induced tumor. Success in some preclinical animal studies has led to
clinical trials, many of which are ongoing, which use n-3 PUFAs as a
nutritional supplement to reduce inflammation and modulate immune response [85]. Previously, we have
demonstrated that dietary supplementation with conjugated linoleic acid (CLA)
upregulated colonic expression of PPARγ and downregulated colonic expression
of TNF-α and inflammatory lesions in DSS-challenged pigs [86].  In DSS-challenged mice, immune and epithelial
cell PPARγ  was required for the anti-inflammatory
efficacy of CLA [75].Table 1
Natural compounds with therapeutic action against
inflammation.
Compound nameImplicationsDisease targetStudy typeMolecular targetsResveratrol
(found in red wine, white hellebore) [59, 60]PreventionSkin cancer,
colon cancer, diabetes, neurodegenerationCell culture,
rodent, phase I clinical trialInhibition or
reduction of COX-1 and COX-2, ROSBeta-carotene
(terpenoid found in yellow and orange fruits and vegetables) [61]PreventionInflammation,
high cholesterolMouse, ferretROSCurcumin
(spice derived from turmeric) [62, 63]Prevention,
therapyPancreatic
cancer, myelodysplastic syndromes, colon cancer, psoriasis, inflammationCell culture,
rat, clinical trialsInhibits, COX
activities, ROS, inhibits production of many pro-inflammatory cytokines (IL-8,
MCP-1, TNF-α)Folic acid (leafy
vegetables and grain product) [64]PreventionRectal
health, pancreatic and CRCsCell
culture/rodentInvolved in
function, synthesis, and repair of DNA in cell cycleTocopherols
(form of vitamin E found in oils and wheat germ) [65]Treatment (supplement
to anticancer drugs)Prostate and
lung cancers, CRC, and melanomaCell
culture/ratMitochondrial
interactions with compounds leading to apoptosis, upstream inhibition of NF-κBOmega-3
polyunsaturated fatty acids (PUFAs; found in grains, fish, and some oils) [66]TreatmentIBDRat, mouse,
human cancer cellsCell cycle
arrest and apoptosis through inhibition of the PI3-kinase signaling pathway,
PPARγ activationVitamin D or
calcitrol (plant sources, fungi, dairy, and fish) [67, 68]TreatmentRheumatoid
arthritis, dermatological conditions, osteoporosis, prostate, colon and
breast cancersMouse, human
clinical trialPhase G0/G1 cell cycle arrest,
regulation of cell cycle proteins, reduction of Akt and Erk which are cell
survival markersCalcium (dairy,
nuts, seeds, soy, plants such as kelp and seaweed) [67]Treatment/ preventionRheumatoid
arthritis, dermatological conditions, osteoporosis, prostate, colon cancer,
breast cancers and diabetesCell culture,
mouse, human clinical trialBalances
cellular proliferation in the colon by inducing apoptosisDietary fiber
(plant products, beans, root vegetables) [69, 70]PreventionIBD, CRCCell culture,
human clinical trialButyrate,
product of dietary fiber functions best with retenoids to inhibit histone
deacetylase, butyrate regulates colonic epithelial homeostasisProbiotics
(fermented dairy) [71, 72]Treatment/ preventionIBDHuman
clinical trialKnown
mechanisms or targets are intestinal microflora, chemical balance, binds to
carcinogens, production of short-chain FAs and anti-carcinogensPrebiotics
and synbiotics (oligosaccharides, garlic, onion, artichoke, and
asparagus) [72, 73]TreatmentColitis,
inflammation, cancerRats,  clinical trialProduction of
short-chain FAs, induce apoptosis of damaged cells, enhances activity of NK
cellsQuercetin (a
flavonoid found in cranberries and onions) [74]PreventionBreast, lung,
skin, and colon cancers, heart diseaseCell culture,
rodentROS, a
proposed aryl-hydrocarbon receptor,
suppresses pro-inflammatory mediatorsCLA (dairy,
meat) [75]PreventionIBDMouse, pigsEnhances the
immune function, activates PPARγ, downregulates pro-inflammatory cytokines through NF-κBGinseng (root
of the panax plant in the familyaraliaceae) [76]Prevention/ enhancement
of current treatmentColon cancerCell culture,
mouseSuppresses
TNF-α and NF-κB signaling decreasing inflammation. Also targets movement and
angiogenesis of carcinoma cellsTurmeric
extract (curry, curumin) [77]TreatmentArthritis,
inflammation, cardiovascular diseaseRodentInflammation,
angiogensis, eliminates free redicals and ROS, suppresses TNF-αPhytoestrogen
(soy products, whole grains) [78, 79]PreventionCRC, breast
cancer, prostate cancerRat, clinical
trialInduction of
apoptosis and inhibition of tyrosine kinases, regulates some pro-inflammatory
cytokines (IL-6) hormones which induce cancerKaempferol (flavonoid in apples, onions, broccoli,
and citrus fruits) [80]Treatment/ preventionObesity and
type II diabetes, cardiovascular
diseases, neurodegenerative diseases, cancerCell cultureUpregulates
TNF-related apoptosis-inducing ligand (TRAIL) receptors, sensitizes
cancer cells to anti-carcinogenic compounds and pathwaysGreen tea phenols (tea leaves) [81]TreatmentGastric
cancer and H. Pylori infectionsCell
culture, mouseReduce ROS,
gluthione metabolism, activates apoptotic markers and tightly regulates the
cell-cycleBlueberry
Extracts (fruit  from the shrub,vaccinium cyanococcus) [82]TreatmentCancer,
inflammationCell
culture, mouseInhibit
growth, stimulate apoptosisAnother
naturally occurring agent which shows promise in CRC isγ-Tocopherol—a vitamin
that decreases COX-2 activity and nitric oxide (NO) expression [87].  The chemoprotective effect of γ-Tocopherol
may also occur through an upregulation PPARγ as treatment of human colon
cancer cells (SW480 cells) with both 5 and 10 μM concentrations of γ-Tocopherol
resulted in an increase of both PPARγ mRNA and protein expression [88].The
role of diet in colorectal cancer may be even more important than in other
cancers due to the direct effect compounds have with the gut. This local effect
has been shown to be critical for curcumin—a compound with negligible distribution
outside the gut [89].
Broadly, methods of direct inhibition through nutraceuticals include reducing
damage to DNA by neutralizing carcinogens, cytotoxicity or apoptosis of tumor
cells, antiangiogenesis, and acting as anti-inflammatory agents [90].  In line with the concept of personalized
medicine, some physicians recommend that people with a family history of
cancers, or previously detected dysplasia or microtumors consume nutraceuticals
first and foremost in the form of food and also in the form of multivitamins to
decrease the risk of cancer [90]. However, the limited
understanding of the mechanisms of action underlying the effects of botanicals,
vitamins, and fatty acids has slowed down the rational development of preventive
and therapeutic approaches against inflammation-induced CRC.


## 7. Conclusions and Future Directions

People with CD or UC are predisposed to developing CRC, an outcome that
depends on the extent and duration of chronic inflammation, which in turn is
dependent on NF-κB and
ROS activity [6] (Figure 1). The key to maintaining
homeostasis in the gut entails both downregulating inflammation as a
chemopreventative method and promoting epithelial cell apoptosis and anti-tumor
immune responses after the onset of cancer. As such, it is reasonable to
suspect that introducing bioactive food ingredients which modulate NF-κB or ROS
pathways could be used to regulate inflammation before the onset of
cancer.  PPARγ ligands have consistently
acted as modulators and suppressors of NF-κB activity [45–48, 91].Figure 1
Chronic inflammation activates pathways
leading to cancer. Chronic inflammation stemming from ulcerative colitis (UC)
and Crohn's disease (CD), the two clinical manifestations of inflammatory bowel
disease, activates nuclear factor-κB (NF-κB) downstream of MyD88 through
the TLR and IL-1R.  In turn, NF-κB
activation increases the expression of pro-inflammatory cytokines IL-6 and
IL-1β. TNF-α also activates NF-κB which, in turn, increases the expression of
TNF-α, leading to a positive feedback loop between TNF-α and NF-κB.  Chronic inflammation also leads to the
production of ROS which can damage DNA which can cause mutations responsible for
tumorigenesis.  ROS also cause the
production of IL-8, iNOS, and MMP-1, which promote tumor growth. On the other
hand, activation of PPARγ can block carcinogenesis at two levels: (1) by
antagonizing NF-κB activity and (2) by suppressing IL-8 and iNOS expression.Thiazolidinediones (TZDs) are a well-known class of diabetes medication
which acts as PPARγ ligands.  TZDs also
suppress tumorigenesis in several types of cancers, including colon cancer [92]. Therefore, the identification of novel,
naturally occurring PPARγ ligands may represent a promising route of CRC
chemoprevention.There is also strong potential for
the use of these bioactive compounds in conjunction with current treatments as
this approach has already been shown to have positive results in cancer
treatment [43].The
therapeutic effects of dietary CLA, and PUFAs through the activation of PPARγ
have already been summarized.  Natural
compounds for the treatment of CRC through PPARγ have the potential to
modulate the immune response and to be safe, easily accessible, and
cost-effective.



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