# Peroxisome Proliferator-Activated Receptors and Progression of Colorectal Cancer

Authors: Dingzhi Wang; Raymond N. DuBois
Journal: PPAR Research
 (2008)

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## Abstract

The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily.  These receptors are also ligand-dependent transcription factors responsible for the regulation of cellular events that range from glucose and lipid homeostases to cell differentiation and apoptosis.  The importance of these receptors in lipid homeostasis and energy balance is well established.  In addition to these metabolic and anti-inflammatory properties, emerging evidence indicates that PPARs can function as either tumor suppressors or accelerators, suggesting that these receptors are potential candidates as drug targets for cancer prevention and treatment.  However, conflicting results have emerged regarding the role of PPARs on colon carcinogenesis.  Therefore, further investigation is warranted prior to considering modulation of PPARs as an efficacious therapy for colorectal cancer chemoprevention and treatment.


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## Body

## 1. Introduction

Understanding  the biology of intestinal epithelial cells may reveal the molecular
pathogenesis of a number of digestive diseases.
One such disease, colorectal cancer (CRC), leads to significant
cancer-related morbidity and mortality in most industrialized countries. Initiation and progression of CRC are a complex process
that results from the loss of the normal regulatory pathways that govern a balance between
epithelial cell proliferation and death. For
example, alterations in multiple pathways such as Wnt/APC, COX-2, and
Ras are known to play major roles in CRC progression. The standard treatment for advanced
malignancies has improved greatly over the past decade but is still not
satisfactory. Therefore, significant
effort has been exerted to identify novel drug targets for both the prevention
and treatment of this disease. One group
of compounds found to decrease the risk of colorectal cancer includes
nonsteroidal anti-inflammatory drugs (NSAIDs), which target the cyclooxygenase
enzymes (COX-1 and COX-2). However,
prolonged use of high doses of these inhibitors (except for aspirin) is
associated with unacceptable cardiovascular side effects [1–3]. Thus, it is now crucial to develop more effective
chemopreventive agents with minimal toxicity and maximum benefit.Dietary fat intake is an environmental factor that is associated with some human
diseases such as diabetes, obesity, and dyslipidemias. Some nuclear hormone receptors play a central role in regulating
nutrient metabolism and energy homeostasis. These nuclear
receptors are activated by natural ligands, including fatty acids and
cholesterol metabolites. Among these
receptors, special attention has been focused on the members of the peroxisome
proliferator-activated receptors (PPARs) family, which were initially identified as mediators
of the peroxisome proliferators in the early 1990s [4]. PPARs
play a central role in regulating the storage and catabolism of dietary fats
via complex metabolic pathways, including fatty acid oxidation and lipogenesis [5]. To date, three mammalian PPARs have been
identified and are referred to as PPARα (NR1C1), PPARδ/β (NR1C2), and PPARγ (NR1C3). Each PPAR isotype displays a tissue-selective
expression pattern. PPARα and PPARγ are predominantly present in the liver
and adipose tissue, respectively, while PPARδ expresses in diverse tissues [6]. In common with other members of the type II
steroid hormone receptor superfamily, PPARs are ligand-dependent transcription
factors and form heterodimers with another obligate nuclear receptors, such as
retinoid X receptors (RXRs) [4, 7, 8]. Each PPAR-RXR
heterodimer binds to the peroxisome proliferator responsive element (PPRE)
located in the promoter region of responsive genes.It is well established that modulation of PPAR activity maintains cellular and whole-body
glucose and lipid homeostases. Hence, great efforts have been made to
develop drugs targeting these receptors. For example, PPARγ synthetic agonists, rosiglitazone and
pioglitazone, are antidiabetic agents which suppress insulin resistance in
adipose tissue. The antiatherosclerotic and hypolipidemic agents including fenofibrate and gemfibrozil are PPARα synthetic agonists that induce hepatic
lipid uptake and catabolism. Genetic and
pharmacological studies have also revealed important roles of PPARδ in regulating lipid metabolism and energy
homeostasis. Genetic studies indicate that overexpression of constitutively active PPARδ in mouse
adipose tissue reduced hyperlipidemia, steatosis, and obesity induced by either
genetics or a high-fat diet. In contrast, PPARδ null mice treated in similar fashion exhibited an obese
phenotype [9]. Pharmacologic
studies demonstrate that the PPARδ selective-agonist (GW501516) attenuated
weight gain and insulin resistance in mice fed with high-fat diets [10] and increased HDL-C while
lowering tryglyceride levels and insulin in obese rhesus monkeys [11].
Furthermore, preclinical studies revealed that PPARδ agonists diminished metabolic
derangements and obesity through increasing lipid combustion in skeletal muscle
[12]. These results suggest that PPARδ agonists are potential
drugs for use in the treatment of dyslipidemias, obesity, and insulin resistance. Therefore,
the PPARδ agonist (GW501516) is currently in phase III clinical trials to evaluate its use for treatment of patients with
hyperlipidemias and obesity. However, recent studies showing
that some agonists of PPARs promote carcinogenesis in animal models have raised concerns about
using these agonists for the treatment of metabolic diseases. For example, long-term administration
of a PPARα agonist induces the development of
hepatocarcinomas in mice but not in PPARα null animals, conclusively
demonstrating that PPARα mediates these effects in promoting
liver cancer [13]. Furthermore, the PPARδ agonist (GW501516) accelerates
intestinal polyp growth in ApcMin/+ mice [14, 15]. These results raise concerns for developing this class of agents
for human use and support the rationale for developing PPARδ antagonists as chemopreventive agents.


## 2. PPARS and Colorectal Cancer

Significant effort has been concentrated on deducing the role of PPARs in CRC and other cancers. A large body of evidence indicates that PPARγ serves as a tumor suppressor. Contradictory evidences suggest that PPARδ can act as either a tumor suppressor or tumor promoter. A few evidences support a
role of PPARα in CRC.


### 2.1. PPARα

Although the tumor-promoting effects of PPARα in hepatocarcinomas are clear, less is known about the role
of PPARα in human tumors.
Generally, activation of PPARα by exogenous agonists
causes inhibition of tumor cell growth in cell lines derived from CRC,
melanoma, and glial
brain tumors [16–18]. There is no
evidence showing that PPARα expression is elevated in human
cancers.


### 2.2. PPARγ

The prominent role of PPARγ in regulating cellular differentiation
prompted a great effort to investigate the function of PPARγ in cancer field. While PPARγ is elevated in CRC [19], suggesting that this
receptor may contribute to tumor biology, studies of PPARγ mutation in CRC from humans, animals, and cultured cells
produced controversial results. One study showed that 8% of primary human colorectal tumors had a loss of function mutation in one allele of
the PPARγ gene [20]. Recent data revealed
that a Pro12Ala (P12A) polymorphism in the PPARγ gene is associated with increased
risk of CRC [21, 22]. These results
suggest a putative role for this receptor as a tumor suppressor. In contrast, another study showed that mutant
PPARγ gene has not been detected in human colon tumor samples and
CRC cell lines, suggesting that PPARγ mutations in human CRC is a rare event [23].In vitro studies show that activation of PPARγ results in growth arrest of colon
carcinoma cells through induction of cell-cycle arrest or/and apoptosis. Several potential downstream targets of PPARγ for mediating antitumor effects of PPARγ have been identified in various cancer cell types. Activation of PPARγ negatively regulatescell cycle progression by modulating a number of cell cycle
regulators: (1) inhibiting E2F activity in transformed adipogenic cells [24], (2) Rb hyperphosphorylation in vascular smooth muscle
cells and pituitary adenoma cells [25, 26], (3) cyclin D1 expression in Ras-transformed
intestinal epithelial cells, pancreatic, or breast cancer cells [27–29], and (4) inducing CDK inhibitor expression
such as p18, p21, and p27 in hepatoma cells [30]. Activation of PPARγ has also been reported to inhibit tumor cell growth by
upregulation of the transcriptional repressor TSC22 in colon cancer cells [31] and GADD153 in nonsmall-cell lung carcinoma cells [32]. PPARγ agonists induce apoptosis by induction
of PTEN expression in pancreatic, breast, and colon cancer cells [33] and inhibition of NFκB and Bcl-2 expression in colon cancer
cells [34]. Moreover, PPARγ exhibits antiangiogenic effects by
inhibiting VEGF expression in tumor cells and VEGF receptors in endothelial
cells [35, 36]. It has also been reported that PPARγ agonists suppress tumor cell invasion in colon and breast
cancer cells by downregulation of matrix metalloproteinase-7 (MMP-7) and
induction of MMP inhibitors [37, 38]. In addition, the
ability of PPARγ to suppress tumor growth is also through inhibiting APC/β-catenin and
COX-2/PGE2 signaling pathways, which are pivotally involved in colon
carcinogenesis [39–42].However, the role of PPARγ in colorectal cancer progression is
controversial because there are conflicting results in mouse models of colon
cancer. Although PPARγ agonists inhibit colorectal carcinogenesis in
xenograft models and in the azoxymethane (AOM)-induced colon cancer model [43, 44], these drugs are reported to have both
tumor-promoting and tumor-inhibiting effects in a mouse model for familial
adenomatous polyposis, the ApcMin/+ mouse. It has been reported that administration
of PPARγ agonists significantly increases the number
of colon adenomas in the ApcMin/+ mice [45–47] and even in wild-type C57BL/6 mice [48]. However, other studies show that
treatment of 2 different Apc-mutant models (ApcMin/+
and ApcΔ1309) with the PPARγ agonist pioglitazone resulted in reduction in the number of
both small and large intestinal polyps in a dose-dependent manner [49, 50]. These
paradoxical observations appear to have been resolved by genetic studies
showing that the heterozygous disruption of PPARγ is sufficient to increase tumor number
in AOM-treated mice and that intestinal-specific PPARγ knockout promotes tumor growth
in ApcMin/+ mice [39, 51]. These genetic evidences support the hypothesis that
PPARγ serves as tumor suppressor in
colorectal cancer. One possible explanation for the differences in phenotype caused by pharmaceutical versus genetic
manipulation of PPARγ in mouse models may be due to the PPARγ-independent effect of the agonist
drugs, drug doses used, and animal models employed. This controversial extends beyond CRC.
For example, data are conflicting from different animal models of breast
cancer as well. PPARγ agonist suppresses NMU-induced mammary
carcinomas [52].
However, overexpression of a constitutively active form of PPARγ accelerates mammary gland tumor development
in MMTV-PyV transgenic mice [53].


### 2.3. PPARδ

PPARδ has been shown to play an important role in
embryo implantation [54], atherogenic inflammation [55], regulating cell survival
in the kidney following hypertonic stress [56], and skin following wound
injury [57, 58]. The role of PPARδ in colorectal carcinogenesis is more controversial than that of PPARγ.
The first evidence linking the PPARδ to carcinogenesis actually emerged from
studies on gastrointestinal cancer. PPARδ is elevated in most human colorectal cancers
and in tumors arising in the ApcMin/+ mice, and AOM-treated
rats [59, 60]. Importantly, the PPARδ proteins are accumulated only in human CRC cells with highly
malignant morphology [61]. Downregulation of PPARδ is correlated with antitumor effects of
dietary fish oil/pectin in rats treated with radiation and AOM [62]. PPARδ was identified as a direct
transcriptional target of APC/β-catenin/Tcf pathway and as a repression
target of NSAIDs [59, 63]. A
case-control study in a large population showed that the protective
effect of NSAIDs against colorectal adenomas was reported to be modulated by a
polymorphism in the PPARδ gene [64]. PPARδ expression and activity are also induced by oncogenic
K-ras [65]. In addition, COX-2-derived PGl2 directly transactivates
PPARδ [60], and COX-2-derived PGE2 indirectly induces PPARδ activation in CRC, hepatocellular carcinoma,
and cholangiocarcinoma cells [66–68]. These studies indicate that PPARδ is a focal point of cross-talk between
these signaling pathways.In a murine xenograft cancer model, the disruption of both PPARδ alleles in human HCT-116 colon carcinoma cells
decreased tumorigenicity, suggesting that activation of PPARδ promotes
tumor growth [69]. However, PPARδ has been reported to have both
tumor-promoting and tumor-inhibiting effects based on conflicting data obtained
from mouse models of colon cancer. For
example, activation of PPARδ by a selective synthetic PPARδ agonist (GW501516) or a PPARδ endogenous activator (PGE2)
accelerates intestinal adenoma growth in ApcMin/+ mice by promoting
tumor cell survival [14, 66]. A subsequent
genetic study showed that deletion of PPARδ attenuates both small and large
intestinal adenoma growth, and PPARδ is required for the tumor-promoting
effects of PPARδ ligand (GW501516) and PGE2 in ApcMin/+
mice [15, 66]. Another study
showed that loss of PPARδ in ApcMin/+ mice
significantly reduced growth of tumors larger than a diameter of 2 mm, even
though PPARδ deficiency did not affect overall tumor incidence [70]. In contrast to these reports suggesting that PPARδ serves as tumor accelerator, recent conflicting
reports show that PPARδ deficiency enhances
polyp growth in ApcMin/+ and AOM-treated mice in
the absence of exogenous PPARδ stimulation [71, 72].
Moreover, a PPARδ ligand (GW0742) inhibits colon carcinogenesis in AOM-treated mice but promotes
small intestinal polyp growth in ApcMin/+
mice [73].One explanation for these disparate results may be due to differences in the
genetic background ofApcMin/+ mice, animal breeding,
or possibly to differences in the specific targeting strategy employed to delete PPARδ.
For example, the average number of polyps in 13-week old ApcMin/+ mice
on a C57BL/6 genetic background is about 50, while the polyp number in ApcMin/+
mice on a mixed-genetic-background (C57BL/6 × 129/SV) is about 120. Our results also show that the breeding strategy
affects the number and size of polyps in mice even on the same genetic
background. Mice generated
by breeding female PPARδ−/−/ApcMin/+ with
male PPARδ−/−/Apc+/+ exhibit increased
adenoma number with a larger average size than those obtained by breeding
female PPARδ−/−/Apc+/+ with
male PPARδ−/−/ApcMin/+. Finally, the
PPARδ null mice we studied were obtained from
Beatrice Desvergne in Switzerland. These mice were generated by deleting exons 4 and 5 encoding
the DNA binding domain [74], while Peters group generated the
PPARδ knockout mice by inserting a neomycin resistance cassette into
the last exon (exon 8) [75]. It has been suggested that the strategy employed to disrupt PPARδ by the Peters group might have led to a hypomorphic allele, which
retains some aporeceptor function, thus making it difficult to correctly
interpret their results. Indeed,
conflicting results in the context of embryonic lethality have also been
observed from these two PPARδ mutant mouse strains [74, 75].
To further clarify the role of PPARδ in colorectal tumorigenesis, it is
important to investigate the role of PPARδ in animal models that are dependent on
activation of other oncogenes or disruption of other tumor suppressors to
verify our conclusions that activation of PPARδ is proneoplastic.Studies in other types of
cancer also support the hypothesis that PPARδ serves as a tumor accelerator. A selective PPARδ agonist (GW501516) has been shown to stimulate proliferation
of human breast, prostate, and hepatocellular carcinoma cells [68, 76, 77]. In a xenograft model, blocking PPARδ activation reduced ovarian tumor growth
[78]. PPARδ knockout mice exhibited significant
impaired angiogenesis and tumor growth after these mice were injected s.c. with
mouse Lewis lung carcinoma and melanoma cells [79].
In a mouse mammary tumor model, treatment with the PPARδ agonist (GW501516) accelerated tumor formation, while a PPARγ agonist (GW7845) delayed tumor growth [80]. Taken
together, the role of PPARδ in cancer biology
remains unclear.


## 2.1. PPARα

Although the tumor-promoting effects of PPARα in hepatocarcinomas are clear, less is known about the role
of PPARα in human tumors.
Generally, activation of PPARα by exogenous agonists
causes inhibition of tumor cell growth in cell lines derived from CRC,
melanoma, and glial
brain tumors [16–18]. There is no
evidence showing that PPARα expression is elevated in human
cancers.


## 2.2. PPARγ

The prominent role of PPARγ in regulating cellular differentiation
prompted a great effort to investigate the function of PPARγ in cancer field. While PPARγ is elevated in CRC [19], suggesting that this
receptor may contribute to tumor biology, studies of PPARγ mutation in CRC from humans, animals, and cultured cells
produced controversial results. One study showed that 8% of primary human colorectal tumors had a loss of function mutation in one allele of
the PPARγ gene [20]. Recent data revealed
that a Pro12Ala (P12A) polymorphism in the PPARγ gene is associated with increased
risk of CRC [21, 22]. These results
suggest a putative role for this receptor as a tumor suppressor. In contrast, another study showed that mutant
PPARγ gene has not been detected in human colon tumor samples and
CRC cell lines, suggesting that PPARγ mutations in human CRC is a rare event [23].In vitro studies show that activation of PPARγ results in growth arrest of colon
carcinoma cells through induction of cell-cycle arrest or/and apoptosis. Several potential downstream targets of PPARγ for mediating antitumor effects of PPARγ have been identified in various cancer cell types. Activation of PPARγ negatively regulatescell cycle progression by modulating a number of cell cycle
regulators: (1) inhibiting E2F activity in transformed adipogenic cells [24], (2) Rb hyperphosphorylation in vascular smooth muscle
cells and pituitary adenoma cells [25, 26], (3) cyclin D1 expression in Ras-transformed
intestinal epithelial cells, pancreatic, or breast cancer cells [27–29], and (4) inducing CDK inhibitor expression
such as p18, p21, and p27 in hepatoma cells [30]. Activation of PPARγ has also been reported to inhibit tumor cell growth by
upregulation of the transcriptional repressor TSC22 in colon cancer cells [31] and GADD153 in nonsmall-cell lung carcinoma cells [32]. PPARγ agonists induce apoptosis by induction
of PTEN expression in pancreatic, breast, and colon cancer cells [33] and inhibition of NFκB and Bcl-2 expression in colon cancer
cells [34]. Moreover, PPARγ exhibits antiangiogenic effects by
inhibiting VEGF expression in tumor cells and VEGF receptors in endothelial
cells [35, 36]. It has also been reported that PPARγ agonists suppress tumor cell invasion in colon and breast
cancer cells by downregulation of matrix metalloproteinase-7 (MMP-7) and
induction of MMP inhibitors [37, 38]. In addition, the
ability of PPARγ to suppress tumor growth is also through inhibiting APC/β-catenin and
COX-2/PGE2 signaling pathways, which are pivotally involved in colon
carcinogenesis [39–42].However, the role of PPARγ in colorectal cancer progression is
controversial because there are conflicting results in mouse models of colon
cancer. Although PPARγ agonists inhibit colorectal carcinogenesis in
xenograft models and in the azoxymethane (AOM)-induced colon cancer model [43, 44], these drugs are reported to have both
tumor-promoting and tumor-inhibiting effects in a mouse model for familial
adenomatous polyposis, the ApcMin/+ mouse. It has been reported that administration
of PPARγ agonists significantly increases the number
of colon adenomas in the ApcMin/+ mice [45–47] and even in wild-type C57BL/6 mice [48]. However, other studies show that
treatment of 2 different Apc-mutant models (ApcMin/+
and ApcΔ1309) with the PPARγ agonist pioglitazone resulted in reduction in the number of
both small and large intestinal polyps in a dose-dependent manner [49, 50]. These
paradoxical observations appear to have been resolved by genetic studies
showing that the heterozygous disruption of PPARγ is sufficient to increase tumor number
in AOM-treated mice and that intestinal-specific PPARγ knockout promotes tumor growth
in ApcMin/+ mice [39, 51]. These genetic evidences support the hypothesis that
PPARγ serves as tumor suppressor in
colorectal cancer. One possible explanation for the differences in phenotype caused by pharmaceutical versus genetic
manipulation of PPARγ in mouse models may be due to the PPARγ-independent effect of the agonist
drugs, drug doses used, and animal models employed. This controversial extends beyond CRC.
For example, data are conflicting from different animal models of breast
cancer as well. PPARγ agonist suppresses NMU-induced mammary
carcinomas [52].
However, overexpression of a constitutively active form of PPARγ accelerates mammary gland tumor development
in MMTV-PyV transgenic mice [53].


## 2.3. PPARδ

PPARδ has been shown to play an important role in
embryo implantation [54], atherogenic inflammation [55], regulating cell survival
in the kidney following hypertonic stress [56], and skin following wound
injury [57, 58]. The role of PPARδ in colorectal carcinogenesis is more controversial than that of PPARγ.
The first evidence linking the PPARδ to carcinogenesis actually emerged from
studies on gastrointestinal cancer. PPARδ is elevated in most human colorectal cancers
and in tumors arising in the ApcMin/+ mice, and AOM-treated
rats [59, 60]. Importantly, the PPARδ proteins are accumulated only in human CRC cells with highly
malignant morphology [61]. Downregulation of PPARδ is correlated with antitumor effects of
dietary fish oil/pectin in rats treated with radiation and AOM [62]. PPARδ was identified as a direct
transcriptional target of APC/β-catenin/Tcf pathway and as a repression
target of NSAIDs [59, 63]. A
case-control study in a large population showed that the protective
effect of NSAIDs against colorectal adenomas was reported to be modulated by a
polymorphism in the PPARδ gene [64]. PPARδ expression and activity are also induced by oncogenic
K-ras [65]. In addition, COX-2-derived PGl2 directly transactivates
PPARδ [60], and COX-2-derived PGE2 indirectly induces PPARδ activation in CRC, hepatocellular carcinoma,
and cholangiocarcinoma cells [66–68]. These studies indicate that PPARδ is a focal point of cross-talk between
these signaling pathways.In a murine xenograft cancer model, the disruption of both PPARδ alleles in human HCT-116 colon carcinoma cells
decreased tumorigenicity, suggesting that activation of PPARδ promotes
tumor growth [69]. However, PPARδ has been reported to have both
tumor-promoting and tumor-inhibiting effects based on conflicting data obtained
from mouse models of colon cancer. For
example, activation of PPARδ by a selective synthetic PPARδ agonist (GW501516) or a PPARδ endogenous activator (PGE2)
accelerates intestinal adenoma growth in ApcMin/+ mice by promoting
tumor cell survival [14, 66]. A subsequent
genetic study showed that deletion of PPARδ attenuates both small and large
intestinal adenoma growth, and PPARδ is required for the tumor-promoting
effects of PPARδ ligand (GW501516) and PGE2 in ApcMin/+
mice [15, 66]. Another study
showed that loss of PPARδ in ApcMin/+ mice
significantly reduced growth of tumors larger than a diameter of 2 mm, even
though PPARδ deficiency did not affect overall tumor incidence [70]. In contrast to these reports suggesting that PPARδ serves as tumor accelerator, recent conflicting
reports show that PPARδ deficiency enhances
polyp growth in ApcMin/+ and AOM-treated mice in
the absence of exogenous PPARδ stimulation [71, 72].
Moreover, a PPARδ ligand (GW0742) inhibits colon carcinogenesis in AOM-treated mice but promotes
small intestinal polyp growth in ApcMin/+
mice [73].One explanation for these disparate results may be due to differences in the
genetic background ofApcMin/+ mice, animal breeding,
or possibly to differences in the specific targeting strategy employed to delete PPARδ.
For example, the average number of polyps in 13-week old ApcMin/+ mice
on a C57BL/6 genetic background is about 50, while the polyp number in ApcMin/+
mice on a mixed-genetic-background (C57BL/6 × 129/SV) is about 120. Our results also show that the breeding strategy
affects the number and size of polyps in mice even on the same genetic
background. Mice generated
by breeding female PPARδ−/−/ApcMin/+ with
male PPARδ−/−/Apc+/+ exhibit increased
adenoma number with a larger average size than those obtained by breeding
female PPARδ−/−/Apc+/+ with
male PPARδ−/−/ApcMin/+. Finally, the
PPARδ null mice we studied were obtained from
Beatrice Desvergne in Switzerland. These mice were generated by deleting exons 4 and 5 encoding
the DNA binding domain [74], while Peters group generated the
PPARδ knockout mice by inserting a neomycin resistance cassette into
the last exon (exon 8) [75]. It has been suggested that the strategy employed to disrupt PPARδ by the Peters group might have led to a hypomorphic allele, which
retains some aporeceptor function, thus making it difficult to correctly
interpret their results. Indeed,
conflicting results in the context of embryonic lethality have also been
observed from these two PPARδ mutant mouse strains [74, 75].
To further clarify the role of PPARδ in colorectal tumorigenesis, it is
important to investigate the role of PPARδ in animal models that are dependent on
activation of other oncogenes or disruption of other tumor suppressors to
verify our conclusions that activation of PPARδ is proneoplastic.Studies in other types of
cancer also support the hypothesis that PPARδ serves as a tumor accelerator. A selective PPARδ agonist (GW501516) has been shown to stimulate proliferation
of human breast, prostate, and hepatocellular carcinoma cells [68, 76, 77]. In a xenograft model, blocking PPARδ activation reduced ovarian tumor growth
[78]. PPARδ knockout mice exhibited significant
impaired angiogenesis and tumor growth after these mice were injected s.c. with
mouse Lewis lung carcinoma and melanoma cells [79].
In a mouse mammary tumor model, treatment with the PPARδ agonist (GW501516) accelerated tumor formation, while a PPARγ agonist (GW7845) delayed tumor growth [80]. Taken
together, the role of PPARδ in cancer biology
remains unclear.


## 3. Summary

Despite extensive research on both PPARγ and PPARδ in CRC, the role of these receptors
remains highly controversial in this disease. Emerging evidence demonstrates that cooperative interactions between
Wnt, COX-2, and PPARs signaling pathways can initiate cellular transformation
and promote progression of colorectal cancer. These studies provide support for
evaluating the efficacy of PPARδ antagonists for cancer prevention
and/or treatment. We propose a potential
working model as a useful starting point for future studies (see
Figure 1).Figure 1
A potential model for PPARs regulating colorectal tumor growth.



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*Source: 931074-2008-06-05.xml*