# Role of Peroxisome Proliferator-Activated Receptor Alpha in the Control of Cyclooxygenase 2 and Vascular Endothelial Growth Factor: Involvement in Tumor Growth

Authors: Raquel Grau; Manuel D. Díaz-Muñoz; Cristina Cacheiro-Llaguno; Manuel Fresno; Miguel A. Iñiguez
Journal: PPAR Research
 (2008)

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## Abstract

A growing body of evidence indicates that PPAR (peroxisome
proliferator-activated receptor)α agonists might have therapeutic usefulness in antitumoral therapy by decreasing abnormal cell growth, and reducing tumoral angiogenesis. Most of the anti-inflammatory and antineoplastic properties of PPAR ligands are due to their inhibitory effects on transcription of a variety of genes involved in inflammation, cell growth and angiogenesis. Cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF) are crucial agents in inflammatory and angiogenic processes. They also have been significantly associated to cell proliferation, tumor growth, and metastasis, promoting tumor-associated angiogenesis. Aberrant expression of VEGF and COX-2 has been observed in a variety of tumors, pointing to these proteins as important therapeutic targets in the treatment of pathological angiogenesis and tumor growth. This review summarizes the current understanding of the role of PPARα and its ligands in the regulation of COX-2 and VEGF gene expression in the context of tumor progression.


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## Body

## 1. Introduction

Peroxisome proliferator-activated receptors
(PPARs) are members of the nuclear receptor family of transcription factors. They
modulate gene transcription in response to specific ligands by binding as
heterodimers with the retinoidX receptor (RXR) to a specific peroxisome
proliferator-response element (PPREs) on target genes (reviewed in [1, 2]). Three distinct isoforms of PPARs
have been described PPAR α,β/δ, and γ, each encoded by a different gene and showing
a distinct tissue distribution [3]. Originally found to be
involved in the regulation of lipid and glucose metabolism, [4, 5] interest in these receptors has
increased dramatically as a consequence of recent studies showing their
involvement in tumoral cell growth and inflammation (reviewed in [6–9]). Therefore, in addition to their well-known
effects in diabetes and hyperlipidemic disorders, pharmacological agents that
target PPARs may have therapeutic applications in inflammatory diseases and
cancer.PPARα was the first PPAR identified [10]. It has a wide tissue distribution
being expressed in liver, skeletal muscle, intestine, kidney, adipose tissue,
and vascular endothelial cells, tissues in which fatty acids are predominantly
catabolized [11, 12]. Several ligands have been shown
to bind PPARα and to regulate transcriptional activity of
target genes involved in the regulation of fatty acid metabolism as fatty acid
transporters, catabolic enzymes involved in mitochondrial, and peroxisomal
oxidation as well as genes necessary for the maintenance of redox balance
during the oxidative catabolism of fatty acids [4, 5, 13]. PPARα-activating ligands include a number of
pharmacological compounds as well as fatty acid and fatty acid-derived
molecules (reviewed in [2]). Lipid-lowering fibrates
as Bezafibrate, Clofibrate, Fenofibrate and Gemfibrozil as well as certain nonsteroidal
anti-inflammatory drugs (NSAIDs) bind and activate PPARα [14, 15]. In addition, a variety of
unsaturated and saturated fatty acids including arachidonic acid, palmitic
acid, linoleic acid, linolenic acid, and oleic acid can act as natural ligands
of PPARα as they can bind and activate this receptor. Some
eicosanoids derived from the metabolism of arachidonic acid such as
leukotrienes (LTs), hydroxyeicosatetraenoic acids (HETEs), and prostaglandins
(PGs) can also be effective ligand agonists for specific PPAR isoforms [16–19]. However, it is not clear whether
the concentrations at which binding of these compounds occurs are
physiologically relevant.In
addition to its known role in the regulation of genes involved in fatty acid
metabolism, this isoform has been shown to attenuate the inflammatory response [6, 7, 9]. Most recently, an antitumoral
role of PPARα and its ligands has been proposed [7, 8]. This assumption is supported by recent experimental
evidence, revealing antitumoral and anti-angiogenic properties of PPARα activators both in vitro and in vivo.


## 2. Anti-Inflammatory Actions of PPARα

In
recent years, considerable attention has focused on the involvement of PPARs in
inflammatory processes. Anti-inflammatory effects of PPAR ligands, in
particular those of PPARα and PPARγ, have been ascribed to inhibition of the expression
of inflammatory genes and negative interference with pro inflammatory
transcription factor signaling pathways in vascular and inflammatory cells (reviewed
in [1, 6, 20]. The first evidence for the involvement of PPARα in the control of inflammation came from the
studies of the inflammatory response elicited by LTB4 in PPARα deficient mice. In these animals, inflammatory
response to LTB4 was prolonged compared to WT mice, correlating with the
ability of LTB4 to activate PPARα and regulate the expression of genes involved
in its own catabolism [21]. Thus, proinflammatory lipid metabolites may serve as
ligands for PPARs thereby activating PPARα responsive enzymes responsible for their
clearance. Therefore, some of the anti-inflammatory actions of these receptors can
occur through this autoregulatory loop in lipid homeostasis. Several lipids
mediators, as the polyunsaturated fatty acids (PUFAs), can function as ligands
for PPARs [2]. Arachidonic acid is a precursor of several eicosanoids that have
pro inflammatory properties whereas the ω-3 PUFAs are precursors of anti-inflammatory
eicosanoids as EPA (eicosapentanoid acid) and docosahexaenoic acid (DHA). These
ω-3 PUFAs derivatives have been reported to
decrease the production of several pro inflammatory cytokines, having
beneficial effects in several inflammatory diseases as rheumatoid arthritis and
inflammatory bowel disease [22, 23].Several studies have
confirmed the anti-inflammatory properties of PPARs in vitro and in vivo
through the regulation of genes involved in the inflammatory response. PPAR
agonists decrease plasma concentrations of interleukin (IL)-6, tumor necrosis
factor (TNF)-α, and interferon (IFN)-γ in humans [24, 25]. In vascular smooth-muscle
cells, PPARα ligands inhibit IL-1-induced production of
IL-6, COX-2, and prostaglandins [25]. PPARα activation inhibits cytokine-induced expression
of vascular cell-adhesion molecule-1 (VCAM-1) and vascular endothelial growth
factor receptor-2 (VEGFR-2) in endothelial cells [26, 27]. PPARα have been also involved in the downregulation
of the production of IL-2 and TNFα by T lymphocytes [28].At the molecular level, most of the inhibitory actions of
PPARα on gene transcription result from its ability
to transrepress the activities of many
activated transcription factors such as nuclear factor (NF)-κB [25, 29], activator protein-1 (AP-1) [29, 30] C/EBPβ [31, 32], signal transducers and
activators of transcription (STATs) [33], and transcription factor
specificity protein 1 (Sp-1) [27]. Negative regulation of gene expression by
PPARα can occur by several mechanisms (Figure 1). Activated PPAR-RXR complexes may compete for
limited amounts of essential coactivators shared with other transcription
factors. Direct physical interactions between PPARs and specific
transcription factors have been also proposed to mediate transcriptional
inhibition by activated PPARα, resulting
in reduced binding to their cognate response elements. Agonists-activated PPARα can effectively antagonize NF-κB and AP-1-mediated signaling pathways in a
bidirectional manner by physical interaction with the Rel homology domain of NFκB-p65 and with the aminoterminal of c-Jun,
respectively [34]. Physical association of the C-terminal DNA binding region of c/EBPβ with PPARα mediates inhibition of alpha1-acid glycoprotein gene expression [31]. PPARα agonists can also influence transcriptional
activation by modulating the expression of transcriptional repressors such as IκBα (Kleemann, 2003 #1223;
Vanden Berghe, 2003 #2170}). Finally, an additional mechanism of
transrepression relies on the ability of some PPARα ligands to interfere with the activation of
certain members of the mitogen-activated protein kinase (MAPK) cascade as Jun
kinase (JNK) and p38 MAPK [30, 35, 36].Figure 1
Negative
regulation of gene expression by PPARs. Different mechanisms of transrepression through
interference of activated PPARs with activation of transcription factors have
been described. (1) Activated PPAR-RXR
complexes may sequester essential coactivators shared with other transcription
factors. (2) Physical association of PPARs with specific transcription
factors results in reduced binding to
their cognate response elements. (3) PPARα agonists can also influence transcriptional
activation by upregulating the expression of transcriptional repressors such as
IκBα. (4) PPARα-mediated interference on the activation of
members of the mitogen-activated protein kinase (MAPK) cascade influences
transcription factor activation.


## 3. Involvement of PPARα in Cancer

Rapidly accumulating
evidence links members of the PPAR family and their agonists to cellular growth
and tumor progression. The role of the PPARγ isotype in cancer has been widely studied with
a large number of reports demonstrating antitumoral properties of PPARγ agonists in a variety of different malignancies
[8]. Concerning to the involvement
of the PPARα form and its ligands in cancer, both tumor
promotion and suppression properties have been reported [37]. Sustained PPARα activation by agonists as clofibrate and Wy-14643
induce hepatocarcinogenesis in rodents [38, 39]. However, epidemiological data on
long-term administration of PPARα activators in the clinic discard the occurrence
of these effects in human [40–43]. Discrepancies on the effects of
PPARα ligands in rodents and human liver seem to be due
to several differences between species [44]. PPARα mediated signaling is less efficient in human than
in mice [37, 43, 45] and expression of this receptor is
10 to 20 times higher in rodent hepatocytes compared to human liver [46].Emerging
evidence indicates that PPARα ligands are able to suppress the growth of
different types of human carcinomas. PPARα is expressed in a variety of human and murine tumor
cell lines [47–49]. Expression of PPARα have been also reported in clinical samples of
several types of human cancers as colorectal carcinoma [50], prostate adenocarcinoma, [47, 51], testicular cancer [52], bladder carcinoma [53], and medulloblastoma [54]. PPARα ligands are able to arrest the growth of human
cancer cell lines in vitro and to slow the growth of transplanted human tumor
cells in nude mice. These anticancer effects have been observed in several
different cancer cell types including hepatoma [55], melanoma [56], glioblastoma and fibrosarcoma [49], endometrial and ovarian cancer [57–59], as well as colon carcinoma [50, 60, 61]. Clofibric acid, a ligand for PPARα inhibits growth of ovarian cancer both in vivo
and in vitro [58, 59]. Mice treated topically with the PPARα ligand Wy-14643 exhibited diminished skin
tumorigenesis [62]. Moreover, Fenofibrate suppresses the metastatic potential of
melanoma cells [56, 63].Even though accumulative evidence
shows data suggesting that PPARα ligands may display antitumoral properties, the
precise mechanism remains unclear. A number of reports suggest that antitumor
properties of PPARα activators reside on their anti-inflammatory
and anti-angiogenic effects [27, 64, 65] (Figure 2). The dependence on the
presence of PPARα for the antitumorigenic and anti-angiogenic
role of PPAR ligands has been determined by the analysis of their effects in
PPARα null mice. Wy-14643-mediated
antitumoral and anti-angiogenic responses on tumor and endothelial cells are
absent in PPARα KO mice [66]. Panigrahy and coworkers [49] have shown the importance of the
microenvironment in tumor progression in such a way that the activation of PPARα expressed in endothelial and inflammatory
cells of the host rather than in the tumoral cells is critical for
anti-inflammatory, antitumor and anti-angiogenic activity of PPARα agonists. Consistent with the
anti-inflammatory role of this receptor, PPARα null mice exhibit an increase of inflammatory
infiltrates in tumors. Paradoxically, in spite of the enhanced inflammatory
response in the absence of PPARα, tumor growth is suppressed in these animals
as a consequence of an increased production of anti-angiogenic factors TSP-1
and endostatin [67]. The immune system can have
a multitude of effects on cancer development and progression, both favorable
and detrimental [68, 69]. This apparent contradiction has
been explained by the severity and duration of the inflammatory response
associated to tumor growth. While acute inflammation is part of the defense
response that may participate in the remission of preclinical cancers, chronic
inflammation can promote tumor development with infiltrating innate immune
cells providing proinflammatory and proangiogenic factors including cytokines,
chemokines, VEGF, and prostanoids [70–72]. The association between cancer
and inflammation has been also illustrated by epidemiological studies showing
that the use of anti-inflammatory compounds in chronic inflammatory diseases
reduces cancer risk tumor [73, 74]. In this sense, PPARα-mediated anti-inflammatory actions can be responsible for their
potential chemopreventive effects in tumor progression.Figure 2
Antitumoral effects of PPARα ligands. Tumor progression depends on a
cascade of cellular signals
involving: (a) proinflammatory factors (cytokines, COX-2 derived prostaglandins
(PGs), chemokines); (b) proangiogenic factors (VEGF, bFGF, and PGs) produced by
endothelial and inflammatory cells, stromal fibroblasts, and tumor cells. These
factors promote cell proliferation, migration, and induce new vessels that
deliver nutrients and oxygen to the malignant cells and therefore allow tumor
growth and metastasis. PPARα ligands may display antitumoral properties by
their inhibitory effects on the transcription of genes involved in inflammation, cell growth, and
angiogenesis thus leading to the inhibition
of tumor growth.An emerging area of interest is the association
of anti-inflammatory actions of dietary PUFAs as potential natural agonists of
PPARs with cancer risk. Increasing evidence suggests that dietary fat regulation
of gene expression can play a critical role in initiation and progression of
human cancer and epidemiological studies have suggested an association between
dietary fat and cancer risk [75, 76]. A number of reports have shown
the beneficial
effects of consumption of ω-3 PUFAs, associated with anti-inflammatory
effects and with protection against primary tumor development [22, 23, 75]. Although some of the effects of
dietary lipids can be linked to PPARs-mediated signaling,
additional research is needed to understand the potential connection between
dietary fat intake and PPARs in the control of inflammation and tumor
progression.


## 4. PPARα, COX-2, and Cancer

### 4.1. COX-2: An
Essential Role in Inflammation and Tumor Growth

Cyclooxygenases (COX-1 and COX-2) convert arachidonic acid to
prostaglandinH2(PGH2), an endoperoxide intermediate
that, via specific synthases, is then transformed to prostaglandins (PGE2, PGD2, PGF2α, PGI2) and thromboxanes (TXA2).
Whereas COX-1 is constitutively expressed in most tissues, COX-2 is transcriptionally upregulated in response to
mitogens, tumor promoters, and pro inflammatory stimuli in a discrete
number of cell types (reviewed in [77–79]). These enzymes are the target of nonsteroidal
anti-inflammatory drugs (NSAIDs), one of the most widely used therapeutic for
the relief of pain and inflammation (reviewed in [80–82]). The anti-inflammatory and
analgesic efficacy of drugs arises essentially from inhibition of the enzymatic
activity of COXs. As COX-2 is though to be the predominant isoform
involved in the inflammatory response, the ability of NSAIDs to inhibit COX-2
activity may explain their therapeutic effects as anti-inflammatory drugs.
Therefore, most of the new research on anti-inflammatory drugs has been aiming at
targeting the COX-2 inducible production of PGs.In addition to its
essential role in inflammation, accumulating evidence links COX-2 with cancer
and angiogenesis, suggesting that drugs that target COX-2 and related signaling
cascades could be used as antitumoral agents [74]. Many human cancers
display elevated COX-2 expression and studies in COX-2 null mice have demonstrated the role of this enzyme in
tumor progression and metastasis [83–85]. Moreover, epidemiological studies
have revealed a role of selective COX-2 inhibitors in decreasing the risk of
developing colon cancer and in suppressing tumor formation and growth in animal
models [73, 86–88]. COX-2 inhibitors can block both the production of angiogenic
factors and the migration of vascular endothelial cells, and thus decrease
tumor growth [89, 90]. Although some of the
effects of these drugs on tumor regression might result from modulation of
COX-2-independent pathways [91], it is likely that COX-2 is
an important mediator of tumor growth.


### 4.2. Effects of PPARα Ligands on COX-2 Expression

The activity of COX-2 is closely
linked to PPARs as COX-2 catalyzes the production of fatty acid derivates as
prostanoids that are PPAR activators [2]. Modulation of COX-2
activity should influence the local availability of PPAR ligands; therefore,
indirectly modulating PPAR activity. Moreover, some NSAIDs may act as PPARα and γ ligands,
suggesting that, in addition to inhibit prostaglandin production, they might
regulate gene expression as part of their anti-inflammatory and chemopreventive
mechanisms [92, 93]. Downregulation of COX-2 expression by PPARα ligands may account for some of the
anti-inflammatory, anti-angiogenic and antitumoral properties of these drugs in
a variety of cell types [20] (Table 1). PPARα agonists as Wy-14643 inhibit macrophage
differentiation and COX-2 gene expression [94]. In liver, COX-2 upregulation upon experimental nutritional
steatohepatitis is suppressed by the PPARα agonist Wy-14,643 in wt but not in PPARα KO mice. This effect has been ascribed to the
ability of activated PPARα to interfere with the NF-κB-signaling pathway [95]. Transcriptional interference of
activated PPARα with NF-κB also explains the inhibition of COX-2
induction and PG production in response to IL-1 in vascular smooth muscle cells
[25]. The NF-κB target genes VCAM-1 and COX-2 are also
downregulated by PPARα ligands in response to cytokine activation [29]. Regarding to experimental support for anti-angiogenic and
antitumoral actions of these drugs related to their effects on COX-2 expression,
it has been shown that Fenofibrate inhibits bFGF-mediated
angiogenesis and COX-2 mRNA expression in endothelial cells [65]. Panigrahy and cols have observed
suppression of COX-2 expression in Fenofibrate and Wy-14643 treated tumors [49]. Clofibric acid suppresses the growth of tumor
xenograts of ovarian cancer cell lines with decreased microvessel density, PGE2 production, and COX-2 and mPGES-1 expression [58, 59]. Diminished expression of
COX-2 upon PPARα agonist treatment was parallel with reduced
expression of AP-1. Similarly, in colon carcinoma cells, PPARα agonists severely diminish phorbol ester-mediated
AP-1-dependent induction of COX-2 expression [30].Table 1
Effects of
PPARα ligands on COX-2 signaling.
PPARα ligandAction/effectReferencesWy-14643Inhibition of IL-1-induced COX-2 expression in vascular smooth muscle cells[25]Inhibition of LPS-induced COX-2 expression in THP-1 monocytes[94]Inhibition of TPA-induced COX-2 expression in colon carcinoma cell lines[30]Inhibition of COX-2 expression in B16-F10 melanoma tumor[49]Inhibition of COX-2 up regulation by experimental steatohepatitis in liver[95]FenofibrateInhibition of COX-2 expression in B16-F10 melanoma tumor[49]Inhibition of b-FGF induced COX-2 expression in endothelial cells[65]Clofibric acidInhibition of COX-2 expression in tumor xenografts[58]Inhibition of mPGES-1 expression in tumor xenografts[59]


## 4.1. COX-2: An
Essential Role in Inflammation and Tumor Growth

Cyclooxygenases (COX-1 and COX-2) convert arachidonic acid to
prostaglandinH2(PGH2), an endoperoxide intermediate
that, via specific synthases, is then transformed to prostaglandins (PGE2, PGD2, PGF2α, PGI2) and thromboxanes (TXA2).
Whereas COX-1 is constitutively expressed in most tissues, COX-2 is transcriptionally upregulated in response to
mitogens, tumor promoters, and pro inflammatory stimuli in a discrete
number of cell types (reviewed in [77–79]). These enzymes are the target of nonsteroidal
anti-inflammatory drugs (NSAIDs), one of the most widely used therapeutic for
the relief of pain and inflammation (reviewed in [80–82]). The anti-inflammatory and
analgesic efficacy of drugs arises essentially from inhibition of the enzymatic
activity of COXs. As COX-2 is though to be the predominant isoform
involved in the inflammatory response, the ability of NSAIDs to inhibit COX-2
activity may explain their therapeutic effects as anti-inflammatory drugs.
Therefore, most of the new research on anti-inflammatory drugs has been aiming at
targeting the COX-2 inducible production of PGs.In addition to its
essential role in inflammation, accumulating evidence links COX-2 with cancer
and angiogenesis, suggesting that drugs that target COX-2 and related signaling
cascades could be used as antitumoral agents [74]. Many human cancers
display elevated COX-2 expression and studies in COX-2 null mice have demonstrated the role of this enzyme in
tumor progression and metastasis [83–85]. Moreover, epidemiological studies
have revealed a role of selective COX-2 inhibitors in decreasing the risk of
developing colon cancer and in suppressing tumor formation and growth in animal
models [73, 86–88]. COX-2 inhibitors can block both the production of angiogenic
factors and the migration of vascular endothelial cells, and thus decrease
tumor growth [89, 90]. Although some of the
effects of these drugs on tumor regression might result from modulation of
COX-2-independent pathways [91], it is likely that COX-2 is
an important mediator of tumor growth.


## 4.2. Effects of PPARα Ligands on COX-2 Expression

The activity of COX-2 is closely
linked to PPARs as COX-2 catalyzes the production of fatty acid derivates as
prostanoids that are PPAR activators [2]. Modulation of COX-2
activity should influence the local availability of PPAR ligands; therefore,
indirectly modulating PPAR activity. Moreover, some NSAIDs may act as PPARα and γ ligands,
suggesting that, in addition to inhibit prostaglandin production, they might
regulate gene expression as part of their anti-inflammatory and chemopreventive
mechanisms [92, 93]. Downregulation of COX-2 expression by PPARα ligands may account for some of the
anti-inflammatory, anti-angiogenic and antitumoral properties of these drugs in
a variety of cell types [20] (Table 1). PPARα agonists as Wy-14643 inhibit macrophage
differentiation and COX-2 gene expression [94]. In liver, COX-2 upregulation upon experimental nutritional
steatohepatitis is suppressed by the PPARα agonist Wy-14,643 in wt but not in PPARα KO mice. This effect has been ascribed to the
ability of activated PPARα to interfere with the NF-κB-signaling pathway [95]. Transcriptional interference of
activated PPARα with NF-κB also explains the inhibition of COX-2
induction and PG production in response to IL-1 in vascular smooth muscle cells
[25]. The NF-κB target genes VCAM-1 and COX-2 are also
downregulated by PPARα ligands in response to cytokine activation [29]. Regarding to experimental support for anti-angiogenic and
antitumoral actions of these drugs related to their effects on COX-2 expression,
it has been shown that Fenofibrate inhibits bFGF-mediated
angiogenesis and COX-2 mRNA expression in endothelial cells [65]. Panigrahy and cols have observed
suppression of COX-2 expression in Fenofibrate and Wy-14643 treated tumors [49]. Clofibric acid suppresses the growth of tumor
xenograts of ovarian cancer cell lines with decreased microvessel density, PGE2 production, and COX-2 and mPGES-1 expression [58, 59]. Diminished expression of
COX-2 upon PPARα agonist treatment was parallel with reduced
expression of AP-1. Similarly, in colon carcinoma cells, PPARα agonists severely diminish phorbol ester-mediated
AP-1-dependent induction of COX-2 expression [30].Table 1
Effects of
PPARα ligands on COX-2 signaling.
PPARα ligandAction/effectReferencesWy-14643Inhibition of IL-1-induced COX-2 expression in vascular smooth muscle cells[25]Inhibition of LPS-induced COX-2 expression in THP-1 monocytes[94]Inhibition of TPA-induced COX-2 expression in colon carcinoma cell lines[30]Inhibition of COX-2 expression in B16-F10 melanoma tumor[49]Inhibition of COX-2 up regulation by experimental steatohepatitis in liver[95]FenofibrateInhibition of COX-2 expression in B16-F10 melanoma tumor[49]Inhibition of b-FGF induced COX-2 expression in endothelial cells[65]Clofibric acidInhibition of COX-2 expression in tumor xenografts[58]Inhibition of mPGES-1 expression in tumor xenografts[59]


## 5. PPARα, VEGF, and Cancer

### 5.1. VEGF: A
Therapeutic Target in Tumoral Angiogenesis

Angiogenesis, defined as the formation of new blood vessels from
preexisting vasculature, occurs under physiological conditions during embryonic
development and is required for wound healing and reproduction in the adult. Indispensable
for physiological processes, angiogenesis is highly regulated via fine tuning
of the balance between pro- and anti-angiogenic factors [97]. Excessive angiogenesis is tightly linked to human disease,
including chronic inflammatory disease, diabetic retinopathy, and cancer [98, 99]. Ample evidence shows that
blockade of tumoral angiogenesis often relieves the severity of cancer [100].Both cancer cells and
cells attracted to the sites of inflammation are able to produce proangiogenic
factors that cause endothelial cell recruitment and proliferation for the
supply of oxygen and nutrients that favor the growth of solid tumors and
facilitate metastasis. In this context, tumor-associated hypoxia plays an essential role in the regulation of angiogenesis [101]. Response to hypoxia is mediated
by members of the hypoxia-inducible
transcription factors (HIFs) involved in the regulation of the expression of
genes participating in oxygen homeostasis [102, 103]. In addition, hypoxia has been also
found to drive induction of potent angiogenic and inflammatory factors including
VEGF, VEGF-R1 and -R2, angiotensin, metalloproteinases, and COX-2 [104–106]. This response of tumors to
hypoxia contributes to the malignant phenotype and to more aggressive tumor progression
[107].It has been well
established that VEGF signaling pathway
is one of the key regulators in angiogenesis [108, 109]. Cytokines, growth factors, tumor
promoters, and hypoxia modulate the expression of VEGF [110, 111]. Activated VEGF may bind to two
types of tyrosine kinases receptors: VEGFR-1 and VEGFR-2. Proangiogenic actions
of VEGF as vascular endothelial cell permeability, proliferation migration, and
survival are mediated mainly through binding an activation of the VEGFR-2 [112, 113]. Accumulating evidence supports a key role of VEGF in
cancer, contributing to tumor neovascularization and dissemination. Increased
expression of this factor has been found in most tumors, and agents
neutralizing VEGF expression or activity inhibit tumor growth in vivo (reviewed
in [99, 100, 114]).


### 5.2. Inhibition of VEGF Signaling
by PPARα Agonists

PPARα ligands can inhibit endothelial cell
proliferation and migration and induce endothelial cell apoptosis in vitro,
suggesting an important role of this receptor in tumor angiogenesis. Part of
these effects occurs through the ability of PPARα ligands to interfere with VEGF-mediated signaling.
(Table 2). At the transcriptional level, PPAR agonists have been shown to
inhibit endothelial VEGFR-2 expression by repressing transactivation and
binding of Sp1 to DNA [27]. Wy-14643 downregulates
TPA-mediated transcriptional
induction of VEGF by interference with activation of AP-1 [30]. Interestingly, lipid-lowering therapy with Fenofibrate induces a
significant reduction of VEGF levels in serum [96]. Anti-angiogenic actions of PPARα agonists may explain some of their antitumoral
effects. Fenofibrate reduces adventitial angiogenesis and inflammation in a
porcine model of coronary angioplasty [115]. Both Fenofibrate and Wy-14643 are
able to suppress VEGF secretion in glioblastoma cells and Lewis lung carcinoma
cells and to inhibit angiogenesis both in vivo and in vitro [49]. Moreover, Clofibric acid inhibits VEGF expression in tumor
xenografts of ovarian cancer cell lines with a reduction in angiogenesis and decreased
microvessel density in solid tumors [58, 59].Table 2
Effects of PPARα ligands on VEGF signaling.
PPARα ligandAction/effectReferencesWy-14643Inhibition of VEGF-mediated endothelial cell migration[27, 49, 64]Inhibition of VEGF production by glioblastoma U87 cells[49]Inhibition of VEGF-induced phosphorylation of Akt[64]Inhibition of VEGF-mediated angiogenesis in vitro[27]FenofibrateInhibition of VEGF production by glioblastoma U87 cells[49]Reduction of plasma VEGF[96]Inhibition of VEGF-induced phosphorylation of Akt[64]Inhibition of VEGFR2 expression in endothelial cells[27]Clofibric acidInhibition of VEGF expression in tumor xenografts[58]


## 5.1. VEGF: A
Therapeutic Target in Tumoral Angiogenesis

Angiogenesis, defined as the formation of new blood vessels from
preexisting vasculature, occurs under physiological conditions during embryonic
development and is required for wound healing and reproduction in the adult. Indispensable
for physiological processes, angiogenesis is highly regulated via fine tuning
of the balance between pro- and anti-angiogenic factors [97]. Excessive angiogenesis is tightly linked to human disease,
including chronic inflammatory disease, diabetic retinopathy, and cancer [98, 99]. Ample evidence shows that
blockade of tumoral angiogenesis often relieves the severity of cancer [100].Both cancer cells and
cells attracted to the sites of inflammation are able to produce proangiogenic
factors that cause endothelial cell recruitment and proliferation for the
supply of oxygen and nutrients that favor the growth of solid tumors and
facilitate metastasis. In this context, tumor-associated hypoxia plays an essential role in the regulation of angiogenesis [101]. Response to hypoxia is mediated
by members of the hypoxia-inducible
transcription factors (HIFs) involved in the regulation of the expression of
genes participating in oxygen homeostasis [102, 103]. In addition, hypoxia has been also
found to drive induction of potent angiogenic and inflammatory factors including
VEGF, VEGF-R1 and -R2, angiotensin, metalloproteinases, and COX-2 [104–106]. This response of tumors to
hypoxia contributes to the malignant phenotype and to more aggressive tumor progression
[107].It has been well
established that VEGF signaling pathway
is one of the key regulators in angiogenesis [108, 109]. Cytokines, growth factors, tumor
promoters, and hypoxia modulate the expression of VEGF [110, 111]. Activated VEGF may bind to two
types of tyrosine kinases receptors: VEGFR-1 and VEGFR-2. Proangiogenic actions
of VEGF as vascular endothelial cell permeability, proliferation migration, and
survival are mediated mainly through binding an activation of the VEGFR-2 [112, 113]. Accumulating evidence supports a key role of VEGF in
cancer, contributing to tumor neovascularization and dissemination. Increased
expression of this factor has been found in most tumors, and agents
neutralizing VEGF expression or activity inhibit tumor growth in vivo (reviewed
in [99, 100, 114]).


## 5.2. Inhibition of VEGF Signaling
by PPARα Agonists

PPARα ligands can inhibit endothelial cell
proliferation and migration and induce endothelial cell apoptosis in vitro,
suggesting an important role of this receptor in tumor angiogenesis. Part of
these effects occurs through the ability of PPARα ligands to interfere with VEGF-mediated signaling.
(Table 2). At the transcriptional level, PPAR agonists have been shown to
inhibit endothelial VEGFR-2 expression by repressing transactivation and
binding of Sp1 to DNA [27]. Wy-14643 downregulates
TPA-mediated transcriptional
induction of VEGF by interference with activation of AP-1 [30]. Interestingly, lipid-lowering therapy with Fenofibrate induces a
significant reduction of VEGF levels in serum [96]. Anti-angiogenic actions of PPARα agonists may explain some of their antitumoral
effects. Fenofibrate reduces adventitial angiogenesis and inflammation in a
porcine model of coronary angioplasty [115]. Both Fenofibrate and Wy-14643 are
able to suppress VEGF secretion in glioblastoma cells and Lewis lung carcinoma
cells and to inhibit angiogenesis both in vivo and in vitro [49]. Moreover, Clofibric acid inhibits VEGF expression in tumor
xenografts of ovarian cancer cell lines with a reduction in angiogenesis and decreased
microvessel density in solid tumors [58, 59].Table 2
Effects of PPARα ligands on VEGF signaling.
PPARα ligandAction/effectReferencesWy-14643Inhibition of VEGF-mediated endothelial cell migration[27, 49, 64]Inhibition of VEGF production by glioblastoma U87 cells[49]Inhibition of VEGF-induced phosphorylation of Akt[64]Inhibition of VEGF-mediated angiogenesis in vitro[27]FenofibrateInhibition of VEGF production by glioblastoma U87 cells[49]Reduction of plasma VEGF[96]Inhibition of VEGF-induced phosphorylation of Akt[64]Inhibition of VEGFR2 expression in endothelial cells[27]Clofibric acidInhibition of VEGF expression in tumor xenografts[58]


## 6. Conclusions

Taken
together, findings on the effects of PPARα ligands in inflammation and cancer, suggest
that PPARα activation may be beneficial against
tumorigenesis through the inhibition of transcriptional activation of genes
involved in inflammation and angiogenesis such as COX-2 and VEGF. Although
COX-2 and VEGF are one of the many proinflammatory and proangiogenic factors
that drive tumor growth and metastasis, targeting these proteins suffices to
significantly impair tumor growth and angiogenesis. Inhibition of tumor inflammation and tumor angiogenesis by PPARα ligands might be responsible for their
potential chemopreventive effects in a variety of experimental models of cancer.
However, it must be taken into account that many of the reported effects of PPARα ligands on tumor progression have been
obtained in vitro and await confirmation by additional basic and clinical research
to ascertain whether they can be considered of pharmacological significance in
vivo.



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*Source: 352437-2008-07-28.xml*