Seminars in Ophthalmology, Early Online, 1–17, 2014

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ISSN: 0882-0538 print / 1744-5205 online
DOI: 10.3109/08820538.2014.971822

REVIEW

Molecular Basis of Pterygium Development

Eduardo Cárdenas-Cantú, PhD1, Judith Zavala, PhD1, Jorge Valenzuela, MD1, and
Jorge E. Valdez-Garcı́a, MD1,2

1
Ophthalmology Research Chair, School of Medicine and Health Sciences, Tecnologico de Monterrey, Monterrey,
Mexico and 2Ophthalmology Institute, Tec Salud, Tecnologico de Monterrey, Monterrey, Mexico
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ABSTRACT
Pterygium pathogenesis is mainly related to UV light exposure. However, the exact mechanisms by which it is
formed have not been elucidated. Clinical advances in surgical treatment use conjunctival autografts and amni-
otic membranes in combination with adjuvant therapies, including mitomycin C, b-radiation, and 5-fluoroacil,
to reduce recurrence. Several studies aim to unveil the molecular mechanisms underlying pterygium growth and
proliferation. They demonstrate the role of different factors, such as viruses, oxidative stress, DNA methylation,
apoptotic and oncogenic proteins, loss of heterozygosity, microsatellite instability, inflammatory mediators,
extracellular matrix modulators, lymphangiogenesis, cell epithelial-mesenchymal transition, and alterations
in cholesterol metabolism in pterygium development. Understanding the molecular basis of pterygium
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provides new potential therapeutic targets for its prevention and elimination. This review focuses on providing
a broad overview of what is currently known regarding molecular mechanisms of pterygium pathogenesis.
Keywords: Epithelial-mesenchymal transition, extracellular matrix proteins, growth factors, oxidative stress,
treatment

INTRODUCTION that have found a direct relationship between one’s

Pterygium is an abnormal wing-shaped growth of
epithelial and fibrovascular tissue from the corneo-
scleral limbus that centripetally invades the cornea,
impairs vision, and causes inflammation. It is char-
acterized by an altered basal epithelial cell prolifer-
ation, vascularization, and invasion of the adjacent
corneal epithelium.1–5 The progression of this disease
first involves the presence of gray circumscribed dots
in the cornea near the limbus, with simultaneous
tense conjunctiva that appear opposite to the area of
corneal affection, and there is also displacement of the
plica. Later, a wing-shaped extension of the fleshy
growth of the bulbar conjunctiva onto the cornea takes
place. A fully developed pterygium present a well
formed ‘‘apex’’ (apical part present on the cornea),
‘‘body’’ (scleral part extending between the limbus
and the canthus), and ‘‘neck’’ (limbal part).6,7
The pathogenesis of this disease remains unclear,
although it is generally considered to be caused by
ultraviolet (UV) radiation, as supported by studies
proximity to the equator and a higher prevalence of
pterygium.8–10 Alternatively, a wide array of patho-
genic factors has been proposed, including viral
infections,11 epigenetic aberrations,12–14 epithelial-
mesenchymal transition,15,16 immunologic17–20 and
anti-apoptotic mechanisms,21–24 angiogenic2,25,26 and
lymphangiogenic stimulation,27,28 deregulation of
extracellular matrix modulators4,29 and growth fac-
tors,30 inflammation cascades,31–33 recruitment of
bone-marrow-derived stem and progenitor cells,34–36
and modifications in cholesterol metabolism.37–39
However, most of these factors are more related to
the development and maintenance of the disease than
to its origin. It has been shown that some of these
factors are directly or indirectly related to UV
radiation exposure, as will be discussed further.
Currently, the main treatment for pterygium con-
sists of surgical excision, followed by different types
of adjuvant therapies directed at stopping the high
recurrence rates associated with bare excision.40 This
review aims to present a comprehensive review of all

Received 17 June 2014; revised 8 September 2014; accepted 20 September 2014; published online 21 November 2014
Correspondence: Jorge Valdez-Garcı́a, Tecnologico de Monterrey, 3000 Morones Prieto Ave., Col. Los Doctores, Monterrey 64710, N.L., Mexico.
E-mail: jorge.valdez@itesm.mx

1
 2 E. Cárdenas-Cantú et al.
of the factors related to pterygium pathogenesis that
have been proposed to date, as well as their relation to
UV radiation. Additionally, a summary of the alter-
native treatments that have been proposed and used
for pterygium are discussed.
CAUSATIVE FACTORS
UV Radiation
Ultraviolet radiation (UVR) is linked to the formation
of pterygia, since a clear relationship between sun
exposure and a higher prevalence of pterygium has
been observed.12,41 This type of radiation has the
potential to harm cells and alter tissues through two
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mechanisms: direct phototoxic effects on cellular
DNA, and generation of reactive oxygen species
(ROS), which damage cellular DNA, proteins, and
lipids.42–44 It is known that small wavelengths (below
300 nm) are the most biologically active forms, and
they are mostly absorbed by the cornea.45 UV-B
radiation wavelengths, ranging between 280 and
315 nm, affect the ocular surface and are directly
related to UV exposure level.46
The precise molecular mechanism through which
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UV radiation generates this disease is still under
study, and several alternatives have been proposed.
Figure 1 illustrates the main causative factors related
to the development of pterygium and the affected
molecular mechanisms in relation with the stage of
pterygium growth.
UV-B radiation is considered the main factor that
is responsible for pterygium formation due to its
capacity to cause oxidative stress.43 The molecule
8-hydroxy-20 -deoxyguanosine (8-OHdG), a ubiqui-
tous marker of oxidative stress with a high mutagenic
potential, has been found in the epithelium of the
head of primary pterygium with an average level 4.7-
fold higher than that of healthy conjunctiva.43,47 In
addition to the antioxidant function, the generation of
this molecule can be one of the defense mechanisms of
cells against oxidative-stress-induced inflammation.48
The presence of 8-OHdG in cellular DNA can be
diminished by the enzyme hOGG1 (human 8-oxogua-
nine glycosylase I), which has been shown to be
overexpressed in pterygium tissue.47 Since the
increase of 8-OHdG was not correlated to a decrease
in hOGG1 expression, further analyses were con-
ducted to determine whether this enzyme had under-
gone modifications which could explain the loss of
its effectiveness. In 2004, Kau et al. found that a
transition of C to G at nucleotide position 1245 in exon
7 of the hOGG1 gene results in Ser326Cys substitution
and is associated with an individual’s increased
susceptibility to develop pterygium.49 However,
these findings remain controversial since, in 2010,
Chen et al. found no association between this
polymorphism and pterygium development.50
Oxidative stress is also responsible for modifications
in lipids and proteins. The ROS formed as a conse-
quence of UV-B radiation have the potential to cause
lipid peroxidation in cellular membranes, thus pro-
moting the degeneration of polyunsaturated fatty
acids (PUFAs) into various compounds, including
the reactive aldehydes 4-hydroxyhexenal (4-HHE)
and 4-hydroxynonenal (4-HNE).51,52 These molecules
have been found in increased levels throughout the
pterygial specimens, including the head, where the
corneal-migration occurs at the front of the ptery-
gium, and the body, where active proliferation of
subepithelial connective tissues occurs.52 4-HHE and
4-HNE have the potential to modify proteins and
affect their normal function by reacting with histidine,
cysteine, and lysine residues.53 Such protein modifi-
cations have been found to be prominent in pter-
ygium tissue, as opposed to normal conjunctiva.52
Also, a significant increase in malone dialdehyde
(MDA), another marker of lipid peroxidation caused
by UV-B radiation, has been observed in pterygium
tissues with consistent decrease in the activity of the
antioxidant enzymes superoxide dismutase (SOD),
catalase, and glutathione peroxidase (GPx), leading to
ROS accumulation that causes DNA damage.44
Nevertheless, the enzyme peroxiredoxin 2, another
antioxidant enzyme which lowers peroxide and
hydroperoxide, has been found overexpressed in
pterygium epithelium by western blotting and
through a proteomic approach carried out in 12
samples. This overexpression has been correlated to
inhibition of peroxide-induced apoptosis.54,55 This
analysis suggests that there is selectivity toward
certain ROS in pterygium, since only peroxide and
hydroperoxide seem to be kept at low levels.
Furthermore, an overexpression of the Hsp90, a
chaperone protein involved in protein folding and
degradation, has been reported in pterygium epithe-
lium.56 Hsp90 is required for induction of the vascular
endothelial growth factor (VEGF), which is important
for angiogenesis that is required for tumor growth.57
Hsp90 overexpression might be the consequence of a
natural cellular response to the modified protein
increase that results from oxidative stress.
In addition to the formation of 8-OHdG, UV
radiation can damage DNA by its direct phototoxic
effects. Cimpean et al.58 found thymine dimers in
primary pterygium fibroblasts, endothelial cells, and
in recurrent pterygium fibroblasts. Clusters of cells
with a higher amount of thymine dimers were found
in the basal portion of the epithelium from primary
pterygium, supporting the hypothesis launched by
Chui et al.,59 which states that the basal epithelial cells
modified by UV radiation are responsible for the
invasion and recurrence rate associated with human
pterygium. Moreover, it has been found that, in
recurrent pterygium, the amount of basal cells is
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FIGURE 1. Pterygium main causative factors, affected molecular mechanisms, and their relation with pterygium progression stage.
ROS (Reactive Oxygen Species); 6-4 PPs (4-6 photoproducts); CPDs (cyclobutane pyrimidines); OHdG (8-hydroxy-20 -deoxyguanosine);
hOGG1 (human 8-deoxyguanosine glycolase-I); PUFAs (Polyunsaturated Fatty Acids); Gpx (Glutathione peroxidase); SOD
(Superoxide dismutase); MDA (Malone dialdehyde); 4-HNE (4-hydroxynonenal); 4-HHE (4-hydroxyhexenal); Hsp90 (Heat Shock
Protein 90).

diminished, perhaps due to a defective DNA repair
mechanism, as proposed by the authors, allowing for
a higher mutation rate to occur as a consequence of
thymine dimer presence.
The direct absorption of UV-B radiation by DNA
also leads to the production of two types of helix-
disorting photolesions: cyclobutane pyrimidine
dimers (CPDs) and 6-4 photoproducts (6-4PPs)
formed between adjacent pyrimidines,60-62 which
can result in the transformation of C to T and CC to
TT during DNA replication.63 Of the two photole-
sions, CPDs are related to more than half of the
mutations produced by UV-B radiation of mammalian
cells, and they have been found only in the structures
of the ocular anterior chamber following UV light
exposure.64,65 These DNA lesions can interfere with
essential cellular metabolic processes like transcrip-
tion and replication. Currently, efforts are being made
in order to develop methods to identify DNA sites of
modified nucleobases throughout the genome, and
analyze DNA repair capacities.66,67
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The cornea absorbs 45% of UV-A.68 The effects of
UV-A on pterygium have also been addressed. In a
study conducted on 838 watermen from Maryland,
in whom corneal disease was investigated, an associ-
ation of pterygium with a broad band of UV radiation
exposure (UV-A and UV-B) was found.69 Recently,
Chao et al. reported mRNA levels and activity of the
urokinase-type plasminogen activator (uPA) in pter-
ygium fibroblasts after UV-A radiation.70 This prote-
ase can activate matrix metalloproteinases (MMPs)
and is responsible for tissue degradation and tumor
cell invasion.71,72 Among the studies conducted with
pterygium cells, both epithelial and stromal fibro-
blasts have been shown to express molecules
related to connective tissue degradation and remodel-
ing of MMP-1 and MMP-2,73–75 suggesting that both
cell types may contribute to the dissolution of the
basement membrane and the Bowman layer. Overall,
these studies demonstrate a relationship between
pterygium and wide-band UVR rather than with
UV-B alone.
 4 E. Cárdenas-Cantú et al.
Viral Infections and Heredity
According to Detorakis et al.,76 pterygium formation
involves a multistep process in which environmental
factors, genetic predisposition, and viral infections are
implicated. This model has been supported by the
detection of a variety of oncogenic viruses, including
human papilloma virus (HPV), cytomegalovirus
(CMV), and herpes simplex virus (HSV) in pterygium
samples. HPV virus encodes proteins that inactivate
p53, leading to chromosomal instability and increas-
ing the probability of a cell evolving toward malig-
nancy.77–79 Previous investigations have analyzed the
influence of viruses on pterygium pathogenesis.11,80,81
From these reports, it was concluded that HPV is the
virus most frequently found in pterygium, with
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prevalence rates ranging from very low up to 100%.
According to these reviews, the lowest prevalence of
HPV in pterygium samples has been identified in
Turkish, Japanese, and Ecuadoran patients (0%, 4.8%,
and 21%, respectively),82–84 while the highest preva-
lence has been reported for Italian, Brazilian, and
English patients (100%, 58.3%, and 50%, respect-
ively).84–86 Recent research also reports contrasting
results: Chong et al.87 found a prevalence of 64.4% in
patients from the Malay Peninsula, whereas Woods88
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reported 0% in patients from Australia. The disparity
in these prevalence rates has been attributed to ethnic
and geographical factors, as well as to the laboratory
techniques and study designs used. Moreover, it has
also been proposed that hereditary predisposition is
fundamental for the onset and sustenance of pter-
ygium. Anguria et al.89 summarized the role of
hereditary predisposition in pterygium development.
In this report, they proposed that pterygium mode of
inheritance is autosomal dominant. They also sug-
gested that the size and severity of pterygium are
most likely to be determined by hereditary factors,
and that pterygium occurrence most likely follows a
multifactorial mode of inheritance, in which two types
of genes, one for inhibitory smad proteins and the
second for smurf proteins, are inactive. Most of the
scientific evidence that supports these hypotheses
comes from past reports conducted with a small
number of families and/or patients.9,90,91 In order to
establish the influence of inheritance in pterygium
pathogenesis and increase the credibility in the
proposed mode of inheritance, updated clinical
studies with larger samples are necessary.
MOLECULAR MECHANISMS RELATED
TO PTERYGIUM DEVELOPMENT
Several factors have been related to pterygium patho-
genesis, including epigenetic factors, cell proliferation
factors, inflammatory mediators, growth factors,
extracellular matrix modulators, angiogenic and
lymphangiogenic factors, immunologic mechanisms,
epithelial-mesenchymal transition, and alterations in
cholesterol metabolism. Figure 2 represents a sche-
matic view of all the pterygium-related factors here
described.
Epigenetic Factors
Pterygium shares similarities with cancer, including
cell proliferation, invasion, and recurrence after resec-
tion. Proteins associated with increased proliferative
activity (Ki-67, proliferation cell nuclear antigen
[PCNA], and erythropoietin), low levels of cellular
apoptosis (Bcl-2 and p53), and malignancy (Hsp90)
have been found to be overexpressed in the epithelial
cell layer of pterygium when compared with healthy
conjunctiva.5,92–94 These proteins have been found to
be increased in different cancer types,95–97 underlying
neoplastic conditions,98–100 and they have been used
for the assessment of a tumor’s proliferative
activity.101,102
Dramatic changes in the DNA methylation patterns
are common in many cancer types, and due to the
similarities that exist between cancer and pterygium,
some studies on the methylation patterns of ptery-
gium have been performed. Aberrant DNA methyla-
tion of genes related to matrix remodelling (MMP-2,
hypomethylation) and cell adhesion (TGM-2 and
CD24 hypermethylation) are processes highly related
to pterygium invasion.12 Additionally, hypermethyla-
tion of the tumor suppressor gene p16 has been
correlated to an overexpression of the DNA methyl-
transferase 3b (DNMT3b) in pterygium.103 These
epigenetic modifications are an alternative to DNA
mutations, which may cause an uncontrolled expres-
sion or suppression of important genes related to the
pathogenesis of pterygium. Oxidative stress caused
by UV radiation may be responsible for these abnor-
mal methylation patterns, although no such research
has yet been conducted.
Cell Proliferation Factors
Pterygium basal epithelial cells exhibit molecular
markers that are associated with an increased prolif-
eration rate and low or negligible apoptosis,5,93
suggesting that the pathways related to proliferation
play key roles in pterygium formation.
The role of the S100 family of proteins in the
pathogenesis of pterygium has recently been reported.
These are dimeric calcium-binding proteins that
interact with other proteins to modulate biological
processes. On the ocular surface, the binding of S100
proteins to structural proteins, transcription factors,
and immune modulators affects the adhesion and
migration of migration of immune cells over the
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FIGURE 2. Molecular factors related to pterygium development.
cornea’s basement membranes, and it also affects the
production of downstream MMPs and pro-inflamma-
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tory cytokines, as well as the activation of immune
effectors or antibody production.104
In previous studies on immunodetection, an
increase in S100A6, S100A8, S100A9, and S100A11
proteins in human pterygium epithelium samples was
established relative to normal conjunctiva.105 In a
study consisting of a cDNA library obtained from 15
pooled human pterygium samples, a high expression
of several genes was reported: N1-acetyltransferase 1
(SAT1), which is the rate-limiting enzyme in poly-
amine metabolism; annexin A2, which plays a role in
the induction of MMP-9 activity; and S100A9 protein,
which is involved in controlling cell migration.106 In
this study, immunofluorescence analysis showed that
SAT1 and S100A9 were present on the leading edge of
the pterygium body. A recent experiment also
reported that S100A8 and S100A9 were up-regulated
in human pterygium samples when analyzed using
microarrays107; unlike the previous study, this
research was conducted using pterygium and healthy
conjunctiva samples from the same patients. Finally,
S100A8 and S100A9 have also been detected in higher
concentrations in tears from pterygium eyes.108
Since S100A8 and S100A9 bind to keratin filaments,
which are encoded during terminal epidermal
differentiation,109 a functional role in the reorganiza-
tion of the cytoskeleton during hyperproliferative
ocular surface disease (such as pterygium) is sug-
gested for these proteins. Further research regarding
the role of S100A8 and S100A9 proteins could facili-
tate their use as indicators for outlining pterygium
progression.
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Molecular Basis of Pterygium Development 5
Two pro-apoptotic markers, TUNEL and Bax, have
only been significantly found in the epithelial basal
layer of pterygia, while the anti-apoptotic protein Bcl-
2 has been observed to be more widely distributed
across the entire pterygium tissue.22 The absence of
the pro-apoptotic proteins on the head of pterygia
correlates with its proliferative behavior. Moreover,
oxidative stress caused by UV-B exposure has been
shown to induce the expression of survivin, an anti-
apoptotic protein.21
One of the major checkpoints of cell proliferation is
controlled by the tumor suppressor p53, whose role in
pterygium development has been widely studied. An
increase in p53 in the basal epithelium of pterygia has
been reported.23,24,110 Some studies suggest the possi-
bility that mutations in p53 could inhibit its normal
pro-apoptotic function.110–112 However, subsequent
studies have found no significant increase in the
abundance of this protein, arguing against the
hypothesis of mutations in p53 and proposing
that there must be a mechanism for p53 resistance in
pterygium.113,114 Another tumor suppressor protein,
p16, has been found to be down-regulated in
pterygium, presumably by hypermethylation of its
promoter region.13 The oncogenic protein p63 has
not been shown to be differentially expressed in
pterygium tissue and healthy conjunctiva.115
Nevertheless, mutations at codon 12 of the oncogene
KI-Ras have been observed.116 Furthermore, it has
been reported that pterygium contains a significantly
higher number of cells positive for cyclin-D1 and Ki-
67, which are markers of an active cell cycle, and there
are fewer cells positive for p27, a cell cycle inhibitor.93
C-Myc, a protein involved in cell proliferation and
 6 E. Cárdenas-Cantú et al.

apoptosis, was found to be down-regulated in
pterygium,93 while IPO13, an importin that partici-
pates in cell proliferation, was found to be
up-regulated.117 An increase in telomerase activity
has also been reported in the epithelium of pterygium
tissue.118 Together, these findings together suggest
that pterygium might be a consequence of the abnor-
mal regulation of apoptosis.
Two other factors related to cell proliferation
have been studied: loss of heterozygosity (LOH) and
microsatellite instability (MI). LOH relates to cell
proliferation and cancer since it usually corresponds
to the absence of a functional tumor suppressor gene,
while MI is an indicator of an impaired DNA
mismatch repair mechanism. The results obtained to
date are controversial. A work published in 1998 by
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tears from patients with the disease. This protein
could serve as a natural mechanism of protection
against inflammation.122 The nuclear factor kb (NF-
kb) pathway has also been found to be activated in
human pterygium tissue. In a study conducted with
nuclear extracts from pterygium and healthy conjunc-
tiva tissue, higher levels of NF-kb proteins RelA and
p50 were found in pterygia.123 In the same study,
when primary pterygium fibroblasts were stimulated
with TNF-a, translocation of RelA (p65) to the nucleus
after 30 min and of RelB after 24 h was observed. In
contrast, untreated cells showed predominant cyto-
solic localization of RelA and very low levels of RelB.
These findings suggest that both canonical and non-
canonical pathways (relate to acute and delayed
inflammatory processes, respectively) of NF-kb are

Kria et al., where 50 pterygia were analyzed, included
15 microsatellite markers; the authors reported a high
incidence of LOH and low incidence of MI.119 On the
other hand, in 2007, Schneider et al. could not detect
LOH or MI in 13 samples, and this included the
analysis of five microsatellite markers.32 These find-
ings would suggest that the cell proliferation present
in pterygium is not related to an impaired DNA
mismatch repair mechanism.
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active in pterygium, and can be involved in several
biological effects, including the recruitment of inflam-
matory cells to the pterygium tissue,124 increasing the
motility and invasiveness of cells,125 and influencing
the expression of pro-apoptotic and anti-apoptotic
genes and cell cycle proteins,126 thus contributing the
pathogenesis of pterygium. All these inflammatory
mediators are likely a consequence of pterygium
development, rather than a primary cause of forma-
tion; however, they are important in the maintenance

of the disease, and thus might be considered patho-

Inflammatory Mediators and Growth
Factors
Regardless of the origin, inflammatory mediators
should be present in significant amounts in order to
be considered key factors in pterygium development.
A complete list of all the inflammatory mediators that
have been studied in relation with pterygium is
outlined in Table 1. Increased levels of interleukins 1
(IL-1),30 6 (IL-6), and 8 (IL-8),33 as well as tumor
necrosis factor alpha (TNFa),120 have been found in
pterygium following UV-B radiation.
Cyclooxygenase-2 (COX2) is overexpressed in pter-
ygium, and is deemed responsible for a further
augmentation in prostaglandin products and inflam-
matory cascades.31 An increase in phospholipase D,
an enzyme involved in inflammation and cellular
differentiation, was also found in pterygium.121
Cystatin C, an inhibitor of cysteine proteinases, is
overexpressed in pterygium and is more abundant in
genic factors.
Because of the cell proliferation that is characteris-
tic of pterygium formation, a wide array of growth
factors has been studied. A complete list of all these
molecules, as well as a brief summary of their role as
pathogenic factors, can be found in Table 2. The
heparin-binding epidermal growth factor (HB-EGF)
has been found to induce cell migration in ptery-
gium.127 Basic fibroblast growth factor (bFGF),120
vascular endothelial growth factor (VEGF),128 and
HB-EGF127 have been reported to be up-regulated
following UV-B radiation. VEGF, along with COX2,
has been found in pterygium macrophages, suggest-
ing a role in angiogenesis, collagen deposition, and
possibly pterygium growth.129 A decrease in the
pigment epithelium-derived factor (PEDF)128 and an
increase in the insulin-like growth factor binding
protein-2 (IGFBP-2)130 have also been observed in
pterygia. This decrease in PEDF could cause angio-
genesis, since it is an angiogenic inhibitor.128 An

TABLE 1. Inflammatory mediators overexpressed and their role in pterygium pathogenesis.

Inflammatory mediator Potential pathogenic role Reference

30
IL-1 Up-regulation of other mediators and extracellular matrix modulators
33
IL-6 Promotes angiogenesis, cell differentiation, tissue invasion, and further inflammation
30
IL-8 Promotes angiogenesis, cell differentiation, tissue invasion, and further inflammation
120
TNFa Promotes angiogenesis, cell differentiation, tissue invasion, and further inflammation
31
COX2 Further inflammatory cascades
121
Phospholipase D Further inflammation and cellular differentiation
122
Cystatin C Regulation of extracellular matrix modulators

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TABLE 2. Growth factors and their role in pterygium pathogenesis.
Growth factor Abnormality found
bFGF Up-regulated after UVB radiation
PDGF Overexpression
TGF-b Overexpression
HB-EGF Up-regulated after UVB radiation
PEDF Down-regulated
VEGF Up-regulated after UVB radiation
IGFBP-2 Overexpression
Stem cell factor Overexpression
CTGF Overexpression
increase in the expression levels of stem cell factor,131
platelet-derived growth factor (PDGF),120 connective
tissue growth factor (CTGF),132 and transforming
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growth factor-beta (TGF-b)120 have been documented
in pterygium.
Inflammatory processes of pterygium can trigger
reactive wound formation, which may induce dysre-
gulated and inappropriate tissue remodeling, fibro-
proliferation, enhanced vascularization, and
deposition of the extracellular matrix, leading to the
formation of hypertrophic scarring.133 Recently, it has
been reported that the stromal derived factor (SDF-1),
an up-regulator of organ repair, as well as its receptor
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(CXCR-4) are overexpressed in the stroma of severe
pterygium.134 In this study, a significant correlation
was found between SDF-1 and the a-smooth muscle
actin (a-Sma), a hallmark protein of myofibroblasts,
which may contribute to the myofibroblast transform-
ation. Further research regarding SDF-1 signaling as a
candidate mechanism in determining the severity of
pterygia may contribute to the development of an
anti-SDF-1 treatment, which attenuates pterygia tissue
fibrosis.
Extracellular Matrix Modulators
In pterygium, extracellular matrix remodeling occurs
and is considered a key characteristic of the disease.
In this process, proliferative cells could gain access to
different growth factors and cytokines, thus breaking
the collagen barriers that keep theme from migrating.
Extracellular matrix remodeling is mainly achieved
through the action of different proteinases, among
which the MMPs have been more deeply studied.135
The expression levels of many MMP including
MMP-1,74 MMP-2,136 MMP-3,74 MMP-7,137 and
MMP-9136 have been found to be elevated in pterygia,
particularly in the head, the main point of migra-
tion and proliferation.138 The expression of MMP-8
and MMP-13 has also been related to pterygium
pathogenesis.29 Transglutaminase-2 (TGM2), which
enhances extracellular matrix remodeling, and
MMP-2 have been found to possess aberrant DNA
methylation, suggesting that pathogenesis of
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Molecular Basis of Pterygium Development 7
Potential pathogenic role Reference
120
Promotes cell proliferation
120
Promotes cell proliferation
120
Promotes cell proliferation and inflammation
127
Promotes cell migration
128
Promotes angiogenesis
128
Promotes angiogenesis
130
Promotes cell proliferation
131
Promotes angiogenesis
132
Promotes connective tissue remodeling
pterygium may be related to the methylation state of
essential extracellular matrix genes.12 MMPs inhibi-
tors (TIMPs) have been found with high expression in
pterygium samples; along with the high levels of
MMPs, these proteins may be active participants in
the extensive matrix turnover and infiltration that
characterize pterygium.4 The expression levels of
these proteinases and their inhibitors could mediate
the velocity of pterygium formation and expansion.
Angiogenesis and Lymphangiogenesis
In the healthy adult organism, the development
of new vessels (angiogenesis) is observed during
wound healing. Under pathological conditions,
angiogenesis appears to be deregulated. In particu-
lar, tumor angiogenesis supports the transition
from limited tumor growth to invasion and metas-
tasis. Malignancy-transformed cells produce angio-
genic factors which, in turn, induce the autocrine
growth control and paracrine control of
neovascularization.139
Inflammation is known to induce angiogenic path-
ways, which could result in neovascularization and
contribute to pterygium growth. The angiogenic
stimulation found in pterygium seems to be related
to elevated levels of VEGF, low levels of thrombo-
dopsin-1 (Tsp-1),2 and a decrease in substance P,140
which all promote the activity of the ETS-1 transcrip-
tion factor that directly induces angiogenic activity.25
VEGF acts as a chemokine in the initial step of
basement membrane degradation during angiogen-
esis, which is a requisite process for the further
locomotion and proliferation of endothelial cells, so
they finally develop tubule-like structures.141 Tsp-1 is
a multifunctional platelet and extracellular matrix
protein that acts as an anti-angiogenic factor.142 Its
decreased levels, which are found in pterygia, could
allow inducers of angiogenesis to act in an inhibited
mode.2 Together with VEGF, the inducible nitric oxide
synthase (iNOS) has been found to be overexpressed,
resulting in an increase in nitric oxide and further
angiogenic stimulation.26 The ephrin-eph system,
which is a protein and its tyrosine kinase-type
 8 E. Cárdenas-Cantú et al.
receptor that are required to form the complex
organization of vascular plexus during embryogen-
esis, has been found to be involved in ocular angio-
genesis.143,144 Moreover, thymine dimers induced
by UV-light have been associated with angiogenesis
in the pathogenesis of primary and recurrent pter-
ygium, especially given that they have been detected
in the fibrovascular tissue’s vascular network, as well
as in the blood and lymphatic vessels of primary and
recurrent pterygium.58
Recently, it has been shown that lymphangiogen-
esis occurs and develops in pterygium. A relationship
between the abundance of lymphatic vessels and the
severity of pterygium has been found. In a study in
which 96 patients with different grades of severity of
unilateral nasal pterygium were included, it was
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found that blood microvessel density and lymphatic
microvessel density increased significantly in pter-
ygium tissue. It was also reported that an increased
lymphatic microvessel density in the surgical speci-
mens predicted pterygium recurrence.27 Blood vessels
provide a route of entry for immune effector cells that
create more inflammation, and lymphatic vessels
enable the exit of antigenic material from the ocular
surface to the regional lymph node, thus generating a
positive feedback loop of inflammation.145–147 Though
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these mechanisms could hardly be related to pter-
ygium onset, they are surely related to the growth and
development of the disease.
Immunologic Mechanisms
Although this idea is not well understood, it seems
likely that the immune system is directly related to
pterygium development, either in its pathogenesis, or
as a consequence of its formation. Increased levels of
markers of immunologic activity, including the vas-
cular cellular adhesion molecule-1 (VCAM-1), the
intercellular adhesion molecule-1 (ICAM-1), and the
human leukocyte antigen-DR (HLA-DR), have been
reported.17,18 Up-regulation of E-cadherin14 and
b-catenin16 have also been observed. An increase in
mast cells, lymphocytes, plasma cells, dendritic cells,
and CD4+ and CD8+ T-cells in pterygium has also
been documented.17,19 In a study conducted with 84
samples of pterygium, in which immunocytochem-
istry highlighted the T-lymphocytes, B-lymphocytes,
and macrophages, it was reported that T-lymphocytes
formed the majority of the mass of immune intensity
of immune system cell present in connective tissue of
the pterygium. Macrophage-type cells were distrib-
uted unevenly in the pterygium tissue, as the intensity
of the inflammatory process varies depending on
antigen levels. This immune cell infiltrate was more
abundant in the subepithelial and in areas with
erosion of the covering epithelium, suggesting that
the inflammatory process is not responsible for the
cell proliferation, angiogenesis process, or the recur-
rence of pterygium.148
Epithelial-Mesenchymal Transition
The phenomenon whereby epithelial cells change
their phenotype to fibroblastic cells following mor-
phogenic pressure from injured tissue is called
epithelial-mesenchymal transition (EMT), and it is a
common feature of cancer cells.149 In a study con-
ducted with eight pterygia samples, immunoreactiv-
ity was found for tissue factor (TF), a main EMT
stimulator. TF-immunopositive cells were detected
with higher levels of expression in the cytoplasm of
basal, suprabasal, and superficial epithelial cells.
Additionally, the protein expression of a-SMA, a
classic sign of EMT, was detected in pterygial epithe-
lial cells, where TF immunoreactivity was co-localized
on double-staining immunohistochemistry. These
results indicate that epithelial cells change to
the mesenchymal phenotype-expressed TF.15 Down-
regulation of E-cadherin and the intra-nuclear accu-
mulation of b-catenin—proteins that regulate cell-cell
adhesion—have also been detected in pterygial epi-
thelium by immunocytochemistry.16 Down-regulation
of E-cadherin is a major final pathway during EMT,
and the canonical b-catenin signaling pathway is a
necessary component that drives EMT in develop-
ment and is frequently activated in cancer.150
Jaworski and colleagues reported in 2009 the
expression of EMT-associated genes including
S100A4 (two clones), bone morphogenetic protein 7
(one clone), heterogeneous nuclear ribonucleoprotein
A/B (one clone), and alanine–glyoxylate aminotrans-
ferase 2-like 2 (one clone) in pterygium tissue
samples.106 However, these genes were not notably
abundant in the pterygium cDNA. A recent study has
demonstrated the differential expression of miRNA
regulators of EMT in pterygium. The down-regulation
of four members from clusters of the miR-200
family, which inhibit EMT and enhance migration
and invasion in cancer, as well as up-regulation of
the mesenchymal marker fibronectin, suggest that
EMT could potentially play a role in the pathogenesis
of pterygium and may constitute a therapeutic
target.151
Alterations in Cholesterol Metabolism
A change in cholesterol metabolism has been
observed in pterygium-derived fibroblasts. In a
study conducted with primary pterygia cells isolated
from four patients, an increased activity of intracellu-
lar cholesterol metabolism was demonstrated by
measuring (14)C-oleate incorporation into cholesterol
esters and oil red O staining.38 Additionally, increased
Seminars in Ophthalmology

mRNA levels of hydroxyl-methylglutaryl-coenzyme-
A-reductase (the rate-limiting enzyme of cholesterol
biosynthesis) and low-density lipoprotein receptor
(which internalizes cholesterol-rich lipoproteins) have
been found in pterygium fibroblasts isolated from
human specimens.37 Everolimus and pioglitazone,
drugs that alter the metabolism of cholesterol, have
been shown to decrease pterygia fibroblasts prolifer-
ation, as well as the levels of molecules involved in
the regulating intracellular cholesterol homeostasis
acyl-coenzyme A cholesterol acyltransferase and
multidrug resistance protein.39 The results of these
studies suggest the use of topical drugs in the
prevention of pterygium proliferation by the modu-
lation of cholesterol ester metabolism.
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TREATMENT
Early in the disease process, pterygia are usually
asymptomatic; however, there can be signs of dry eye
(such as burning, itching, and tearing). As the disease
progress, the lesions increase in size and may cause
visual symptoms due to induced astigmatism that
directly encroaches onto the visual axis. When this
occurs, surgical intervention becomes necessary.
For personal use only.
Excision of the pterygium is the first step to repair.
Surgery includes bare sclera techniques, conjunctival
autograft, and amniotic membrane grafting. The bare
sclera technique consists of excising the pterygia,
allowing the scleral bed to re-epithelialize. This
procedure tends to leave small portions of the
pterygium tissue on the excised surface, resulting in
a high rate of recurrence. In addition, a meta-analysis
of published randomized controlled clinical trials that
compared bare sclera resection and conjunctival
autograft demonstrated that the odds of pterygium
recurrence following surgical treatment are close to
six and 25 times higher if no conjunctival autograft
placement is performed.152 Therefore, the placement
of a graft in place of the pterygium is used as a barrier
to new growth.
A conjunctival autograft involves obtaining an
autograft from the superotemporal bulbar conjunctiva
and suturing it over the exposed scleral bed once the
pterygium has been removed. This procedure yields
lower recurrence rates than the bare sclera, thus
resulting in long-term efficacy.153–155 Conjunctival
autografts can be placed using sutures or fibrin glue.
Sutures are associated with postoperative discomfort,
chronic inflammation, and granuloma formation.
Fibrin glue, on the other hand, is a synthetic tissue
adhesive prepared from a donor plasma, and it was
first described for pterygia surgery by Cohen in
1993.156 This procedure diminishes the complication
rates and reduces postoperative pain and discomfort;
however, it is more expensive and possesses the risk
of dehiscense.157,158 Overall, both procedures have
! 2014 Informa Healthcare USA, Inc.
Molecular Basis of Pterygium Development 9
yielded stable grafts.154,155,157,159 An amniotic mem-
brane is also used in the surgical treatment of
pterygium, given that it possesses anti-inflammatory
and anti-fibrotic properties.160 Typically, it is placed
over the bare sclera, with the basement membrane
facing up and the stroma facing down. Fibrin glue is
also used to help the amniotic membrane graft adhere
to the underlying episcleral tissue. Its use appears to
be safe and effective, and it is associated with lower
recurrence rates when compared to bare sclera.161,162
However, there are controversial results regarding the
effectiveness of this method in preventing pterygium
recurrence when compared with conjunctival auto-
grafts.163–167 Autologous nasal mucosa transplant-
ation has proven to be effective for ocular surface
reconstruction in chemical burn-damaged corneas.168
This procedure could be used for the treatment of
conjunctiva-deficient or severely damaged pterygia.
Recently, the intraoperative insertion of expanded
polytetrafluoroethylene (e-PTFE), a biocompatible
fluoropolymer used for soft tissue reconstruction,
has been shown to significantly reduce pterygium
recurrence when transplanted between the amniotic
membrane and conjunctiva in multirecurrent
pterygium.169
Once surgical excision has been performed,
adjunctive therapy is used to prevent pterygium
recurrence. The most common therapies are
Mitomycin C (MMC), b-radiation, and 5-fluoruroacil
(5-Fu). MMC is an anti-mitotic agent that induces the
apoptosis of keratocytes and myofibroblasts.170 It can
be administered intraoperatively or postoperatively in
combination with a conjunctival autograft and amni-
otic membrane, yielding low recurrence and compli-
cation rates.171–174 The intraoperative application of
mitomycin C results in a high success rate; however,
serious complications have been reported.175 Its use
requires strict selection of patients because of the
severe symptoms associated with the uncontrolled
doses, including corneal edema, corneal perforation,
and scleral calcification.176
Beta radiation is an emission that has medium
penetration and is absorbed in the outer layers of the
ocular tissue. It constitutes a practical method of
focally applying ionizing radiation to ocular struc-
tures to inhibit fibroblast proliferation.177 Strontium is
among the radioactive elements of interest with
respect to the ocular surface, given that it emits
abundant b-radiation and has a long half-life.178,179
Early post-operative b-radiation started within 24 h of
the surgical excision is effective, safe, can improve
symptoms, and provides better cosmetic results when
compared with chemotherapeutic agents, conjunctival
autograft, and simple excision alone. Combined doses
in fractioned applications have been shown to be safe
and effective.179–181 5-Fu is a pyrimidine analogue that
inhibits DNA synthesis on the S-phase of the cell
cycle. It affects rapidly proliferating cells, like
 10 E. Cárdenas-Cantú et al.
fibroblast attachment and migration.182 5-Fu has
proven to be safe and effective in reducing pterygium
recurrence rate.183 However, the recurrent cases can
develop an unacceptable cosmetic appearance with
excessive neovascularization.184
Ethanol is known to cause denaturation of peptides
and proteins in tissues, and it splits the basement
membrane and destroys hemidesmosome junctions
between corneal epithelial cells. Its application to the
cornea has been done in excimer laser refractory
surgeries to epithelial debridement, given that it
creates a smoother and clearer separation
plane.185,186 Intraoperative ethanol treatment has
been shown to minimize pterygium recurrence
when administered over a short period of time, and
with high level of cosmetic satisfaction.103 Recently,
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the use of ethanol alone to remove pterygium in a
simple procedure with low recurrence rates and no
intraoperative complications has been reported, and it
seems to be a promising alternative for pterygium
treatment.187
Bevacizumab is a recombinant humanized mono-
clonal immunoglobulin that inhibits the VEGF-
induced proliferation of endothelial cells.188 The
overexpression of VGEF in the pterygium has led
researchers to consider anti-VEGF therapy in the
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prevention of pterygium recurrence. It has been
reported that the single postoperative administration
of subconjunctival bevacizumab is well tolerated and
decreases the number and caliber of corneal blood
vessels.189 Nevertheless, this favorable effect is incom-
plete and temporary. Other researchers have reported
a decrease in the frequency of fibrovascular tissue
after bevacizumab treatment, with no statistically
significant differences in levels between the treated
and non-treated groups.190,191 Repeated injections in
the first year after surgery may help prevent the high
recurrence rate192; however, side-effects of multiple or
increased doses must be addressed.
Doxycycline, a broad-spectrum antibiotic, pos-
sesses biologic properties that affect inflammation,
proteolysis, angiogenesis, and apoptosis, among other
processes.193–196 It has been shown in carcinoma cell
lines and animal carcinogenesis models that doxycyc-
line may inhibit tumor growth by inhibiting MMPs,
and it may have a direct effect on cell proliferation.
Cox and colleagues, in 2010, demonstrated that
doxycycline inhibits experimental pterygium lesion
growth.196 In this study, the anterior segment of the
pterygium showed histological regression after doxy-
cycline treatment. A different study used massive
transcriptome sequencing to analyze surgically
removed pterygia cells. It was shown that doxycycline
exerts a strong dose-dependent response in pterygium
cells by inducing intracellular pathways such as
mitochondrial gene expression, the endoplasmic
reticulum stress pathway, genes related to the extra-
cellular matrix environment, growth factors,
interleukins, and cell cycle-related proteins.197 The
clinical use of oral doxyxycline in untreated primary
pterygium patients has been shown to be effective in
controlling pterygium size.198 Nevertheless, larger
clinical trials are needed to characterize the effect of
this treatment.
Recently, several compounds have shown anti-
proliferative activity in pterygium fibroblasts in vitro,
thus providing new potential therapies. Polyamine
analogue (S)-N1-(2-methyl-1-butyl1)-N11-ethyl-4,8-
dazaundeane (IPENSpm) has demonstrated its abil-
ity to reduce cell migration in primary cultures via
the inhibition of SAT1.106 Tetrandrine, an alkaloid
with anti-proliferative effects, has been proven to
decrease the expression of PCNA in pterygium
fibroblasts and it induces apoptosis in a time- and
dose-dependent manner.199 TrkA inhibitor can pre-
vent the growth of human pterygium fibroblasts
in vitro with up-regulation of Caspase-3 and apoptosis
rate.200 Curcumin, a phenolic compound extracted
from turmeric, has shown direct inhibitory effects
over pterygium fibroblast proliferation with inhibition
of PCNA levels.201
CONTROVERSIES AND LIMITATIONS
In order to develop reliable strategies for pterygium
treatment and/or prevention, a better understanding
of the molecular mechanisms that underlie its patho-
genesis is necessary. Until now, major advances have
been achieved in this regard. Several molecular
pathways related to the cellular mechanisms involved
in pterygium pathogenesis and progress have been
reported, providing knowledge regarding potential
biomarkers. Nevertheless, there are two cell types that
can be isolated from pterygia tissue samples: epithe-
lial cells and fibroblasts. Moreover, the cells that are
used as control in the experimental assays are isolated
from normal conjunctiva, which consists mostly of
epithelium (Table 3 summarizes the difference
between the molecular profile of epithelial and fibro-
blast pterygial cells discussed in this review). From
the research presented in this review, it can be noted
that epithelial are more directly related to presence of
proliferation biomarkers, whereas fibroblasts are
closely involved with the recurrence and severity of
pterygium. In order to characterize the molecular
expression pattern of the pterygium, the analysis must
be carried out on both cell types. It is also important to
consider the pathologic stage of the specimen, given
that most of the data are obtained from surgically
removed pterygium. To better understand pterygium
pathogenesis, is necessary to carry out molecular
analyses in the early stages for primary and recurrent
pterygium. High-throughput techniques that study
transcriptomes of pterygium have been conducted
using lysates from whole-pterygium tissue. Data
Seminars in Ophthalmology
 Molecular Basis of Pterygium Development 11

TABLE 3. Differential profile of unregulated molecules in pterygium epithelial and fibroblasts cells.

Cell type Type of deregulation

Molecule Epithelial Fibroblast Increased Decreased Reference
43,114
8-OHdG 3 3 3
106
Annexin A2 3 3 3
22
Bax 3 3
16
B-catenin 3 3
120
bFGF 3 3
132
CTGF 3 3
14
E-cadherin 3 3
25
Ets-1 3 3 3
44
GPx 3
127
HB-EGF 3 3 3
56
Hsp90 3 3 3
17,18
ICAM-1 3 3
33
IL-6/IL-8 3 3 3
117
Importin 3 3 3
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93
Ki-67 3 3 3
32
MLH1 3 3 3
29,74,135–137
MMPs 3 3
32
MSH2 3 3 3
200
NF-kB 3 3
13
p16 3 3 3
12,23,24,110–112,114
p53 3 3 3
128
PEDF 3 3
54
Peroxiredoxine-2 3 3
106
S100A9 3 3 3
44
SOD 3 3 3
117
Survivin 3 3 3
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4
TIMP-1 3 3
200
Trk-A inhibitor 3 3
17,18
VCAM-1 3 3
26
VEGF 3 3

obtained from these analyses are later complemented
with additional techniques, such as immunofluores-
cence, to histologically localize the protein of interest.
These approaches at the cellular level will provide a
better understanding of the affected pathways in
pterygium development.
To further research the effectiveness of potential
treatments on targeted molecules, a proper animal is
necessary. The model developed by Cox and col-
leagues196 consists of a subconjunctival injection of
human epithelial pterygium cells mixed with a
matrigel in athymic, nude mice. This procedure
allows for the development of masses with fibrovas-
cular components over the corneal surface after six
days, similar to what occurs in humans. To our
knowledge, no other animal models for pterygium
have been developed. However, it would be interest-
ing to analyze the histological and immunological
characteristics of the ocular lesion that develops from
this procedure, as well as its molecular expression
pattern, to fully identify its similarities and differences
with human pterygium. Moreover, it would be bene-
ficial to validate this procedure in larger animals, such
as rabbits or dogs, in order to ease surgical manipu-
lation and increase the size of the tissue lesion
obtained to conduct clinical and molecular analyses.
! 2014 Informa Healthcare USA, Inc.
Data obtained from the molecular analysis of
removed pterygium allow for the development of
therapeutic approaches that address recurrence and
prognosis severity rather than pathogenesis. Since
non-surgical treatment for pterygium is currently
available, the results from this research, together
with the increased feasibility to perform high-
throughput analysis for diagnostic purposes, could
help to identify deregulated genes/proteins in a
specific patient’s specimen in order to explore any
modulators in a targeted way. Thus, the practice of
personalized medicine in this field would aid the
progress toward the knowledge of pterygium
pathogenesis.
CONCLUSION
Pterygium is a disease characterized by the altered
proliferation of basal epithelial cells, neovasculariza-
tion, and invasion to the adjacent corneal epithelium.
The pathogenesis of this disease remains unclear,
although many attempts to elucidate possible patho-
genic pathways have been studied. From what has
been shown to occur at the molecular level in
pterygium tissue, it could be concluded that the
 12 E. Cárdenas-Cantú et al.
effects of UV radiation, together with the epigenetic
aberrations, provide a better approach in determining
the actual pathogenic origin of pterygium. However,
the role that viral infections play must not be
underestimated; thus, more is needed. The abundance
of the growth factors and cytokines presented here
seem to be related to the intriguing phenomena of
angiogenesis and lymphangiogenesis, as well as to the
activities of many different proteinases. These process,
however, have a higher chance of being related to
pterygium maintenance and development, rather than
to its pathogenesis. Cholesterol metabolism modifica-
tion is a promising field of study for the treatment of
this disease, although more research needs to be
undertaken. The epithelial-mesenchymal transition of
pterygium must be addressed more frequently in
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future works to elucidate further potential similarities
between pterygium and cancer that could shed light
on the pathogenesis of pterygium. The current treat-
ments aim to reduce the recurrence rate of pterygium
once it is surgically removed. In addition, advances in
the study of the molecular basis of the pterygium’s
pathogenesis, along with the new clinical treatments
and surgical adjuvants, hold promise for the devel-
opment of effective treatments against pterygium, as
well as for its prevention, and elimination of recur-
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rence following surgery.
DECLARATION OF INTEREST
The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of
this article.
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