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Gynecological Endocrinology
2012
28
8
577
581
© 2012 Informa UK, Ltd.
10.3109/09513590.2011.650761
0951-3590
1473-0766
Gynecological Endocrinology, 2012; 28(8): 577–581
© 2012 Informa UK, Ltd.
ISSN 0951-3590 print/ISSN 1473-0766 online
DOI: 10.3109/09513590.2011.650761
Endometriosis is the leading cause of morbidity among premeno-
pausal women affecting about 1 in 10 females. The features
shared by endometriosis and cancer include the ability to evade
apoptosis, the stem cell-like ability and angiogenic potential.
As such characteristics are encoded by the cell’s genetic consti-
tution, acquired mutations are responsible for the malignant
transformation of endometriosis. Indeed, a number of tumour-
suppressor genes and proto-oncogenes, such as protein 53
(P53) and B-cell lymphoma 2 (BCL-2) respectively, are mutated
and as a result differentially expressed between endometriotic
and malignant tissue associated with endometriosis. Moreover,
cytokines and macrophages, both of which are inflammatory
mediators have been implicated in the transformation process.
The angiogenic properties possessed by cancer arising from
endometriosis signifies a bad prognosis, while the stem cell-like
activity possessed by both endometriosis and cancer has been
attributed to the effect of oestrogen. A number of differences
between endometriosis and cancer are found at the molecular
level. Considering the link between these two pathologies, the
three components which fuel the malignant transformation of
endometriosis can be embodied in the endometriosis-induced
carcinoma (EIC) triangle which shows the intricate relationship
between endocrinologic, immunologic and genetic components.
Keywords: Apoptosis, cancer, cytokines, endometriosis
Abbreviations: AE, atypical endometriosis; ARID-1A, AT-rich
interactive domain 1A; BCL-2, B-cell lymphoma 2; bFGF, basic
fibroblast growth factor; EAOC, endometriosis-associated
ovarian carcinoma; GALT, galactose-1-phosphate uridyl
transferase; hMLH1, human MutL homolog 1; HNF-1β,
Hepatocyte nuclear factor-1β; HUMARA, human androgen
receptor gene; IL-1, interleukin-1; IL-1β, interleukin-1β; JNK,
c-Jun N-terminal kinase; LOH, loss of heterozygosity; MMR,
mismatch repair; mRNA, messenger RNA; MSI, microsatellite
instability; NF-κB, nuclear factor-κb; OC, ovarian cancer; P53,
protein 53; PGE-2, prostaglandin E2; PGK-1, phosphoglycerate
kinase 1; PTEN, phosphatase and tensin homolog; RANK,
receptor activator of nuclear factor ĸB; ROS, reactive oxygen
species; TAM, tumour-associated macrophage; TGF-β,
transforming growth factor-β; VEGF, vascular endothelial
growth factor
Introduction
Endometriosis is a benign gynaecological pathology aecting about
1 in 10 females during their reproductive years [1]. is condition
shares a number of features with cancer [2] such as its stem cell-like
activity [3], the ability to evade apoptosis [4] and to induce angiogen-
esis [5,6], as well as the intrinsic self-regulation of its rate of prolifera-
tion [7,8]. Such properties can be explained through the molecular
signals between the cells which regulate the intracellular signalling
cascades. is allows the population of ectopic cells to survive
within its new tissue environment [9]. Is it possible that a change
in the genetic code of the endometriotic cells during the course of
the benign disease can modify the gene expression pattern of such
cells rendering them capable of metastatic behaviour. Indeed, the
malignant transformation of endometriosis has been the subject of
a lot of studies whereby the risk of developing certain cancers, most
notably ovarian cancer (OC), was found to be signicantly increased
in women having a history of endometriosis [7,10–18]. is review
seeks to outline the link between the molecular properties of endo-
metriosis and cancer and identify possible candidate signals respon-
sible for the malignant transformation of endometriosis. Moreover,
according to a study by Banz et al. [2], two distinct sets of genes
were found, one of which includes genes which show dierential
expression in endometriosis and endometriosis-associated ovarian
cancer (EAOC), but not in OC and benign ovaries whilst the other
consists of genes which are dierently expressed in endometriosis-
associated ovarian cancer (EAOC) and OC but not in endometriosis
and benign ovaries. e genes which are dierentially expressed in
endometriosis and EAOC as opposed to OC and benign ovaries,
may be possible candidates for predisposing to the development of
EAOCs.
Apoptosis in endometriosis and cancer
In apoptosis, there are two major apoptotic regulatory proteins
which dier in their level of expression between benign and
malignant tissue: B-cell lymphoma 2 protein (BCL-2) and protein
53 (P53) [4]. BCL-2 is one of a diverse class of regulatory proteins,
the majority of which are antiapoptotic [19]. P53 is a regulatory
protein which allows the repair of minor insults which occur in
the process of DNA replication and which signals apoptosis in
case of major DNA damage [20]. BCL-2 levels are upregulated in
endometriotic tissues with about one in four endometriotic cysts
expressing BCL-2 [4]. e expression of BCL-2 in ovarian carci-
noma is higher than that for the ovarian endometriotic cysts [4].
Moreover, according to the same study, areas of the carcinoma
which showed up as being malignant had a higher expression than
those areas which showed up as being benign [4]. is suggests
that upregulation of BCL-2 in endometriotic tissue may be one of
the factors that promotes malignant transformation. e level of
BCL-2 expression in the serous papillary ovarian carcinoma is also
highly upregulated in comparison to the ovarian endometriotic
GYNECOLOGICAL CANCER
Molecular links between endometriosis and cancer
Joel Pollacco1, Keith Sacco1, Mark Portelli1, Pierre Schembri-Wismayer1 & Jean Calleja-Agius1,2
1 Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, Tal-Qroqq, Msida, MSD 2080, Malta and 2Department
of Obstetrics and Gynaecology, Mater Dei Hospital, Msida, MSD 2090, Malta
Correspondence: Dr Jean Calleja-Agius, Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, Msida, MSD 2080, Malta.
Tel: +356 21693041. Fax: +356 21319527. E-mail: jean.calleja-agius@um.edu.mt
578 J. Pollacco et al.
Gynecological Endocrinology
cyst [4]. Benign endometriotic cysts do not overexpress P53,
while the expression of P53 is upregulated in the carcinomatous
tissues [4]. Ovarian carcinoma was shown to exhibit a signicantly
higher level of protein expression than the benign counterpart of
the same histologic sub-type [4]. P53 has been documented in the
case of an ovarian yolk-sac tumour associated with endometrioid
adenocarcinoma and endometriosis [21]. Another study has
shown that expression of BCL-2 was downregulated while that
of P53 was upregulated in the case of ovarian epithelial tumours
[22]. e same pattern of results was obtained in another study
[18], whereby all the tumours examined also tested positive for
KI-67, which was used as a marker for proliferation [18]. It is not
only the level of expression of BCL-2 and P53 which is altered
in the malignant transformation of endometriosis, but certain
studies suggest that the proteins themselves are structurally modi-
ed as a result of mutations sustained within the specic gene loci
coding for such proteins [22,23]. is may in turn account for the
upregulation of P53 in ovarian endometrioid carcinomas arising
in endometriosis [24].
The role of macrophages
Macrophages play a key role in inammatory processes.
Previous research has shown that macrophages contribute to
tumorigenesis through the chronic inammatory processes
which they mediate [25]. Endometriosis induces a localized
inammatory reaction in the immediate vicinity of the area
of the peritoneum or viscera, where the endometriotic cells
inltrate [26]. e macrophages produce a wide range of cytok-
ines such as interleukin-1β (IL-1β) which in turn encourage
the progression of tumorigenesis [9]. IL-1β is one of the most
potent mediators of inammation, and it promotes tumorige-
nicity by stimulating the production of a diverse array of cytok-
ines, chemokines and intercellular communication mediators
which also lead to angiogenesis [9,27]. IL-1β is one of the two
members of the interleukin-1(IL-1) class family, which act as
agonists of the IL-1 receptor [27].
Macrophages also produce an array of cytotoxic reactive
oxygen species (ROS) in their function to destroy pathogenic
material [28]. e production of cytotoxic ROS is also contrib-
uted through the Fenton reaction [29] by the high levels of free
iron ions found in the endometriotic cysts due to the repeated
degradation of ectopic menstrual blood [30]. ese free radicals
scavenge the cells’ macromolecules including DNA and proteins
[31], causing structural DNA damage by oxidation of the DNA
bases [32]. ey also act indirectly through specic molecular
pathways. Although this has not been substantiated to the endo-
metrial tissue, in breast cancer it has been found that nuclear
factor-κb (NF-ĸB) and AP molecular pathway activation by ROS
are actually mediated by convergence of the molecular signals
received from activation of receptor activator of nuclear factor
ĸB (RANK) and transforming growth factor-β (TGF-β) recep-
tors [33]. ese transcription factors promote the expression of
proteins which increase the cells’ angiogenic and proliferative
potential [34]. Indirect free-radical DNA damage can also be due
to adduct formation between the nucleic acid bases and the lipid
peroxides [32].
In normal physiologic responses to tissue injury, macrophages
function in extensive remodelling of the injured tissue area
leading to complete resolution [28]. In order to carry out these
functions, macrophages harbour a set of catabolic enzymes. In
particular, the matrix metalloproteinases are presumably able
to induce the secretion of a large amount of growth factors such
as vascular endothelial growth factor (VEGF) and basic bro-
blast growth factor (bFGF) from the underlying extracellular
matrix [35] so as to activate the trophic eect of the local tissues
in an attempt to replace the damaged tissue. It is hypothesized
that there is continuous cell to cell communication between the
macrophages and the premalignant cells in the chronic inam-
ma to ry st ate [36]. e same genes which impart the macrophage
with the ability to degrade extracellular matrix material are
induced in the stromal cells [28]. is increased invasiveness
occurs via activation of two molecular pathways, the NF-κB
and c-Jun N-terminal kinase (JNK) pathways respectively,
through the action of tumour necrosis factor α (TNF-α) [36].
Having lost their intrinsic ability to regulate the rate of cell divi-
sion through repeated insults to their genome, these stromal
cells can progress to malignancy [28]. Such macrophages are
known as tissue-activated macrophages (TAMs). Indeed, this
not only applies to the endometriosis-carcinoma sequence but
also applies to the malignant transformation of other benign
counterparts of endometriosis [28]. e TAMs are known to
be involved in antagonizing T-cell mediated immunity [25]
either by producing immunosuppressive substances such as
indoleamine dioxygenase [37] or by inhibiting dendritic cell
maturation and thus antigen presentation [25].
Angiogenesis in endometriosis and cancer
VEGF has been detected in almost all samples of EAOC. This is
in contrast to the detection of VEGF in only 12.5% of atypical
endometriosis (AE) specimens [38]. This indicates that VEGF
plays a major critical role in the survival of the tumour cells.
Hence, the increase in level of VEGF expression by the endo-
metriotic tissue may be an indication of transformation to
malignancy [38]. Ovarian cancers with a higher VEGF expres-
sion were shown to have a significantly worse prognosis [5].
Moreover, in one study, the presence of increasingly high levels
of VEGF in tissues corresponded to the absence of T cells in the
immediate vicinity of the tumour [39]. Subcutaneous tumours
implanted in immunodeficient mice stop growing when VEGF
function was blocked using a complementary antibody [6].
This suggests that VEGF provides adequate vascular perfu-
sion to new populations of cells which emerge in a body tissue
[6]. Besides the role of VEGF as an angiogenic factor, it has
been proposed that VEGF functions as a growth factor for the
tumour, independent of angiogenesis [5].
Stem cell-like activity in endometriosis and cancer
e limit to a cell’s replicative ability lies in the short repeti-
tive DNA sequences found at the ends of chromosomes termed
telomeres. e progressive shortening of the telomeres which
occurs as a cell passes from one cell cycle to the next leads
to its senescence and eventually to its death [32]. However,
endometrial cells are induced to express telomerase enzyme
by oestrogen [3]. is may be the factor which imparts the
endometrial cells with increased proliferative ability that allows
them to replace the functional layers of the endometrium
during the menstrual cycle [40]. In endometriosis, the ability of
self-renewal of the endometrial tissue is somewhat increased,
and this allows them to proliferate in such a way as to form
macroscopic lesions outside the uterus [41]. Since telomerase
reactivation and prolonged proliferation are features of cancer
cells, the upregulation of telomerase enzyme may be another
factor which contributes to the malignant transformation of
endometriosis.
Endometriosis and cancer 579
© Informa UK, Ltd.
Genomic differences between endometrial cells, endometriosis
and cancer
A number of comparisons have been described between the
genetic constitution of endometriotic cells and clear cell or
endometrioid ovarian carcinomatous cells in terms of the gene
expression patterns [24,42,43]. e c-erbB-2 ge ne i s mo re h ighl y
expressed in endometriosis adjacent to ovarian carcinoma than
in endometriotic tissue without any adjacent malignant tissue
[24]. However, many dierences in terms of gene expression
patterns have been found. A number of dierent polymor-
phisms are found at the codon 72 of the p53 gene in women
with endometriosis [44]. is is one of the dierences in the
genetic constitution between wild-type endometrial cells and
endometriotic cells. Loss of heterozygosity (LOH) at the 10q23.3
locus of the genome in ovarian endometrioid carcinomas,
clear-cell ovarian carcinomas and endometriotic cysts has been
documented [42] with the LOH prevailing to the highest extent
in endometriotic cysts. A series of mutations at the same locus
have also been detected in a signicant amount of carcinomas
of the ovary. Moreover, some of the carcinomas associated with
endometriosis also displayed LOH at the 10q23.3 gene locus
[42]. LOH has also been found in a number of genetic loci such
as on the chromosome arms 9p, 11q and 22q [45]. In another
study [43], LOH was shown to occur at 17 dierent genetic loci
in 9 out of 17 cases of endometriosis coincident with carci-
noma. e LOH was present in both the malignant tissue and
the adjacent benign endometriotic tissue.
Mutations have been found in the AT-rich interactive domain
1A (ARID-1A) in less than half of samples of ovarian clear-cell
carcinomas and endometrioid carcinomas [46]. e ARID-1A
gene codes for BAF250, a tumour-suppressor protein. In the same
study, these mutations have been linked to the loss of expression of
BAF250. e fact that such a mutation is found in only the two types
of cancer, which can arise from endometriosis means that such a
change in endometriotic cysts may give rise to such cancers [46].
e human MutL homolog 1 (hMLH1) gene is known to
be hypermethylated in Stage IV endometriosis not associ-
ated with carcinoma and AE in association with clear-cell or
endometrioid ovarian carcinoma [47]. e hypermethylation
of the tumour-suppressor P16 gene together with an increase
in the level of tumour markers is also associated with stage IV
endometriosis [47]. hMLH1 itself also functions as a tumour-
suppressor gene since it encodes an enzyme involved in the
mismatch repair (MMR) system. e MMR system is one of
the intrinsic mechanisms a cell possesses which proofread the
DNA for any errors in base-pairing aer DNA replication [32].
Consequently it has been shown that the loss of expression of
the hMLH1 protein in endometrioid cancers with microsatellite
instability (MSI) is largely due to gene silencing of the hMLH1
gene through hypermethylation.
Alternatively, the presence of MSI in cells which do not have
hypermethylation or any abnormal methylation patterns at the
hMLH1 locus have been attributed to the occurrence of somatic
mutations at the respective microsatellite regions [48]. Since MSI
is so tightly associated with endometrioid carcinomas and is
largely caused by inactivation of the hMLH1 gene locus [48,49],
it follows that hMLH1 gene inactivation could be an early marker
of the malignant conversion of endometriotic lesions to endo-
metrioid carcinomas [47].
e expression of a particularly modied gene for the
progesterone receptor, the PROGINS gene is associated with
an increased risk of developing OC [50]. Hence, subsequent
somatic mutations at the gene locus which codes for proges-
terone receptor in the course of the rapid cell cycling which
occurs in endometriosis may predispose a woman to onco-
genesis. To assess the monoclonality of carcinomas arising
from endometriosis, the methylation of various gene loci on
the X-chromosome such as human androgen receptor gene
(HUMARA) [51] and phosphoglycerate kinase 1 (PGK-1) [52]
can be used as markers. Endometriotic lesions have been shown
to be polyclonal [52]. e monoclonality of cancers arising
from endometriosis means that the cancer has arisen from the
clonal expansion of a single cell and hence supports the notion
of EAOCs, as being cancers arising from the clonal expansion
of a single endometriotic cell.
Possible mechanisms responsible for the malignant
transformation of endometriotic lesions
Malignant cells exploit the cells’ intrinsic mechanisms to regulate
the length of its lifespan and its metabolism to their own advantage.
As oxygen, heat and fuel constitute the re triangle, we propose
the endometriosis-induced carcinoma (EIC) triangle (Figure 1).
e three factors which directly contribute to endometriosis-
induced oncogenesis are (1) alterations within the endometriotic
cells’ genome, (2) endocrinological factors and (3) immunological
factors. e relationship between inammation, genetic inuences
and cancer has been described by Balkwill et al. [25], as the genetic
inuences being “the fuel that feeds the ame” and inammation
being the “fuel that feeds the ame.” However, in endometriosis,
there is also the endocrinological component which interacts with
the genetic inuences, in addition to the immunological factors. In
eect, the high local levels of oestrogen in the ovarian endometri-
otic foci, due to the upregulation of aromatase cause an increase
in the level of prostaglandin E2 (PGE-2) [53], which in turn
suppresses normal immunologic responses such as phagocytosis
[54] and leads to diminished apoptosis [55]. e increased levels
of local oestrogens increases the level of expression of angiogenic
Figure 1. e endometriosis-induced carcinoma (EIC) triangle. bcl-2, B-cell
lymphoma 2; hMLH1, human MutL homolog 1; PTEN, phosphatase and
tensin homolog; p16, protein 16; p53, protein 53; TNF-α, tumour necrosis
factor α; TSGs, tumour-suppressor genes.
580 J. Pollacco et al.
Gynecological Endocrinology
factors such as VEGF [56] and may contribute to the increased
expression of telomerase [32].
In our view, there is a continuum between the physiologically
normal endometrium, endometriosis and eventually carcinoma,
which explains the dierent characteristics exhibited by the
pathological tissue obtained from dierent women suering from
endometriosis. Endometriosis lies in the middle of the spectrum
ranging from the physiologically normal endometrium at one
end, to carcinoma at the other extreme. us, even endometriosis
itself is a consequence of the three components of the EIC triangle
to a certain extent. e EIC triangle being proposed is the gateway
for progression to malignancy from the benign endometriotic
state. e three components are closely interconnected to each
other at the molecular level such that the more they contribute to
the oncogenic process, the greater the risk for a woman to develop
neoplasia early on in her life. e genetic component of the EIC
triangle would be somatic loss of function mutations in tumour-
suppressor genes such as phosphatase and tensin homolog (PTEN),
P53, hMLH1 genes and BCL-2. e endocrinologic component
would be the role of oestrogen in determining the potential of
the endometriotic tissue to become cancerous by inducing the
expression of telomerase amongst others. e immunologic
component of the triad making up the EIC triangle would be the
consequences of endometriosis as an inammatory process, espe-
cially the role played by macrophages.
Considering this scenario, it should be possible to halt the
progression of endometriosis to carcinoma by breaking up the
EIC triangle. is could be done by antagonizing the endocrino-
logic or immunologic eects contributing to the triangle such as
by antagonizing the action of TAMs. Indeed, the use of methods
by which the action of inammatory mediators is inhibited to halt
tumorigenesis or cancer progression has already been described
in the literature [25]. Moreover, the components which are to
be therapeutically targeted in such a case must be specic to the
endometriosis-carcinoma sequence so as to avoid adverse eects.
Details as to how this can be actualized within the clinical setting
are not yet currently available, and further studies in this prom-
ising eld of research are required.
Conclusion
Despite the molecular links between the two, endometriosis and
malignancy, endometriosis remains a benign gynaecological condi-
tion having a major impact on women’s health [57], while cancer
claims the lives of many women annually [58], with OC being the
second most lethal gynaecological malignancy in 2008 in the UK
[59]. A knowledge of the divergences and convergencies of these
two diseases may shed light on innovative therapy in this respect.
Declaration of Interest: e authors declare no conict of interest.
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