JH 0215

ISSN 1598-8767
BioWave Vol. 10 No.4 2008

http://bric.postech.ac.kr/webzine/
Ovarian Epithelial Cancer: Etiology and Pathogenesis
Jung-Hye Choi
Department of Pathology, Johns Hopkins University School of Medicine
To whom correspondence should be addressed. E-mail jchoi63@jhmi.edu
. Abstract
. Ovarian cancer
A. Clinical features
B. Classification and features
. Etiology
A. Epidemiological findings
B. Tumorigenesis hypothesis
C. Stem cell-like etiology
. Molecular pathogenesis
A. Molecular changes
B. Molecular carcinogenesis model
. Concluding remark
. References
Ovarian Epithelial Cancer: Etiology and Pathogenesis-Jung-Hye Choi
ISSN 1598-8767

. Abstract
Ovarian epithelial cancer is the fifth leading cuase of cancerrelated death among women in developed countires, and it is the most lethal
gynecological
malignancy.
Despite
its
clincal
significance,
the
pathophysiology of ovarian cancer is the least understood among all major
human malignancies due to a poor understanding of the etiological factors
and mechanisms of ovarian cancer progression. This review first summarize
the key findings and rencent advances in our understanding of etiology of
this disease, with particular emphasis on reproductive factors including
ovulation and hormones. The stem cell-like etiology of ovarian cancer is
briefly disccused as well. Ovarian carcinogenesis model based on recent
clinical, histopathological, and molecular genetic findings is next
summarized.
. Ovarian cancer
A. Clinical features
Ovarian cancer is the sixth most common cancer and the fifth leading
cause of cancer-related death among women in developed countries (1).
Worldwide, the total number of cases is approximately 190,000 per year (2).
In the United States, about 23,000 new cases were diagnosed while
approximately 14,000 women died from the disorder in the same year (3).
About 1 in 70 women in the United States will develop ovarian cancer (4).
In Korea, 11,404 cases were diagnosed and 855 women died of ovarian cancer
between 1993 and 2002 (5).
Only about 25% of women have localized disease at the time of
diagnosis because of the absence of specific symptoms and signs and the
lack of trustworthy screening system. Signs and symptoms of ovarian cancer
may include nausea, loss of appetite, abdominal discomfort and/or pain,
abnormal vaginal bleeding, and weight change. Despite the limitations of
sensitivity and specificity, the combination of pelvic exam, transvaginal
ultrasound, and CA125 assay are currently used as diagnostic tools. The
International Federation of Gynecology and Obstetrics (FIGO) stage has been
recognized as a significant prognostic factor in most studies (6, 7).
Patients in most cases present in stage III or IV with a 5-year survival of
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around 28% and 16%, respectively, while the 5-year survival rate is up to
80% for patients in stage I. Standard management for advanced ovarian
cancer is cytoreductive surgery followed by paclitaxel/platinum-based
chemotherapy. Current regimens can achieve 25-30% complete pathological
response rate and 15.5-22 months median progression-free survival (2, 8).
Although ovarian cancer is considered a chemosensitive neoplasm with 80%
initially responding to conventional treatment, the common chemoresistance
resulting in eventual tumor recurrence gives rise to a poor long-term
survival rate among the women with advanced stage cancer at diagnosis. Thus,
improving the predictive value of screening and identifying the critical
drug targets are urgent for prevention, treatment, and survival of patients.
In this regard, current efforts are being directed toward increasing the
understanding of mechanism by which ovarian cancer develops and progresses.
B. Classification and features
According to the World Health Organization (WHO) histological
classification, an ovarian tumor can be classified into three categories
according to the most probable tissue of origin: surface epithelial tumors,
sex cord-stromal tumors, and germ cell tumors. Approximately 90% of
malignant tumors arise from the ovarian surface epithelium (OSE) with the
rest originating from granulosa cells (~ 5%) or, rarely, germs cells (~1%).
The OSE is a single layer of flat-to-cuboidal epithelial cells covering the
ovary. Ovarian epithelial cancers are heterogeneous and are primarily
divided into a number of subtypes, including serous (fallopian tube),
mucinous (endocervical-like), and endometrioid (endometrium-like) tumors (9,
10) based on the morphological, functional, and antigenic resemblance to
epithelium of Mullerian ducts. The rare clear cell and transitional cell
carcinomas are also classified as epithelial carcinoma, and they express
features like mesonephros and urothelium, respectively (9, 10). According
to the propensity of their proliferative and invasive behavior, ovarian
tumors are further subdivided into benign, borderline, or malignant tumor.
For example, benign tumors have little copious proliferation and invasive
behavior while malignant cancers have both proliferative and invasive
features. Borderline tumors, also known as low malignant potential, have
aggressive cellular proliferation but no invasive behavior.
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. Etiology
A. Epidemiological findings
The etiology of ovarian cancer remains poorly understood. To date,
family history of ovarian cancer, age, early menarche, and nulliparity have
been consistently recognized as risk factors of ovarian epithelial cancer,
while pregnancy, oral contraceptive use, hysterectomy, and tubal ligation
are protective factors.
Familial ovarian epithelial cancer comprise approximately 5-10% of
ovarian cancer (11). BRCA1 or BRCA2 mutations are found in about 50% and
70% of ovarian cancer patients with at least one first-degree and two or
more affected relatives, respectively (12-14). The risk to develop ovarian
cancer is likely to increase, as women grow older. In the United States,
the mean age of incidence of ovarian cancer is 57-59 years, 50% of all
cases occur over age 65, and age-specific incidence peaks in the mid-70s
(15, 16). Recent studies have linked tobacco products/smoking to an
increased incidence of a specific type of ovarian cancer (17-19). In
addition, talc (20, 21), asbestos (22), and alcohol (23) have been
sometimes associated with an increased risk. However, these issues are
limited by inconsistent data and/or the lack of supportive animal models.
Thus, to date, epidemiological studies have failed to yield a consensus
regarding the contribution of chemical carcinogens to the development of
ovarian cancer. The data on obesity and ovarian cancer risk are
inconclusive, but generally suggest an increased risk for obese women.
Obesity is likely associated with some physiological or pathological
conditions in gynecology such as hormone levels, ovulatory function,
infertility, polycystic ovary syndrome, hyperandrogenism, and endometriosis
(24-26).
Countless epidemiological findings demonstrated the influence of
menstrual and/or reproductive factors in ovarian cancer development. Each
additional pregnancy decreases the risk 10-16% (27, 28). Interestingly,
several studies have reported a significant trend of decreasing ovarian
cancer risk with increasing age at first birth and/or greater age at last
birth (29-31). For example, Pike et al. in their population-based case
control study demonstrated that women whose only and last birth was after
age 35 years had about a 50% reduced risk of invasive ovarian cancer while
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the protective effect was decreased with childbirth earlier than age 35
years (30). It is most likely that the use of oral contraceptives (OC)
decreases ovarian cancer risk. In several recent studies, the reduction of
ovarian cancer risk in women ever taking OC compared with non-users is
about 30% (32-34). The protection increases approximately 7% per year of
use, such that the long term users (over 10 years) had up to an 80%
reduction (33, 35). The beneficial effect of OC against ovarian cancer
risk persists for at least 10-15 years since last use, or even as long as
20-25 years (33, 36, 37). The favorable effect of OC has been observed in
most histological subtypes, but mucinous, and even in BRCA mutation
carriers (35). No significant difference in protective effect among the
diverse types of OC preparations is apparent. Hormone replacement therapy
(HRT), which is frequently prescribed for menopausal women due to its
possible benefits in reducing the risks of osteoporosis and heart disease,
provides another source for exogenous steroid. The epidemiologic findings
concerning HRT use and ovarian cancer risk are equivocal. However,
available data suggest that a moderately increased risk of ovarian cancer
may be related to estrogen therapy alone, but not with estrogen-progestin
combined regimes (37-39). Women suffering from infertility have about a
twofold higher ovarian cancer risk than does the general population (40).
Ovulation induction agents used in the treatment of infertility (clomiphene
or gonadotropins) may also be a risk factor for ovarian cancer (37-39, 41,
42). Tubal ligation and hysterectomy without oophorectomy reduced the risk
of ovarian cancer, presumably due to decreased exposure of the ovary to
potential carcinogen factors and/or inflammation (36, 43, 44).
B. Tumorigenesis hypothesis
To date, several hypotheses have been suggested to explain the
epidemiological findings. The incessant ovulation hypothesis, which was
initially proposed by Fathalla et al. in 1971 and later extended by other
researchers, postulates that repeated trauma during ovulation leads to an
increased exposure of the OSE to genetic abnormalities and/or other risk
factors (45, 46). Indeed, early menarche, late menopause, and nulliparity,
all of which have more ovulation episodes, increase the risk of developing
ovarian cancer. On the other hand, conditions in which ovulation is
suppressed, such as multiple pregnancies and prolonged breastfeeding, have
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been reported to lower the risk to develop ovarian cancer (1, 47, 48).
Although
this
incessant
ovulation
theory
reconciles
appreciable
epidemiological and experimental data, the underlying mechanism remains
poorly understood. Moreover, some observations do not fit this theory (37,
49-51). Several hypotheses explore the etiology of ovarian cancer, which
are not exclusive with the incessant ovulation theory, and not with each
other. Based on the risk factor of pelvic inflammatory disease and the
favorable effects of hysterectomy and tubal ligation, the inflammation
hypothesis was advocated (22). The stromal hypothesis suggests that
some follicular cells escape from programmed cell death, continuously
produce steroid hormones, and stimulate neoplastic conversion of the OSE
cells in stroma (52). Considering hormonal carcinogenesis shown in
endocrine-related cancers such as breast and prostate cancers, two major
hormonal hypotheses are currently under examination. One is an
androgenic/progesterone hypothesis stating that androgens, which are
increased in menopausal or obese women, stimulate tumorigenesis in the
ovary while progesterone protects it (53). The other is the
gonadotropin
hypothesis
proposing
that
excessive
levels
of
gonadotropins, follicle stimulating hormone (FSH) and luteinizing
hormone(LH), related to the surge occurring during ovulation and the loss
of gonadal negative feedback for menopause and premature ovarian failure,
may play a role in the development and progression of ovarian epithelial
cancer (54). Indeed, author has demonstrated a regulatory role of
gonadotropins in both normal and neoplastic OSE cells (Figure 1). Treatment
with FSH or LH reduced the levels of gonadotropin-releasing hormone type II
(GnRH II) and gonadotropin-releasing hormone receptor (GnRHR) mRNA in IOSE
and ovarian cancer cells (55). The growth inhibitory effect of GnRH I or II
was blocked by pretreatment with FSH or LH. Treatment of pre-neoplastic
IOSE-80PC cells with gonadotropins resulted in a significant increase of
EGFR mRNA and EGFR protein levels(56). Both FSH and LH induced a
significant synergistic stimulation of mitogenesis in the presence of EGF.
The effect of gonadotropins on the expression of EGFR involved enhanced
cell growth via ERK-1/-2 and PI3K activation in pre-neoplastic ovarian
surface epithelial cells. In parallel experiments on metastasis, treatment
with FSH or LH significantly increased the invasion of ovarian cancer
cells(57). Treatment of SKOV-3 cells with FSH or LH enhanced net MMP/TIMP
balance and proteolysis potential. In addition, we demonstrated that
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gonadotropins induced an increase in SKOV-3 invasiveness via the activation

of protein kinase A (PKA) and phosphatidyl-inositol-3-kinase (PI3K)
signaling pathways. There is increasing evidence suggesting that the key
reproductive hormones, not only androgen, progesterone and gonadotropin but
also GnRH (gonadotropin releasing hormone), activin/inhibin, leptin (58),
and estrogen, regulate the growth of normal OSE and ovarian cancer cells
(59).
A.
OSE
EGF/TNFa
Tunica albuginea
EGFR
IC
GnRH
GII and GR
FSH/LH
BV
Follicle
Proliferation/
Neoplastic conversion
B.
Other Tissues
FSH/LH
Invasion
MMP2/9
Metastasis
MMP2/9
and uPA
Peritoneal Fluid
OEC
OSE
Tunica albuginea
and uPA
Metastasis
FSH/LH
Figure
1.
Diagrammatic
representation
of
the
potential
role
of
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gonadotropins in neoplastic transition of OSE cells (A) and metastasis of

ovarian epithelial cancer (B). Gonadotropins have been shown to regulate
the expression of EGFR and GnRH and its receptor, resulting in the
stimulation of growth potential in OSE trapped into the ovarian stroma (A).
Gonadotropins play a role in the invasiveness of ovarian cancer cells by
regulating the expression and secretion of tumor proteinases. FSH, follicle
stimulating hormone; LH, luteinizing hormone; EGF, Epidermal growth factor;
TNFa, tumor necrosis factor alpha; GnRH, gonadotropin releasing hormone;
GII, gonadotropin releasing hormone type two; GR, gonadotropins releasing
hormone receptor; BV, blood vessel; IC, inclusion cyst; OSE, ovarian
surface epithelium; MMP, matrix metalloproteinase.
C. Stem cell-like etiology
More recently, there is the stem cell niche concept for cancer
development (60). Somatic stem cells seem to reside within specialized area,
so called niche, where they may remain quiescent until activation by
injury or other stimulation. Adult OSE cells have the stem cell property of
self-renewal. It is also noteworthy that the OSE is closer in its
differentiation state to the pluripotent or multipotent mesodermal
embryonic precursor cells than other epithelial derivates (61, 62) As
discussed above, OSE is a simple, rather primitive epithelium with some
stromal features, but as it progresses to malignancy it loses stromal
characteristics and acquires the characteristics of the complex glandular
epithelial phenotypes of Mullerian duct-derived tissues such as serous
(fallopian
tube),
mucinous
(endocervical-like),
and
endometrioid
(endometrium-like) types. This retention of pluripotentiality may be
accompanied by greater proliferative capacity with reduced induction of
apoptotic cell death pathways and therefore perhaps enhanced the
susceptibility to neoplastic transformation. However, the cellular and
molecular mechanism by which pluripotent stem-like OSE cells escape from
quiescent status and undergo tumor formation is still not understood. It
may be mediated through incessant ovulation and following stimulation by
various factors such as inflammation, hormone, and growth factors. The OSE
is separated from the hormone/growth factor-producing stroma by the
collagenous tunica albuginea and a basement membrane. Ovulation and agingrelated trapping of OSE fragments result in surface invaginations (clefts)
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and inclusion cysts in the ovarian cortex (63). Numerous studies have
provided direct evidence bearing on the frequent metaplasia and neoplastic
conversion of the clefts and inclusion cysts, presumably, via the aberrant
exposure to the hormone/growth factor-rich stromal microenvironment (64-67).
Thus, the OSE trapped into the ovarian cortex has been generally considered
as a neoplastic progression-prone site for OEC.
However, whether the
surface and/or cyst epithelial cells directly progress to a malignant
neoplasm is still not clear. Ness and Cottreau have suggested that an
inflammatory microenvironment such as cell damage, oxidative stress, and
elevations of cytokines and prostaglandins, rather than the trapping of the
OSE into the stroma, may mediate the mutagenesis induced by ovarian
ovulation (22). Repetitive loss of the basement membrane, which the OSE
cells generally are attached to as well as organized by, during ovulation,
has been implicated as an early event in the preneoplastic transformation
of OSE. This may be mediated through enhanced survival of the OSE cells,
which are multipotent mesodermal embryonic precursor cells, and/or
preferential selection of tumorigenically transformed cells (68-70).
Side population of tumor cells showing stem cells-like features
including unlimited self-renewal and proliferation has been recently
identified in leukemia, breast, and gastrointestinal cancer. If a small
number of these specialized cells escaped from chemotherapy or radiationinduced cytotoxicity, the tumor would be able to recur and subsequently
resistant to chemotherapy. Although 50-80% of patients with high stage
ovarian carcinoma initially response to conventional chemotherapy using
paclitaxel/platinum, the vast majority of patients will relapse and develop
chemoresistant. Thus, the high incidence of recurrence of ovarian cancer as
well as the multiple histological phenotypes indicative of multipotency
strongly suggests a stem cell-like etiology of ovarian cancer. Two recent
studies have identified stem/progenitor-like cells in ovarian cancer. Bapat
et al. found that two transformed clones from the ascites from a patient
possess stem-like characteristics and grow in an anchorage-independent
manner as spheroids (71). Significantly, both clones expressed self-renewal
mechanisms in vivo (sequential tumorigenicity) as well as multipotency and
tissue-specific differentiation markers. Szotek et al. also identified
side population (SP) with characteristics of the cancer stem cells
found with other tumors (72). In addition, the SP cells led to the
formation of new tumors much faster than did injections of non-SP (NSP)
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10
cells when equal numbers were injected into the dorsal fat pad of nude mice.
As for chemoresistance, the SP cells were less responsive than NSP cells to
in vitro treatment with doxorubicin. Interestingly, Mullerian Inhibiting
substance, a glycoprotein hormone that causes Mullerian duct regression in
male embryos, maintained the sensitivity of SP cells to the drug. These
findings suggest that stem cell transformation can be the underlying cause
of development and progression of ovarian cancer.
. Molecular pathogenesis
A. Molecular changes
Several recent studies have contributed to the understanding of the
molecular biology of the OSE and ovarian carcinogenesis. During neoplastic
progression, the tendency of the OSE to undergo epithelio-mesenchymal
conversion diminishes and the cells become increasingly committed to
complex epithelial phenotypes, which include the appearance of E-cadherin
(73, 74), and secretory products, such as mucins and CA 125 (75, 76),
increased expression of the receptor for hepatocyte growth factor (c-Met)
(77) and keratin (78). Tumorigenesis is thought to result, at least in part,
from genetic abnormalities that lead to the disruption or enhancement of
intracellular signaling pathways that control cell proliferation, apoptosis,
or metastasis. In recent years, several key signaling pathways have been
extensively studied in ovarian cancer cells, including the loss of tumor
suppressor genes, failure of cell cycle regulation, telomerase upregulation and activation of oncogenic pathways. Specifically, tumor
suppressor genes such as BRCA1/BRCA2 (1), p53 (79), PTEN (80), Lot-1 (81),
OVCA-1 (82), DOC-2 (83), and NOEY2 (ARHI) (84) are highly mutated in
ovarian cancer. While the interaction of cyclins, cyclin-dependent kinases
(CDKs) and CDK inhibitors (CDKIs) are tightly regulated in normal cells,
some ovarian cancer cells lose their growth regulation as a result of the
overexpression of cyclins/CDKs and/or the loss of CDKIs such as p21 and p27
(85-90). Ovarian cancer cells have high levels of telomerase, a
ribonucleoprotein enzyme complex that adds new oligonucleotide repeats to
the ends of chromosomes, which maintains telomere length and eventually
results in rescue from senescence and resistance to apoptosis (91-93). In
contrast, normal OSE and pre-malignant lesions have little or no telomerase
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11
activity (93, 94). Oncogenic signaling molecules, such as PI3K/Akt (95, 96),
K-Ras (97), Src (98), MAPK (99-103), and STATs (104), as well as tyrosine
kinase receptors, including ERBB2 (105), EGFR (106), and cFMS (the receptor
for colony-stimulating factor I) (107), are frequently amplified in ovarian
carcinomas. In addition, growth factors, hormones, and even fluctuations in
intracellular calcium levels can modulate cell proliferation and/or
metastasis through the MAPK and PI3K/Akt pathways. The intracellular
signals arising from MAPK cascades invariably lead to the activation of a
set of molecules that regulate cell growth, division and/or differentiation.
In ovarian cancer cells, MAPKs are regulated by cisplatin (108), paclitaxel
(103), endothelin-1 (109), gonadotropin-releasing hormone (GnRH) (110), and
gonadotropins (56, 111). It is becoming increasingly clear that the PI3K
signaling pathway plays a major role in the regulation of cell
proliferation, apoptosis, differentiation, tumorigenesis, cell migration,
invasion, and angiogenesis in ovarian cancer (99, 112-117). PI3K can be
activated by estrogen, gonadotropins, 4-hydroxy estradiol, hypoxia,
lysophosphatidic acid, as well as by various growth factors and receptor
tyrosine kinases in ovarian cancer cells (56, 99, 113, 115, 118-120).
Most deaths from ovarian cancer are due to its metastasis that easily
becomes resistant to conventional therapies. Recent findings have suggested
that proteolysis directed at the interface between ovarian cancer cells and
peritoneal tissues may play a role in the localized invasion and
dissemination of ovarian cancer cells in the peritoneal cavity (121, 122).
The metalloproteinases (MMPs) and the urokinase plasminogen activator (uPA)
have been the most intensely investigated proteolyic systems in ovarian
cancer. The MMP family contains 24 human members, of which MMP-2 and MMP-9
(gelatinase A, 72-kD type IV collagenase and gelatinase B, 92-kD type IV
collagenase) have been observed in several ovarian cancer cell lines and
detected in ascitic fluid from patients with advanced ovarian cancers, and
experimental metastasis is suppressed by a synthetic MMP inhibitor (123).
In ovarian cancer, uPA is also present in significant levels in ascites and
increased levels are related to poor prognosis (124-126). The invasiveness
of ovarian cancer cells has been reported to correlate with the expression
of MMP-2/-9 and uPA (124, 127, 128).
Drug resistance is described as a multifactorial phenomenon,
involving the expression of defense factors and/or detoxification
mechanisms, alterations in drug-target interactions (e.g., target
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12
accessibility, target sensitivity, persistence of DNA cleavage, genomic

localization of DNA damage) and cellular response to specific cytotoxic
lesions (129). The resistance to cytotoxic agents might be stimulated by
increased expression of P-glycoprotein, the drug efflux pumps, and
multidrug resistance protein. However, recent data on the chemoresistance
of ovarian cancer suggested that a decreased susceptibility of the cancer
to apoptosis is strongly associated with drug resistance (130-134).
Chemotherapy led to a significant increase in p53 expression, which plays a
role in both apoptosis and DNA repair, along with enhanced chemoresistance
(135, 136). Although prognostic value of the expression of Bcl-2 family is
still inconclusive, up-regulation of Bcl-2 and/or down-regulation of Bax
have been correlated with increased chemoresistance (137-140). In addition,
inhibitors of caspases such as FLICE inhibitory protein (FLIP) and
inhibitor of apoptosis (IAP) were implicated as determinants of the
chemosensitivity of ovarian cancer (141-145).
B. Molecular carcinogenesis model
The OEC encompasses a diverse, biologically complex, group of
malignant neoplasms. As discussed above, this heterogenous neoplasmas are
classified by cell type into serous, mucinous, endometrioid, clear cell,
and transitional type, and then subdivided by clinical behavior into benign,
intermediate (borderline or low malignant-potential) and malignant. Despite
considerable efforts to elucidate the molecular mechanisms of ovarian
carcinoma, unlike colorectal carcinoma, its pathogenesis model has not been
described. Scully suggested that a predominant proportion of serous and
undifferentiated carcinomas, which accounts for about 65% of epithelial
ovarian carcinoma, arise directly from the trapped OSE cells and spread
rapidly (146). However, other studies suggested the possibility of a
stepwise progression from serous benign and borderline tumors to serous
carcinoma as well as de novo (147-149). In contrast with a de novo origin,
mucinous carcinoma (about 13% of epithelial cancers) most likely appear to
arise within or contiguous to pre-existing benign and borderline mucinous
tumors (150, 151). It has been suggested that the clear cell and
endometrioid carcinoma (about 20% of epithelial cancers) may arise from
endometriotic deposits or adenofibromas (146).
Based on the review of recent clinicopathological and molecular
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13
genetic findings, we recently proposed a new ovarian carcinogenesis model

which suggests two main pathways of tumorigenesis (type I and type II).
Type I tumors (low-grade serous carcinoma, mucinous carcinoma, endometrioid
carcinoma, malignant transition tumor, and clear cell carcinoma) tend to be
low-grade neoplasms that arise in a stepwise manner from borderline tumors
that in turn develop from cystadenomas/adenofibromas. In contrast, type II
tumors (high grade serous carcinoma, malignant mixed mesodermal tumors, and
undifferentiated carcinoma) have been proposed to develop directly from the
OSE or inclusion cysts. It is so-called de novo development because
morphologically recognizable precursor lesions, like borderline tumor for
type I, have not been identified. Clinicopathological feature of the two
types are significantly distinct. Low-grade serous carcinomas typically
pursue an indolent course that may last more than 20 years. They are large
and often confined to the ovary at the time of diagnosis. Approximately 50
to 60% of patients ultimately succumb because of widespread intra-abdominal
carcinomatosis but the tumor maintains its low-grade appearance and low
proliferative index throughout its course. This contrasts with conventional
high-grade serous carcinoma that presents as a clinically aggressive
neoplasm that progress rapidly, metastasizes early in their course, and is
associated with a poor outcome. In addition to clinicopathological
observations, significant molecular evidences support the dualistic
carcinogenesis model. Type I low-grade serous carcinomas are frequently
associated with BRAF and KRAS mutations (~65%), while type II high-grade
serous carcinoma is likely involved in p53 mutation (~50-80%) and human
leukocyte antigen-G (HLA-G) overexpression (61%). It is noteworthy that the
molecular alterations for each type are mutually exclusive as shown in
Figure 2.
14

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Ovarian surface epithelium/Inclusion cysts
Serous borderline tumor (SBT)

Atypical proliferative serous tumor (APST)
Micropapillary serous carcinoma (MPSC)
Invasive MPSC
Low-grade serous carcinoma
Type
Type
Low grade (25% of serous carcinoma)

Slow progression,
~55% 5 year survival
Poor response to chemotherapy
High-grade serous carcinoma
High grade (75%)

Clinical
behavior
Rapid progression,
~30% 5 year survival
Initial response ~80%
Kras mutation
Braf mutation
Kras or Braf mutation
p53 mutations
HLA-G expression
35%
30%
65%
0%
0%
0%
0%
0%
50-80%
61%
Figure 2. Schematic representation of the dualistic model depicting the

development of ovarian serous carcinoma, the most common type of ovarian
cancer (147).
. Concluding remarks
To
conquer
ovarian
cancer,
identification
of
specific
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15
diagnostic/prognostic factors and development of new preventive and/or

therapeutic approaches are urgently needed. It will be facilitated by
fundamental understanding of the etiology and pathogenesis of ovarian
cancer. For example, the characterization of ovarian cancer stem cells will
allow for the identification of molecules specifically expressed in these
cells that could serve as targets to eliminate this side population of
cancer cells that can rapidly develop the critical tumor cell mass and/or
resistance to conventional therapy. As reviewed above, there is increasing
evidence implicating a role of several reproductive factors in ovarian
cancer development. It is important that we gain a thorough understanding
of how the hormones/growth factors related to these reproductive events
exert their effect on the OSE, especially in view of the rapid increase in
ovarian cancer incidence after menopause and the potential prevention
associated with oral contraceptive use. The continued characterization of
the molecular and signaling mechanisms underlying the stimulatory or
inhibitory actions of these hormones in the growth, differentiation and
progression of OSE to ovarian cancer should bring about a better
understanding of ovarian pathogenesis. It will provide an opportunity for
the development of diagnostic and/or preventive approaches targeting signal
transduction pathways or key molecules.
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Key Words: Ovarian epithelial cancer, Ovarian surface epithelium, Etiology,
Pathogenesis, Cancer stem cells, p53, BRAF, KRAS, Serous borderline tumor,
Gonadotropin
Disclaimer: "BioWave" is not political. The views and opinions expressed by its
writers do not necessarily reflect those of the Biological Research Information
Center(BRIC). Copyright 2008, the Biological Research Information Center(BRIC),
Pohang 790-784, Korea.
" BioWave" .
" BioWave (http://bric.postech.ac.kr/webzine)
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BioWave Vol. 10 No.4 2008

Ovarian Epithelial Cancer: Etiology and Pathogenesis

To whom correspondence should be addressed. E-mail jchoi63@jhmi.edu

Ovarian Epithelial Cancer: Etiology and Pathogenesis-Jung-Hye Choi

BioWave Vol. 10 No.4 2008

BioWave Vol. 10 No.4 2008

Ovarian Epithelial Cancer: Etiology and Pathogenesis-Jung-Hye Choi

BioWave Vol. 10 No.4 2008

BioWave Vol. 10 No.4 2008

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BioWave Vol. 10 No.4 2008

gonadotropins induced an increase in SKOV-3 invasiveness via the activation

Ovarian Epithelial Cancer: Etiology and Pathogenesis-Jung-Hye Choi

BioWave Vol. 10 No.4 2008

gonadotropins in neoplastic transition of OSE cells (A) and metastasis of

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accessibility, target sensitivity, persistence of DNA cleavage, genomic

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genetic findings, we recently proposed a new ovarian carcinogenesis model

Ovarian Epithelial Cancer: Etiology and Pathogenesis-Jung-Hye Choi

BioWave Vol. 10 No.4 2008

Ovarian surface epithelium/Inclusion cysts

Serous borderline tumor (SBT)

Micropapillary serous carcinoma (MPSC)

Low-grade serous carcinoma

Low grade (25% of serous carcinoma)

High-grade serous carcinoma

High grade (75%)

Figure 2. Schematic representation of the dualistic model depicting the

Ovarian Epithelial Cancer: Etiology and Pathogenesis-Jung-Hye Choi

BioWave Vol. 10 No.4 2008

diagnostic/prognostic factors and development of new preventive and/or

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BioWave Vol. 10 No.4 2008

BioWave Vol. 10 No.4 2008

(Australia). Cancer Causes Control 12:855-863

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Whittemore AS 2004 Relation of contraceptive and reproductive history to

Ovarian Epithelial Cancer: Etiology and Pathogenesis-Jung-Hye Choi

BioWave Vol. 10 No.4 2008

44. Parazzini F, Negri E, La Vecchia C, Luchini L, Mezzopane R 1993

Ovarian Epithelial Cancer: Etiology and Pathogenesis-Jung-Hye Choi

BioWave Vol. 10 No.4 2008

53. Risch H 1998 Hormonal etiology of epithelial ovarian cancer, with a

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Ovarian Epithelial Cancer: Etiology and Pathogenesis-Jung-Hye Choi

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72. Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, Dinulescu DM, Connolly D,

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BioWave Vol. 10 No.4 2008

primary ovarian tumors. Int J Cancer 69:466-470

Ovarian Epithelial Cancer: Etiology and Pathogenesis-Jung-Hye Choi

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97. Enomoto T, Weghorst CM, Inoue M, Tanizawa O, Rice JM 1991 K-ras

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2/neu is associated with poor survival in advanced epithelial ovarian

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BioWave Vol. 10 No.4 2008

122. Song J, Fadiel A, Edusa V, Chen Z, So J, Sakamoto H, Fishman DA,