Early Events in the Pathogenesis of Epithelial Ovarian Cancer-printed - Copy

VO L UM E 26 NUM B ER 6 F EB RUA RY 20 2 008

JOURNAL OF CLINICAL ONCOLOGY BIOLOGY OF NEOPLASIA

Early Events in the Pathogenesis of EpithelialOvarian CancerCharles N. Landen Jr, Michael J. Birrer, and Anil K. Sood

F ro m t h e De par t me nt of G yneco log ic

O nco log y and t h e De par t me nt of

Can cer Bio log y, U nive r sit y of T exas

M .D . An de r son Can cer Cen t er , Hou s-

t on , TX ; an d t he Cent e r f or Cance r

Re sear ch, Nat i onal Cancer I nst i t ut e,

Be t hesd a, M D.

ABSTRACT

Ovarian carcinogenesis, as in most cancers, involves multiple genetic alterations. A great dealhas been learned about proteins and pathways important in the early stages of malignanttransformation and metastasis, as derived from studies of individual tumors, microarray data,animal models, and inherited disorders that confer susceptibility. However, a full understand-ing of the earliest recognizable events in epithelial ovarian carcinogenesis is limited by the lackof a well-defined premalignant state common to all ovarian subtypes and by the paucity of datafrom early-stage cancers. Evidence suggests that ovarian cancers can progress both througha stepwise mutation process (low-grade pathway) and through greater genetic instability thatleads to rapid metastasis without an identifiable precursor lesion (high-grade pathway). In thisreview, we discuss many of the genetic and molecular disorders in each key process that isaltered in cancer cells, and we present a model of ovarian pathogenesis that incorporates therole of tumor cell mutations and factors in the host microenvironment important to tumorinitiation and progression.

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J Clin Oncol 26:995-1005. © 2008 by American Society of Clinical Oncology

INTRODUCTION ETIOLOGY OF SPORADIC EOCOvarian cancer is the fifth leading cause of can-

cer deaths among women, and it is the mostcommon cause among gynecologic malignan-cies.1 The poor ratio of survival to incidence inepithelial ovarian cancer (EOC) results fromthe high percentage of cases diagnosed at anadvanced stage. Despite advances in surgeryand chemotherapy, survival of patients withEOC stands at just 45% at 5 years.1 Althoughthe age of biologic therapies holds the potentialof improved responses in advanced and recur-rent EOC, a greater impact could be made byrecognition of high-risk patients and by offer-ing risk-reducing surgery, a strategy that hasdemonstrated effectiveness in patients with ge-netic predispositions.2 However, there is signif-icant heterogeneity within the EOC group. Forexample, histologically defined subtypes suchas serous, endometrioid, mucinous, and low-and high-grade malignancies all have variableclinical manifestations and underlying molecu-lar signatures.3 Substantial advances have beenmade in understanding the genetic alterationsand biologic processes in ovarian cancer; how-ever, the etiology remains poorly understood.In this article, we will focus on the currentunderstanding of the early events in EOC.

The ovary is surrounded by a single-cell layer ofperitoneal mesothelium, which is derived from thecoelomic layer during development and which hasthe potential to undergo metaplastic transformationto a more differentiated state.4 Unlike most malig-nancies, as this epithelium transforms into a malig-nant phenotype, it becomes more differentiated,and it can differentiate toward many of the differentcell types found in the mu¨llerian tract, includingthose in the fallopian tube, uterus, cervix, andovarian stroma.5 It is widely thought that mostovarian cancers develop from the surface epithe-lium or postovulatory inclusion cysts that weresubjected to prolonged exposure to hormones orother chemokines.4

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Primary peritoneal and fallopian tube carcino-DO I : 1 0. 12 00/ JCO .2 006 .0 7. 997 0mas have similar clinical, molecular, and geneticprofiles to ovarian cancers, though some small dif-ferences in frequency of specific protein expressionhave been described.6 -11 Primary peritoneal carci-nomas may,in fact, have a multifocal and polyclonalorigin.12 Therefore, although these entities are oftenlumped together with ovarian cancer, there may besome significant, but currently poorly defined, dif-ferences. In fact, recent pathologic examination ofconsecutive cases of ovarian, primary peritoneal,and fallopian tube cancers suggests that a greater

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Landen, Birrer, and Sood

percentage of ovarian cancers than originally thought may actuallyhave a fallopian origin with metastasis to the ovary.13 However, be-cause of the changes in definition, inconsistent reporting of subtypes,and the paucity of direct comparative studies, these entities will beconsidered as variations within a disease and will be considered to-gether in this review.

increased risk of EOC by a factor of 2.8, and of borderline tumors by4.0,compared with infertile women who were not usingfertility drugs.However, subsequent case-control and cohort studies demonstratedinconsistent associations between gonadotropin use and epithelialovarian carcinoma.25 These studies collectivelysuggest that the condi-tion of infertility (or the predisposing condition), rather than fertilitydrug use, is responsible for the increased risk.2 6 From a basic scienceperspective, receptors for FSH and LH have been found on 100% ofnormal ovarian surface epithelial cells and on 60% of malignant tu-mor cells.27 FSH, LH, and human chorionic gonadotropin (hCG) allstimulate proliferation of EOCs and may activate mitogen-activatedkinase (MAPK).28 Furthermore, induced overexpression of the FSHreceptor led to upregulation of epidermal growth factor receptor(EGFR), human epidermal growth factor receptor 2 (HER2), and

There have been several proposed hypotheses about the under-

lying physiological processes that increase the risk of malignant trans-

formation of the ovarian epithelium in the 90% of EOCs that do not

have a known genetic component (Table 1). Importantly, these may

also play a role in the 10% of cases in women with a genetic suscepti-

bility through BRCA or mismatch-repair gene mutations. These hy-

potheses will be reviewed brie y, and they are discussed in greater

depth in other excellent reviews.14, 14a ,1 4bThe observation that women with a greater number of ovulatoryC-MYC.29 Other potential oncogenes upregulated by FSH or LH

treatment in vitro include -catenin, Meis-1, cyclin G2, insulin-like

growth factor 1 (IGF-1), and -1 integrin.30, 31 To date, no study has

demonstrated that exposure to gonadotropins is capable of inducing

transformation of ovarian surface epithelium (OSE) cells to a malig-

nant phenotype. However, in animal models of implanted tumors,

exposure to gonadotropins promotes tumor growth,32 angiogenesis,32

cycles have an increased risk of ovarian cancer led to the incessant

ovulation hypothesis by Fathalla in 1971.15 According to this hypoth-

esis, as ovulation occurs, ovarian surface epithelial cells are internal-

ized and damaged, and the subsequent repair mechanisms place the

cells at an increased risk of developing mutations and subsequent

malignancies. Consistent with this hypothesis, women with a history

of multiple pregnancies,16-1 8 increased time of lactation,19 and oral

contraceptive use16, 20 are all at a decreased risk. Moreover, the risk for

ovarian cancer decreases further with the increased occurrence of

each of these factors. There is also experimental evidence from

primate and other animal models that supports the incessant ovu-

lation hypothesis.21, 22 However, this theory is somewhat weakened

by observations that progesterone-only oral contraceptives, which

do not inhibit ovulation, are at least as effective as ovulation-

inhibiting contraceptives.23 Moreover, women with polycystic

ovarian syndrome, who have decreased ovulatory cycles, are at an

increased risk of EOC.24

vascular endothelial growth factor (VEGF) expression,33 and adhesion.34Collectively, these studies suggest a role for gonadotropins in promotingthe progression of ovarian cancer, rather than of the causation.

Notable hormones have also been implicated in ovarian carcino-genesis. On the basis of epidemiologic studies, progestin-only contra-ceptives are as effective as combined oral contraceptive pills in thereduction of ovarian cancer risk,23 ,35 and progesterone is the domi-nant hormone during pregnancy, which also reduces risk.23 Interest-ingly, use of progestin contraceptives can also decrease ovariantestosterone levels.36 In vitro studies have not, however,demonstrateda clear inhibition of cancer cell growth.37 Conditions of increasedandrogens (eg, polycystic ovarian syndrome, hirsutism, acne) are as-sociated with an increased risk of EOC.24 Androgens represent thegreatest hormone concentration within a developing follicle,3 8whichprolongs exposure to the epithelial cells. Androgen receptors arepresent on human OSEcells,and they stimulate proliferation.39 Thereis no strong evidence, however, that exposure to androgens inducesmalignant transformation.

Weaknesses in the incessant ovulation theoryand observations ofan increased risk in infertile women who use fertility drugs led to thegonadotropin hypothesis, which theorizes that stimulation of theovarian surface epithelium by follicle-stimulating hormone (FSH)and by luteinizing hormone (LH) may place the cells at an increasedrisk of developing EOC. In 1992, Whittemore et al16 reported a case-control studyin which infertile patients who used fertilitydrugshad an

Table 1. Hypotheses on Physiologic Susceptibilities to Epithelial Ovarian Cancer

Hypothesis Proposed Mechanism Best Evidence

Incessant ovulation OSE damaged during ovulation, with repair making Risk of EOC decreases with decreased number ofcells susceptible to mutations cycles, such as pregnancy, lactation, and OCP use

Gonadotropin stimulation Stimulatory effect of FSH and LH promote growth, Increased EOC risk with infertility, PCOS; Decreasedincreased cell divisions, and mutationsrisk with progesterone-only OCPs; FSH upregulates

many oncogenes and promotes growth in preclinicalmodelsHormonal stimulation High concentrations of androgens in the tumor Conditions of high circulating androgens (PCOS,

microenvironment promote carcinogenesis,whereas progestins decrease risk

hirsutism, acne) associated with increased risk,androgens are the dominant hormone in theinclusion cyst; progestin use decreases risk of EOC,induces OSE apoptosisIn ammation Damaged OSE with ovulation induces in ammation, Possible reduced risk with NSAID use; increased risk

which promotes reconstruction and mutationsusceptibility

with talc or asbestos; abundance of in ammatorymediators in tumors

Abbreviations: OSE, ovarian surface epithelium; EOC, epithelial ovarian cancer; OCP, oral contraceptive pill; FSH, follicle-stimulating hormone; LH, luteinizinghormone; PCOS, polycystic ovarian syndrome.

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Carcinogenesis of Ovarian Cancer

There is growing interest in the etiologic role of in ammation, Earliest Recognizable Events in Tumor ProgressionEOCs, like most cancers, are thought to arise from a singlewhich accompanies each ovulation, with an associated cytokine re-

lease, in ux of in ammatory cells, and tissue reconstruction.26 Thismechanism has been postulated to stress OSE cells such that theyare predisposed to genetic damage and malignant transformation.Consistent with this hypothesis,patients with chronic aspirin,nonste-roidal anti-in ammatory drug, or acetaminophen use have a re-duced risk of EOC.40 Downstream effectors of the nonsteroidalanti-in ammatory drug pathway, such as nitric oxide synthase,cyclooxygenase-2, VEGF, and NF- B, have been implicated in carci-nogenic pathways.40 Patients exposed to in ammation-inducingagents, such as talc and asbestos, have been shown in some studies tobe at an increased risk.26 Although talc particles have been foundon human and murine ovaries after perineum exposure,41 noanimal model of ovarian carcinogenesis has been proven with talcor asbestos exposure.

multidysfunctional cell in 90% of occurrences. Evidence for theclonality of ovarian cancer lies in the similarity between primaryand metastatic lesions during the examination of the loss of het-erozygosity (LOH), X-chromosome inactivation, and specific genemutations.4 2 The difficulty in describing the earliest events in ovar-ian cancer is in the limited availability of early-stage tumors, theheterogeneity among individuals, and the genetic instability oftumors, which makes it difficult to know if detected mutations areearly or late occurrences.

Genomic comparison of early- versus late-stage, high-grade ovariancancers. Genomic analysis of high-grade tumors has identified am-plification and/or over-expression of numerous genes thought to beimportant in the development of ovarian cancer.However,the preciserole of these genes in earlycarcinogenesis remains unclear. The appli-cation of new genomic technologies, such as comparative genomehybridization (CGH) and microarray expression profiling, has helpedelucidate many of the important genetic events that may lead toovarian cancer. The ability of these technologies to simultaneouslymeasure thousands of genes allows not only the identification ofindividual genes but also the delineation of dominant pathways thatmay be responsible for cancer pathogenesis43 ,44 (Fig 1).

Although any of the above mechanisms may play a role in ovar-ian carcinogenesis in some patients, the modest association with eachsuggests that multiple other processes are involved, which cannot bepredicted by clinically recognizable conditions such as nulliparity,infertility, or hormone exposure. To detect EOC early or to identifyat-risk patients, a search must therefore continue for genetic or epige-netic conditions that predispose patients to the development of EOCor for proteins that may allow for early detection.

A study that compared normal ovarian epithelial cells to early-and late-stage cancers found several differentially expressed genes

Thrombin

Beta-3integrin Alpha-5

MT-SP1 ExtracellularintegrinPAR1 matrix

MAGP2G GPAR2

GHEF1

SNX1 GPRK5FAK YES

Fig 1. Pathway identification by microar-ARHIray analysis. Schematic representation of

potential signaling pathways in ovarian

cancer, identified by incorporating the mi-

croarray results (genes differentially ex-

pressed between normal and malignant

ovarian epithelial cells) into PathwayAssist.

Genes in red are upregulated in cancer

compared with normal ovarian epithelium;

genes in green are downregulated in can-

cer; genes in yellow did not show a signif-

icant difference between specimens.

Reproduced with permission.43

Cell cycle RACI CDC42ERKprogression GD P GTP GD P G TP

VAV3 G

CCND1C CND 1 CytoskeletonGmodulation and IAP

enhanced GATA6 MMPmotilityproductionD OC-2 DOC-2 TSP-1

MTI-MMP

RECK InvasionETAR

ET-1

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been well studied beyond a description of mismatch repair defects.Other familial syndromes associated with an increased risk of ovariancancer include Peutz-Jeghers Syndrome (ie, mutation in the STK11

between normal and malignant tissues.4 5 However, the early- and

late-stage tumors were remarkably similar. This seems to be at odds

with the concept of early-stage tumors that evolve into late-stage ones.

However, in the same study, CGH analysis demonstrated acquired

gene abnormalities in late-stage tumors, which was more consistent

with tumor evolution.Another study that compared tumors collected

from the ovary or the omentum identified a 27-gene signature that

could differentiate between the primary and metastatic tumor.46

gene; 21% lifetime risk) and Gorlin Syndrome (ie, mutation in PTCH;20% lifetime risk), but these tumors are usually stromal cancers andfibromas, respectively.

Animal models. In an attempt to better understand ovariancarcinogenesis, several animals models have been developed. Orsulicet al5 9 introduced various oncogenes into transgenic ovarian surfaceepithelial cells that expressed the avian receptor TVA. These cellsbecame tumorigenic when two of three genes (C-MYC, K-RAS,or

Many of the genes are involved in the p53 pathway, which suggeststhat this pathway is important for the peritoneal metastasis. The chal-lenge is in determining whether a noted difference is truly responsiblefor a particular function, such as malignant transformation or metas-tasis.For example, metastasized tumors with genetic instability wouldcontinue to acquire genetic mutations that could be erroneously as-signed to causingmetastasis. Additionally, early genetic perturbationswould persist in metastasized tumors and would not be identified asan earlyevent when comparing early-and late-stage tumors. However,with validation by additional studies that use larger sample sizes,various array platforms to account for methodologic inconsistencies,and microdissected samples to differentiate tumoral and stromal al-terations, these technologies willallowmore information to be gainedon the earliest events in ovarian cancer.

AKT) were overexpressed in p53-deficient cells. After inducingchanges in vitro, they were implanted into the bursal sac that sur-rounds the ovary of recipient mice, and they developed a carcinoma-tosis pattern similar to human ovarian cancer. Subsequently,Connolly et al60 generated de novo ovary-specific tumors in trans-genic mice that expressed the transforming region of the SV40T-antigen under control of the ovary-specific Mu

¨llerian inhibitorysubstance type II receptor gene promoter.In these mice, poorlydiffer-entiated tumorsof both ovaries developed in 50% of transfected miceand often led to carcinomatosis and ascites formation. A model ofendometrioid ovarian carcinogenesis was described by Dinulescu etal,6 1 in which adenoviral vectors were injected into the bursal sac thatinduced K-RAS overexpression and PTEN inactivation.61 Although

Inherited disorders. A study of genetic disorders can providegreat insight into the etiology and early events in carcinogenesis. He-reditary genetic disorders account for approximately 10% of ovariancancers, and 90% of these are either BRCA1 or BRCA2 mutations.Evaluation of BRCA1 and BRCA2 mutant and sporadic tumors withgene expression profiling has demonstrated that the greatest contrastin expression patterns wasbetween that of BRCA1 and BRCA2 mutanttumorsand that sporadic tumorsshared characteristicsof both.47 Thisintriguing finding suggests that BRCA1 and BRCA2 tumors may havevariable pathways in carcinogenesis and that even sporadic tumorsmay develop as a result of alterations in either pathway. Clinically,patients with BRCA mutations tend to have highly proliferative tu-morsbut more favorable outcomes when adjusted for stage.48 Border-line tumors have a much less frequent incidence of BRCA mutations(4.3% v 24.2% in a Jewish population),49 which also suggests a differ-ent molecular origin.

K-RAS overexpression alone induced lesions that were histologicallycompatible with endometriosis, the combination of both mutationsled to the rapid development of carcinomatosis of endometrioid his-tology. Although these models have limited applicability to de novohuman ovarian cancers because of their different genetic composition,such as greater homogeneity, diploid status (rather than aneuploid),and progression with few mutations, they can provide useful insightsinto specific gene functions.

TWO-PATHWAY MODEL OF OVARIAN CANCER

With the recognition that ovarian tumors are heterogeneous and

generate a wide spectrum of disease states, there is growing clinical,

translational, and genetic evidence to support at least two broad cate-

gories of carcinogenesis.62 High-grade malignanciesare rapidlygrow-

ing, relatively chemosensitive, and without a definitive precursor

lesion. In contrast, low-grade tumors grow more slowly, are less re-

sponsive to chemotherapy, and share molecular characteristics with

low-malignant potential (LMP) neoplasms. Clinically, in a large series

of 112 low-grade patients observed for a median of 71 months, the

average age at diagnosis was 43 years (compared with 61 years for all

ovarian cancers), and the median survival was 81 months63—much

longer than the 57- to 65-month survival observed in phase III trials

that define the standard of care in EOC.64 ,65 Pathologic analysis has

found that approximately 60% of low-grade serous carcinomas also con-

tain areas of serous LMP tumors compared with just 2% of high- grade,66

Other than in hereditary syndromes, BRCA genes are rarely mu-tated in sporadic ovarian cancers,50 although epigenetic changes, al-ternate splicing,and othergenetic factors mayaffect BRCA function inas manyas 82% of sporadic occurrences.5 1-53 The BRCA1 and BRCA2proteins are considered caretakers of the genome,and playkey roles in

the signaling of DNA damage, the activation of DNA repair, the

induction of apoptosis, and the monitoring of cell cycle check-

points.54 -56 Cells that lack functional BRCA have increased aneu-

ploidy, centrosome amplification, and chromosomal aberrations,57which make them susceptible to further mutations. BRCA appears to

function as a cofactor for a variety of transcription factors, including

p53, STAT1, c-Myc, JunB, ATF-1, and others.57Defects in mismatch repair in patients with Lynch syndrome orand LMP tumors recur as a low-grade carcinoma in 75% of cases.67hereditary nonpolyposis colon cancer (HNPCC) account for approx-

imately10% of hereditaryovarian cancers and for 1% to 2% of overallcases. Patients with this syndrome, however, individually carry anapproximately 12% risk of developing ovarian cancer.58 The mecha-nism of increased risk is through defects in the mismatch-repair ma-chinery and its resulting genetic instability that places cells at risk ofmultiple mutations; however,carcinogenesis in ovarian cancerhas not

Molecular and protein analyses of tumors of these two differentsubtypes also suggest different pathogenesis (Table 2). Analyses ofindividual genes have found that K-RAS and BRAF mutations arerarely detected in high-grade invasive carcinomas but are present in30% to 50% of LMP tumors, in low-grade adenocarcinomas, andoften in the adjacent benign epithelium.62 ,68 -70 The P53 gene is mu-tated in 50% to 80% of high-grade invasive carcinomas, but rarely in




GENETIC AND PROTEIN ABERRATIONS IN OVARIAN CANCER

Table 2. Variability in Biology of Low- and High-Grade TumorsCharacteristic LMP/Low-Grade (%) High-Grade (%)The majority of evidence on genetic or protein alterations in ovarian

cancer is based on studies of late-stage cancers. However, currentunderstanding of these processes allows speculation that many alter-ations must occur early to achieve a clinically recognized tumor. It isbelieved that, for the majority of malignancies, a cancer cell mustovercome many protective mechanisms to develop into a clinicallyevident tumor.84 These include unchecked proliferation, inhibition ofapoptosis, angiogenesis, stromal invasion, separation and survivalaway from the primary tumor, and implantation and growthwithin new tissues. We examine the evidence for many of theever-increasing recognized participants in each of these processesin ovarian cancer (Table 3).

p53 inactivity Rare 50-80HLA-G overexpression Rare 61HER2 overexpression Rare 20-66AKT overexpression Rare 12-30Apolipoprotein E expression 12 66B-RAF mutation 30-50 RareK-RAS mutation 30-50 RarePTEN mutation 20* RareMSI 50* 8-28

Abbreviations: LMP, low malignant potential; HER2, human epidermalgrowth factor receptor 2; MSI, microsatellite instability.

*Endometrioid.

Self-sufficiency in growth signals. A number of oncogenes have

been identified in ovarian cancer that allow cells to grow indepen-

dently from the host’s signals. One of the first oncoproteins described

was src, a nonreceptor tyrosine kinase that participates in multiple

carcinogenic pathways and promotes proliferation,adhesion, cellsur-

vival, and angiogenesis.85-8 7 The overexpression of src has been dem-

onstrated in 93% of advanced-stage ovarian tumors and in more than

80% of cell lines.88 This oncoprotein promotes both platinum and

taxane resistance and survival in ovarian cancer cell lines.89 Further-

more, inhibition of src with antisense or with small molecule inhibi-

tors has reduced ovarian cancergrowth in preclinicalmouse models.85

other subtypes or LMPs.71 -73 HER2 and AKT are overexpressed in

20% to 67% and 12% to 30% of high-grade carcinomas, respectively,

but rarely in low-grade and LMP tumors.74, 75 Overexpression of hu-

man leukocyte antigen-G (HLA-G), which may provide a mechanism

of immune escape for the tumor, hasbeen noted in 61% of high-grade

carcinomas but is absent in low-grade or LMP neoplasms.76Whole-genome approaches have also provided key insights into

the developmental relatedness of various ovarian tumors. Compari-

son of whole-genome expression profiles of ovarian tumors of differ-

ent grades reveals that LMP tumors are quite distinct from invasive

cancers, and hierarchical clustering demonstrates that they group

closer to the normal ovarian epithelium than to invasive cancers.3, 77

The type I tyrosine kinase receptor family HER (ie, Erb) consists

of four known monomers: EGFR (ie, Erb1/HER1), HER2 (encoded

by the proto-oncogene neu), HER3, and HER4. EGFR is expressed on

the normal human ovarian surface epithelium (as detected by immu-

nohistochemistry) and is overexpressed in 35% to 70% of EOCs.90Furthermore, low-grade invasive cancers were indistinguishable from

borderline tumors but were distinct from high-grade tumors. More

detailed analyses have identified specific pathways, which correlate

with each specific tumor type. One predominant pathway present in

LMP tumors and low-grade tumors is a functional wild-type p53

pathway, which is absent in high-grade tumors.3 This suggests that

inactivation of p53 is a key branch point, in which an intact p53

pathway could lead to LMP/low-grade tumors, but disfunctional p53

could lead to high-grade cancers. In other genomic studies, LOH78

HER2 has no extracellular ligand-binding domain, but it is activated

when dimerized with other type I receptors. HER2 expression in

ovarian cancer varies widely; overexpression is found in 20% to 30%

of cases.9 1 Many proliferation pathways mediate signals through the RAS

oncoprotein, a G-protein attached to the cell membrane and activated

by many tyrosine kinase receptors. RAS activates a cascade of serine/

threonine and tyrosine nonreceptorkinases, which leads to phosphor-

ylation and activation of Erk1 and Erk2 transcription factors that

make their way to the nucleus to initiate signals of growth and pro-

gression through the cell cycle. As described above, K-RAS mutations

are common in adenocarcinomas, and frequency is variable in differ-

ent histologic subtypes.7 0,8 2

and CGH79 analyses have found similar profiles in benign adenomasand in LMP tumors, which supports the concept of a transformationfrom benign adenoma to LMP.

Although ovarian adenocarcinomas can be subtyped by grade,

histologic subtypes also differ. Although differences in clinical out-

comes among serous,endometrioid, and mucinous adenocarcinomas

are not as dramatic as those between high- and low-grade cancers,

genomic studies have demonstrated that mucinous adenocarcinomas

often harbor mutations and have differential gene expression similar

to LMP tumors and to benign cystadenomas.80 ,81 Specifically, muta-

tions in K-RAS have been described in 61% of borderline tumors, in

68% of low-grade tumors, and in 50% of mucinous adenocarcinomas,

but only in 5% of high-grade serous carcinomas.7 0,8 2 These studies

suggest that the malignant transformation in mucinous tumors may

follow a sequence of adenoma to LMP tumor to invasive adenocarci-

noma8 0,8 1 more frequently than to high-grade serous carcinomas.

Endometrioid adenocarcinomas more frequently harbor PTEN mu-

tations(similar to endometrioid tumorsof the uterine endometrium)

than do serous or mucinous subtypes.83

Resistance to antigrowth signals. In early-transformed cells, anti-growth signals must be overcome.Although definitive data are lackingregarding the sequence of specific genetic events in carcinogenesis,there is evidence for abnormalities in cell cycle mediators, such ascyclins, cyclin-dependent kinases (CDKs, which complex with thecyclins to allow their activity), CDK inhibitors (CDKIs, which inhibitcyclin/CDK complexes), and other proteins or transcription factorssuch as pRb, p53, and E2F. The restriction point, after which a cell iscommitted to divide, is controlled by Cyclin D and E’s regulation ofE2F release by Rb. Cyclin Eis expressed by only 9% of benign tumorsbut by 48% of borderline and by 70% of malignant tumors, and it isassociated with poor survival.92 Similarly, CDK2, which complexesexclusively with Cyclin E, is expressed more frequently in malignantovarian tumors compared with LMPor benign tumors.92 Cyclin D1 is




Table 3. Select Contributors to Ovarian Carcinogenesis

Protein/Gene Function Rate in EOC (%)

Growth Promotion

EGFR (HER1) Membrane TK receptor, promotes cell growth 35-70HER2 Membrane TK receptor, promotes growth 20-66*Src TK, promotes growth, angiogenesis, survival 80-90CSF-1/fms Ligand/receptor, inhibits anoikis 50-70IGF/IGFR Peptide hormone/receptor, promotes growth 21-25K-RAS G-protein, promotes growth through MAP kinase pathway 30-50†BRAF Promotes growth through MAP kinase pathway 30-50†

Insensitivity to Antigrowth Signals

TGF- Ligand, inhibits growth through Rb activation Lost in 40%C-MYC Transcription factor, cell cycle mediator 30Cyclin D/CDK4/6 Advance from G1 to S phase 30-90Cyclin E/CDK2 Advance from G1 to S phase 30-70Cyclin B/CDK1 Advance cell cycle into M phase 80p16 Inhibits Cyclin D/Cdk4/6 Lost in 30%p27 (kip-1) Inhibits Cyclin E/Cdk2 Lost in 55%p21 (WAF-1) Inhibits Cyclin B/Cdk1 Lost in 25%–40%NF B Transcription factor, effector of many survival pathways UnknownNOEY(ARHI) GTPase tumor suppressor, induces apoptosis through p21 40‡

Inhibition of Apoptosis and Immune Surveillance

PIP3/AKT AKT (activated by PIP3) inhibits apoptosis 12-18*PTEN Decrease AKT 20§p53 Promotes cell cycle arrest/apoptosis with DNA damage 50-90*BRCA1 Cofactor for transcription factors, caretaker of genome 6-82¶BRCA2 Cofactor for transcription factors, caretaker of genome 1-3MLH1/MSH2 Mediates mismatch repair, promotes genetic stability 30§Fas ligand Produced by tumor cells to induce apoptosis of T-cells 50-80HLA-G Secreted by tumor cells to inhibit cytotoxic immune cells 61*

Limitless Replicative Potential

hTERT Subunit of telomerase, maintains telomere length 80-85Enhanced Angiogenesis

VEGF/VEGFR Ligand/receptor complex induces angiogenesis 40-100IL-8 Cytokine promoting angiogenesis UnknownEphA2 TK promoting angiogenesis and vasculogenic mimicry 76

Promotion of Invasion and Metastasis

MMPs Degrade extracellular matrix 40-100v 3 Integrin, promotes survival and angiogenesis 95

FAK Cofactor TK promotes adhesion, proliferation, survival 70E-cadherin Promotes adhesion 90-100

Abbreviations: EOC, epithelial ovarian cancer; EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor; TK, tyrosine kinase; IGF,insulin-like growth factor; TGF, transforming growth factor; CDK, cyclin-dependent kinase; VEGF, vascular endothelial growth factor; MMPs, matrix metalloprotein-ases; FAK, focal adhesion kinase.*High-grade serous.

†Low-grade serous.‡40% loss of heterozygocity.§Endometrioid.¶Inherited mutation in 6%–7% of all cancers; may play a role in 82% of sporadic cancers.

cycle regulation that likely provide an unchecked growth advantage toovarian cancer cells.

expressed at low levels in normal ovarian epithelial cells but is prom-

inent in ovarian cancer cells (89% cytoplasmic; 30% nuclear).93 CDK1

complexes with cyclin B to regulate entry into the M phase, and it is

expressed at high levels in 80% of ovarian cancers, although absent

from normal epithelium.94

Evading apoptosis. It has been proposed that a more importantcharacteristic of cancer than increased cell division is the reducedapoptosis and prolonged survival seen in these cells. Indeed, cancercells often divide less frequently than their normal equivalents, espe-cially in epithelial cancers, in which normal epithelial cells have rapidturnover. Many participants in this process are altered in ovariancancer to inhibit cell death. Among these is P53, which normallypromoteseither cell cycle arrest and initiation of repairmechanismsor

Other proteins that control the cell cycle include myc (an onco-genic transcription factor activated by the RAS-RAF pathway andoverexpressed in approximately 30% of ovarian cancers) and AHRI(ie,NOEY2,a GTPase tumor suppressorgene lost in almost all ovariancancers95, 96).Thus,there are multiple aberrations in the geneticsof cell




the shunting of the cell to an apoptotic pathway.97 It has been hypoth-esized that cancers that do not have mutations in the P53 gene likelyhave alterations in the function of p53 in other ways, such as in theproduction of p53-binding proteins or the enhanced degradationthrough ubiquitination. Most P53 mutations in ovarian cancer aremissense,9 8 but specific mutations (ie, null mutations) may play a keyrole in producing a metastatic phenotype, in that they are seen muchless frequently in stage I ovarian cancers.99 Interestingly, P53 muta-tions have been detected in ovarian inclusion cysts adjacent to cysta-denocarcinomas, in microscopic ovarian cancer, and even intubular intraepithelial carcinomas removed prophylactically frompatients with BRCA1 mutations.1 3, 100 The accumulation of evi-dence suggests that p53 inactivation may be a relatively early eventin ovarian cancer pathogenesis.

sites. Although metastasis is thought of as a late event in carcinogene-sis, emergingevidence in breast cancer suggests that early tumorsmayalready hold the genetic profile needed for metastasis,108 which furthersuggests that factors other than the tumor cell itself may regulatemetastasis. Similarly, in ovarian cancer, peritoneal and stromal alter-ations may be permissive for cancer spread.1 09 An understanding ofthese factors mayprovide additional insights into tumorpathogenesisand also may offer unique targets for therapy. No cells, cancerous or benign,can exist without oxygen and other

nutrients. Cells must reside within 100 m of a capillary in order to

receive oxygen.110 Therefore, in order for a malignancy to grow be-

yond approximately 1 mm3, it must induce the growth of new vessels

in or around itself. Regulation of angiogenesis is complex, which

re ects a balance between pro- and antiangiogenic in uences within

the tumor microenvironment. The primary mediator of angiogenesis

is VEGF-A,11 1,1 12 which is known to increase vascular permeability,

stimulate endothelial cell proliferation and migration, alter endothe-

lial cell gene expression, and protect endothelial cells from apopto-

sis.113 ,11 4 VEGF expression strongly correlates with ovarian cancer cell

linesthat induce ascites and carcinomatosis,115 and increased circulat-

ingand tumor VEGF levels are associated with the clinical outcome of

ovarian cancer patients.116 ,11 7

The PI3-kinase/AKT pathway is upregulated in approximately

30% of ovarian cancers.74 Activators of thispathway inhibit apoptosis,

but they also have been shown to increase neovascularization, enhance

invasion, and increase resistance to chemotherapeutic agents.101 Con-

trol of the balance in this pathway lies primarily with PTEN, a tumor

suppressor that dephosphorylates PIP3 back into PIP2, promoting

apoptosis. The PTEN mutation is a frequent finding in endometrioid

ovarian cancers, and animal models suggest that it may be an early

event in ovarian carcinogenesis,at least of the endometrioid subtype.61Mediators of angiogenesis include tumor-derived factors and

NF B is the primary member of a family of five transcriptionhost stromal factors. Interleukin-8 plays a significant role in neovas-

cularization and ovarian cancer growth11 8 and is elevated in patients

with both early- and late-stage cancers.119 The v 3 integrin is pri-

marilyexpressed on newlydeveloping vascular endothelial cells, but it

isalso expressed on ovarian tumor cells.12 0 The tyrosine kinase recep-

tor EphA2 is overexpressed by 75% of ovarian cancers,12 1 and its

inhibition reduces tumor growth, at least in part through antiangio-

genic mechanisms.12 2,1 23 From a translational perspective, patient-

specific tumor microenvironment characteristics may in uence the

response to antiangiogenic therapy.1 24, 125

factors that deliver signalsto the nucleus to both increase proliferation

and inhibit apoptosis. NF B activation upregulates expression of

Bcl-2 family members, inhibitor of apoptosis proteins (IAP), and

additionalgenes identified by cDNA microarrayanalysisthat mayplay

a role in ovarian cancerpathogenesis.102 NF Bblockade also decreases

VEGF and interleukin-8 production and decreases tumorigenicity of

ovarian cancer cell lines in mice.103Limitless replicative potential. Normal cells can only divide a setnumber of timesbefore they achieve senescence and undergo apopto-sis. The clock for this pathway lies in telomere caps on the ends ofchromosomes that are made up of DNA and associated proteins.Without the protection provided by telomeres, exposed chromo-somes undergo massive defects, activating p53 and other policingproteins that propela cellinto an apoptotic pathway.Most cancer cells(75% to 90% of all types; 81% to 86% of those in ovarian cancer)maintain telomere length byproduction of telomerase, a reverse tran-scriptase composed of an RNA component (hTR) and a catalyticsubunit (hTERT).104 The hTR subunit is expressed by all cells, buthTERT expression increases with increasing tumorigenicity, whichsuggests that it is the rate-limiting step in telomerase activity.1 05 Find-ings that P53 knockdown and hTERT expression alone can transformovarian surface epithelial cells106 and that functional BRCA inhibitstelomerase activity107 suggest that telomerase activation is an earlyandrequired event for carcinogenesis.

The all-important first step in metastasis, and the primary feature

that defines malignancy,isinvasion through the basement membrane,

which requires interplay between tumor cells and the permissive un-

derlying stroma. Invasion of malignant cells through the basement

membrane and endothelial cell migration for angiogenesis require

degradation of the extracellular matrix. Matrix metalloproteinases

(MMPs) are a family of zinc-dependent endopeptidases that digest

collagen and other extracellular matrix components. They also stim-

ulate proliferation and induce release of VEGF.126 Ovarian tumors

overexpress MMP-2 and MMP-9,1 27 and this increased expression

correlates with clinical stage12 8 and patient survival.1 29 Interest-

ingly, host production of MMPs may be more important than

production by tumor cells, as demonstrated by Huang et al130 in

MMP-knockout mice. Another potentiator of invasion is host

production of catecholamines through chronic stress. A growing

body of preclinical data support the theory that chronic stress

contributes to the initiation and progression of cancer though

activation of adrenergic receptors, which leads to increased inva-

sion and metastasis.131 ,1 32 These mechanistic data support epide-

miologic studies that show that patients with poor social support

and increased stress are at greater risk for cancer progression.1 33

Early events in the tumor microenvironment: angiogenesis, inva-sion, and metastasis. A growing body of evidence suggests that, al-though genetic events in the tumor cells themselves are certainlycrucial, host and stromal factors in the tumor microenvironment areequally important. A clinically significant tumor includes not onlytumor cells but also matrixcomponents, stromal cells, and in amma-tory cells. An interplay between tumor cells and surrounding normaltissue dictates the establishment of a vascular supply through angio-genesis, invasion into the surrounding stroma, penetration of lym-phatic and vascular spaces, and adhesion and growth at metastatic

In ammatory cellsand associated cytokinesplay significant rolesin the tumor microenvironment. Because tumor cells can produceproteins that are recognized as abnormal,theycan induce an immuneresponse that can result in tumor cell death. As such, many functions




of tumor cells serve to evade recognition and destruction by immune

cells, such as Fas ligand production to induce lymphocyte apoptosis1 34

assess, but positive peritoneal cytologyis detectedinapproximately

30% of stage I cancers.14 1 Given the shedding nature of ovarian

cancer, adhesion molecules in particular have been evaluated for

their role in peritoneal metastasis. Evidence for mediators of this

process playing a role in early carcinogenesis is lacking but may

include such promoters of cell survival as focal adhesion kinase

(FAK) andE-cadherin.142 -1 45 E-cadherin is uniformly expressed in

ovarian cancer, in low–malignant-potential tumors, in benign

neoplasms, and—notably—in inclusion cysts of normal ovaries,

but not in the normal surface epithelium.1 46

and HLA-G secretion to inhibit natural-killer cell activity.7 6,1 35 Cyto-

kine production by mesenchymal cells stimulates ovarian epithelium

and activates processes that may participate in malignant transforma-

tion.13 6 Moreover, cytokine production by tumor cells promotes

growth and inhibits apoptosis.137 As a testament to the importance of

the host antitumor immune response, increased T-cell infiltration

into the tumor is associated with improved survival.138 The role of

specific immune cell populations in controlling versus promoting

tumor growth remains to be fully defined.13 9Although the definition of an advanced stage requires meta-Proposed Model of Ovarian Carcinogenesisstatic spread of cancer cells, recent evidence suggests that metasta-

sis is an earlier event than previously thought.10 8 However, few (0.01%) of shed malignant cells are capable of metastasizing, andeven the persistent presence of cancer cells in the vasculature doesnot necessarily result in seeding to distant sites.14 0 The patterns ofmetastasis with EOC are different than those of most cancers.Release of malignant cells by early-stage cancers is difficult to

The increasing knowledge about early genetic events in ovariancarcinoma cells has provided a better understanding of factors thatmay induce malignant transformation of the normal ovarian epithe-lium. However,we propose that, in a comprehensive model of ovariancarcinogenesis, components that arise in (or are deposited to) thestroma, such as in ammatory cells and immune modulators, MMPs,

Normal ovarian Fig 2. Proposed model of ovarian carcino-surface epithelium

and inclusion cystsgenesis. Normal ovarian epithelium is ex-posed to physiologic processes that maypredispose to malignant transformation,such as prolonged androgen exposure. Anumber of characteristics must be ob-tained, primarily through mutations orother genetic changes, to be transformedto a malignant state. These include unreg-ulated growth, resistance to antigrowthsignals, inhibition of apoptosis, evasion ofrecognition by the immune system,achieving limitless replicative potential, in-duction of angiogenesis, and invasion ofthe basement membrane. Examples ofspecific proteins known to play a role ineach of these processes in ovarian cancerare listed in italics. The order in whichthese mutations may occur is not wellunderstood, but the timing and specificprotein affected may be significant in pro-ducing different histologic subtypes andgrades of ovarian cancer. For example, ifmutations favoring growth and resistanceto apoptosis occurred early, before achiev-ing the potential for invasion and metasta-sis, an intermediate pathologic subtypewould be noted more often, such as K-RAS

Predisposing events suchas androgen exposure

High-grade Low-grade EGFR, KRAS,HER2 BRAFpathway pathway

GrowthfactorsAKT2 PTEN

Inhibition of No perceivable apoptosis

intermediate LMPhistology

Tum orAngiogenesis – VEGF, IL-8

Limitless replicative potential – hTERT

Genetic instabilityp53, BRCA MSI

Immune escape – FasL, HLA-G

Microenvironment effects – MMP’smutations in low malignant potential (LMP)tumors. A mutation leading to genetic in-stability, such as P53, that occurred earlywould predispose cells to other mutations,and rapid progression to a metastatic phe-notype, as seen in high-grade malignan-cies. Permissive or contributing factors ofthe microenvironment, such as productionof matrix metalloproteinases (MMPs) byfibroblasts (pictured in red), infiltration ofin ammatory cells (pictured in blue), andproliferation of endothelial cells for angio-genesis, may be just as important as mu-tations in the tumor cells.

Anoikis resistance – FAK, av 3

Reattachment and growth

Metastasis tobowel and omentum




and integrin ligands, may be equally important for tumor establish-ment and growth (Fig 2). Within the broad dual pathway model, it isclear that several characteristics must be acquired by the tumor celland its environment. Although the order in which these occur is likelyvariable, early alterations in dominant genes may dictate the specificpath that is followed, such as K-RAS leading to an LMP tumor andearly occurrence of a P53 or BRCA alteration leading to genetic insta-bility and rapid progression to a high-grade phenotype. Characteris-tics common to both pathways include the evasion of immunesurveillance, the invasion into the stroma, survival in the peritonealcavity, attachment to intraperitoneal sites, and continued growth andangiogenesis. These additional steps likely require a longer period oftime in LMPand low-grade malignancies, but theyalso occur eventu-ally and lead to relentless growth and metastasis. Despite many over-lapping features, every malignancy is unique, and myriad yet-unidentified genetic alterations probably participate in ovariancarcinogenesis. The challenge remains to identify the most importantinitial alterations in ovarian cancer to allow the development of better

methods for early detection and for the targeting of key pathwayswhile patients are still amenable to a cure.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential con icts of interest.

AUTHOR CONTRIBUTIONS

Conception and design:Charles N. Landen, Anil K. SoodAdministrative support: Anil K. SoodCollection and assembly of data: Charles N. Landen, Michael J. Birrer,Anil K. SoodData analysis and interpretation: Charles N. Landen, Anil K. SoodManuscript writing: Charles N. Landen,Michael J. Birrer, Anil K. SoodFinal approval of manuscript: Charles N. Landen, Michael J. Birrer,Anil K. Sood

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