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Originally published as JCO Early Release 10.1200/JCO.2006.07.9970 on January 14 2008 © 2008 American Society of Clinical Oncology.
Early Events in the Pathogenesis of Epithelial Ovarian Cancer
From the Department of Gynecologic Oncology and the Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Center for Cancer Research, National Cancer Institute, Bethesda, MD Corresponding author: Anil K. Sood, MD, Professor, Departments of Gynecologic Oncology and Cancer Biology, University of Texas M.D. Anderson Cancer Center, 1155 Herman Pressler, Unit 1362, Houston, TX 77030; e-mail: asood{at}mdanderson.org
Ovarian carcinogenesis, as in most cancers, involves multiple genetic alterations. A great deal has been learned about proteins and pathways important in the early stages of malignant transformation and metastasis, as derived from studies of individual tumors, microarray data, animal models, and inherited disorders that confer susceptibility. However, a full understanding of the earliest recognizable events in epithelial ovarian carcinogenesis is limited by the lack of a well-defined premalignant state common to all ovarian subtypes and by the paucity of data from early-stage cancers. Evidence suggests that ovarian cancers can progress both through a stepwise mutation process (low-grade pathway) and through greater genetic instability that leads to rapid metastasis without an identifiable precursor lesion (high-grade pathway). In this review, we discuss many of the genetic and molecular disorders in each key process that is altered in cancer cells, and we present a model of ovarian pathogenesis that incorporates the role of tumor cell mutations and factors in the host microenvironment important to tumor initiation and progression.
Ovarian cancer is the fifth leading cause of cancer deaths among women, and it is the most common cause among gynecologic malignancies.1 The poor ratio of survival to incidence in epithelial ovarian cancer (EOC) results from the high percentage of cases diagnosed at an advanced stage. Despite advances in surgery and chemotherapy, survival of patients with EOC stands at just 45% at 5 years.1 Although the age of biologic therapies holds the potential of improved responses in advanced and recurrent EOC, a greater impact could be made by recognition of high-risk patients and by offering risk-reducing surgery, a strategy that has demonstrated effectiveness in patients with genetic predispositions.2 However, there is significant heterogeneity within the EOC group. For example, histologically defined subtypes such as serous, endometrioid, mucinous, and low- and high-grade malignancies all have variable clinical manifestations and underlying molecular signatures.3 Substantial advances have been made in understanding the genetic alterations and biologic processes in ovarian cancer; however, the etiology remains poorly understood. In this article, we will focus on the current understanding of the early events in EOC.
The ovary is surrounded by a single-cell layer of peritoneal mesothelium, which is derived from the coelomic layer during development and which has the potential to undergo metaplastic transformation to a more differentiated state.4 Unlike most malignancies, as this epithelium transforms into a malignant phenotype, it becomes more differentiated, and it can differentiate toward many of the different cell types found in the müllerian tract, including those in the fallopian tube, uterus, cervix, and ovarian stroma.5 It is widely thought that most ovarian cancers develop from the surface epithelium or postovulatory inclusion cysts that were subjected to prolonged exposure to hormones or other chemokines.4 Primary peritoneal and fallopian tube carcinomas have similar clinical, molecular, and genetic profiles to ovarian cancers, though some small differences in frequency of specific protein expression have been described.6-11 Primary peritoneal carcinomas may, in fact, have a multifocal and polyclonal origin.12 Therefore, although these entities are often lumped together with ovarian cancer, there may be some significant, but currently poorly defined, differences. In fact, recent pathologic examination of consecutive cases of ovarian, primary peritoneal, and fallopian tube cancers suggests that a greater percentage of ovarian cancers than originally thought may actually have a fallopian origin with metastasis to the ovary.13 However, because of the changes in definition, inconsistent reporting of subtypes, and the paucity of direct comparative studies, these entities will be considered as variations within a disease and will be considered together in this review. There have been several proposed hypotheses about the underlying physiological processes that increase the risk of malignant transformation 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 susceptibility through BRCA or mismatch-repair gene mutations. These hypotheses will be reviewed briefly, and they are discussed in greater depth in other excellent reviews.14,14a,14b
The observation that women with a greater number of ovulatory cycles have an increased risk of ovarian cancer led to the incessant ovulation hypothesis by Fathalla in 1971.15 According to this hypothesis, as ovulation occurs, ovarian surface epithelial cells are internalized 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,16-18 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 ovulation 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 Weaknesses in the incessant ovulation theory and observations of an increased risk in infertile women who use fertility drugs led to the gonadotropin hypothesis, which theorizes that stimulation of the ovarian surface epithelium by follicle-stimulating hormone (FSH) and by luteinizing hormone (LH) may place the cells at an increased risk of developing EOC. In 1992, Whittemore et al16 reported a case-control study in which infertile patients who used fertility drugs had an increased risk of EOC by a factor of 2.8, and of borderline tumors by 4.0, compared with infertile women who were not using fertility drugs. However, subsequent case-control and cohort studies demonstrated inconsistent associations between gonadotropin use and epithelial ovarian carcinoma.25 These studies collectively suggest that the condition of infertility (or the predisposing condition), rather than fertility drug use, is responsible for the increased risk.26 From a basic science perspective, receptors for FSH and LH have been found on 100% of normal ovarian surface epithelial cells and on 60% of malignant tumor cells.27 FSH, LH, and human chorionic gonadotropin (hCG) all stimulate proliferation of EOCs and may activate mitogen-activated kinase (MAPK).28 Furthermore, induced overexpression of the FSH receptor led to upregulation of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and C-MYC.29 Other potential oncogenes upregulated by FSH or LH treatment in vitro include β-catenin, Meis-1, cyclin G2, insulin-like growth factor 1 (IGF-1), and β-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 malignant phenotype. However, in animal models of implanted tumors, exposure to gonadotropins promotes tumor growth,32 angiogenesis,32 vascular endothelial growth factor (VEGF) expression,33 and adhesion.34 Collectively, these studies suggest a role for gonadotropins in promoting the progression of ovarian cancer, rather than of the causation. Notable hormones have also been implicated in ovarian carcinogenesis. On the basis of epidemiologic studies, progestin-only contraceptives are as effective as combined oral contraceptive pills in the reduction of ovarian cancer risk,23,35 and progesterone is the dominant hormone during pregnancy, which also reduces risk.23 Interestingly, use of progestin contraceptives can also decrease ovarian testosterone levels.36 In vitro studies have not, however, demonstrated a clear inhibition of cancer cell growth.37 Conditions of increased androgens (eg, polycystic ovarian syndrome, hirsutism, acne) are associated with an increased risk of EOC.24 Androgens represent the greatest hormone concentration within a developing follicle,38 which prolongs exposure to the epithelial cells. Androgen receptors are present on human OSE cells, and they stimulate proliferation.39 There is no strong evidence, however, that exposure to androgens induces malignant transformation.
There is growing interest in the etiologic role of inflammation, which accompanies each ovulation, with an associated cytokine release, influx of inflammatory cells, and tissue reconstruction.26 This mechanism has been postulated to stress OSE cells such that they are predisposed to genetic damage and malignant transformation. Consistent with this hypothesis, patients with chronic aspirin, nonsteroidal anti-inflammatory drug, or acetaminophen use have a reduced risk of EOC.40 Downstream effectors of the nonsteroidal anti-inflammatory drug pathway, such as nitric oxide synthase, cyclooxygenase-2, VEGF, and NF- Although any of the above mechanisms may play a role in ovarian carcinogenesis in some patients, the modest association with each suggests that multiple other processes are involved, which cannot be predicted by clinically recognizable conditions such as nulliparity, infertility, or hormone exposure. To detect EOC early or to identify at-risk patients, a search must therefore continue for genetic or epigenetic conditions that predispose patients to the development of EOC or for proteins that may allow for early detection.
Earliest Recognizable Events in Tumor Progression Genomic comparison of early- versus late-stage, high-grade ovarian cancers. Genomic analysis of high-grade tumors has identified amplification and/or over-expression of numerous genes thought to be important in the development of ovarian cancer. However, the precise role of these genes in early carcinogenesis remains unclear. The application of new genomic technologies, such as comparative genome hybridization (CGH) and microarray expression profiling, has helped elucidate many of the important genetic events that may lead to ovarian cancer. The ability of these technologies to simultaneously measure thousands of genes allows not only the identification of individual genes but also the delineation of dominant pathways that may be responsible for cancer pathogenesis43,44 (Fig 1).
A study that compared normal ovarian epithelial cells to early- and late-stage cancers found several differentially expressed genes between normal and malignant tissues.45 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 Many of the genes are involved in the p53 pathway, which suggests that this pathway is important for the peritoneal metastasis. The challenge is in determining whether a noted difference is truly responsible for a particular function, such as malignant transformation or metastasis. For example, metastasized tumors with genetic instability would continue to acquire genetic mutations that could be erroneously assigned to causing metastasis. Additionally, early genetic perturbations would persist in metastasized tumors and would not be identified as an early event 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 alterations, these technologies will allow more information to be gained on the earliest events in ovarian cancer. Inherited disorders. A study of genetic disorders can provide great insight into the etiology and early events in carcinogenesis. Hereditary genetic disorders account for approximately 10% of ovarian cancers, and 90% of these are either BRCA1 or BRCA2 mutations. Evaluation of BRCA1 and BRCA2 mutant and sporadic tumors with gene expression profiling has demonstrated that the greatest contrast in expression patterns was between that of BRCA1 and BRCA2 mutant tumors and that sporadic tumors shared characteristics of both.47 This intriguing finding suggests that BRCA1 and BRCA2 tumors may have variable pathways in carcinogenesis and that even sporadic tumors may develop as a result of alterations in either pathway. Clinically, patients with BRCA mutations tend to have highly proliferative tumors but more favorable outcomes when adjusted for stage.48 Borderline tumors have a much less frequent incidence of BRCA mutations (4.3% v 24.2% in a Jewish population),49 which also suggests a different molecular origin. Other than in hereditary syndromes, BRCA genes are rarely mutated in sporadic ovarian cancers,50 although epigenetic changes, alternate splicing, and other genetic factors may affect BRCA function in as many as 82% of sporadic occurrences.51-53 The BRCA1 and BRCA2 proteins are considered caretakers of the genome, and play key roles in the signaling of DNA damage, the activation of DNA repair, the induction of apoptosis, and the monitoring of cell cycle checkpoints.54-56 Cells that lack functional BRCA have increased aneuploidy, centrosome amplification, and chromosomal aberrations,57 which 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.57 Defects in mismatch repair in patients with Lynch syndrome or hereditary nonpolyposis colon cancer (HNPCC) account for approximately 10% of hereditary ovarian cancers and for 1% to 2% of overall cases. Patients with this syndrome, however, individually carry an approximately 12% risk of developing ovarian cancer.58 The mechanism of increased risk is through defects in the mismatch-repair machinery and its resulting genetic instability that places cells at risk of multiple mutations; however, carcinogenesis in ovarian cancer has not been well studied beyond a description of mismatch repair defects. Other familial syndromes associated with an increased risk of ovarian cancer include Peutz-Jeghers Syndrome (ie, mutation in the STK11 gene; 21% lifetime risk) and Gorlin Syndrome (ie, mutation in PTCH; 20% lifetime risk), but these tumors are usually stromal cancers and fibromas, respectively. Animal models. In an attempt to better understand ovarian carcinogenesis, several animals models have been developed. Orsulic et al59 introduced various oncogenes into transgenic ovarian surface epithelial cells that expressed the avian receptor TVA. These cells became tumorigenic when two of three genes (C-MYC, K-RAS, or AKT) were overexpressed in p53-deficient cells. After inducing changes in vitro, they were implanted into the bursal sac that surrounds the ovary of recipient mice, and they developed a carcinomatosis pattern similar to human ovarian cancer. Subsequently, Connolly et al60 generated de novo ovary-specific tumors in transgenic mice that expressed the transforming region of the SV40 T-antigen under control of the ovary-specific Müllerian inhibitory substance type II receptor gene promoter. In these mice, poorly differentiated tumors of both ovaries developed in 50% of transfected mice and often led to carcinomatosis and ascites formation. A model of endometrioid ovarian carcinogenesis was described by Dinulescu et al,61 in which adenoviral vectors were injected into the bursal sac that induced K-RAS overexpression and PTEN inactivation.61 Although K-RAS overexpression alone induced lesions that were histologically compatible with endometriosis, the combination of both mutations led to the rapid development of carcinomatosis of endometrioid histology. Although these models have limited applicability to de novo human 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 insights into specific gene functions.
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 categories of carcinogenesis.62 High-grade malignancies are rapidly growing, relatively chemosensitive, and without a definitive precursor lesion. In contrast, low-grade tumors grow more slowly, are less responsive 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 contain areas of serous LMP tumors compared with just 2% of high- grade,66 and LMP tumors recur as a low-grade carcinoma in 75% of cases.67 Molecular and protein analyses of tumors of these two different subtypes also suggest different pathogenesis (Table 2). Analyses of individual genes have found that K-RAS and BRAF mutations are rarely detected in high-grade invasive carcinomas but are present in 30% to 50% of LMP tumors, in low-grade adenocarcinomas, and often in the adjacent benign epithelium.62,68-70 The P53 gene is mutated in 50% to 80% of high-grade invasive carcinomas, but rarely in 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 human leukocyte antigen-G (HLA-G), which may provide a mechanism of immune escape for the tumor, has been noted in 61% of high-grade carcinomas but is absent in low-grade or LMP neoplasms.76
Whole-genome approaches have also provided key insights into the developmental relatedness of various ovarian tumors. Comparison of whole-genome expression profiles of ovarian tumors of different 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 Furthermore, 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 and CGH79 analyses have found similar profiles in benign adenomas and in LMP tumors, which supports the concept of a transformation from benign adenoma to LMP. Although ovarian adenocarcinomas can be subtyped by grade, histologic subtypes also differ. Although differences in clinical outcomes 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, mutations 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.70,82 These studies suggest that the malignant transformation in mucinous tumors may follow a sequence of adenoma to LMP tumor to invasive adenocarcinoma80,81 more frequently than to high-grade serous carcinomas. Endometrioid adenocarcinomas more frequently harbor PTEN mutations (similar to endometrioid tumors of the uterine endometrium) than do serous or mucinous subtypes.83
The majority of evidence on genetic or protein alterations in ovarian cancer is based on studies of late-stage cancers. However, current understanding of these processes allows speculation that many alterations must occur early to achieve a clinically recognized tumor. It is believed that, for the majority of malignancies, a cancer cell must overcome many protective mechanisms to develop into a clinically evident tumor.84 These include unchecked proliferation, inhibition of apoptosis, angiogenesis, stromal invasion, separation and survival away from the primary tumor, and implantation and growth within new tissues. We examine the evidence for many of the ever-increasing recognized participants in each of these processes in ovarian cancer (Table 3).
Self-sufficiency in growth signals. A number of oncogenes have been identified in ovarian cancer that allow cells to grow independently 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, cell survival, and angiogenesis.85-87 The overexpression of src has been demonstrated 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 Furthermore, inhibition of src with antisense or with small molecule inhibitors has reduced ovarian cancer growth in preclinical mouse models.85 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 immunohistochemistry) and is overexpressed in 35% to 70% of EOCs.90 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.91 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 nonreceptor kinases, which leads to phosphorylation and activation of Erk1 and Erk2 transcription factors that make their way to the nucleus to initiate signals of growth and progression through the cell cycle. As described above, K-RAS mutations are common in adenocarcinomas, and frequency is variable in different histologic subtypes.70,82 Resistance to antigrowth signals. In early-transformed cells, antigrowth signals must be overcome. Although definitive data are lacking regarding the sequence of specific genetic events in carcinogenesis, there is evidence for abnormalities in cell cycle mediators, such as cyclins, cyclin-dependent kinases (CDKs, which complex with the cyclins to allow their activity), CDK inhibitors (CDKIs, which inhibit cyclin/CDK complexes), and other proteins or transcription factors such as pRb, p53, and E2F. The restriction point, after which a cell is committed to divide, is controlled by Cyclin D and E's regulation of E2F release by Rb. Cyclin E is expressed by only 9% of benign tumors but by 48% of borderline and by 70% of malignant tumors, and it is associated with poor survival.92 Similarly, CDK2, which complexes exclusively with Cyclin E, is expressed more frequently in malignant ovarian tumors compared with LMP or benign tumors.92 Cyclin D1 is expressed at low levels in normal ovarian epithelial cells but is prominent 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 Other proteins that control the cell cycle include myc (an oncogenic transcription factor activated by the RAS-RAF pathway and overexpressed in approximately 30% of ovarian cancers) and AHRI (ie, NOEY2, a GTPase tumor suppressor gene lost in almost all ovarian cancers95,96). Thus, there are multiple aberrations in the genetics of cell cycle regulation that likely provide an unchecked growth advantage to ovarian cancer cells. Evading apoptosis. It has been proposed that a more important characteristic of cancer than increased cell division is the reduced apoptosis and prolonged survival seen in these cells. Indeed, cancer cells often divide less frequently than their normal equivalents, especially in epithelial cancers, in which normal epithelial cells have rapid turnover. Many participants in this process are altered in ovarian cancer to inhibit cell death. Among these is P53, which normally promotes either cell cycle arrest and initiation of repair mechanisms or the shunting of the cell to an apoptotic pathway.97 It has been hypothesized that cancers that do not have mutations in the P53 gene likely have alterations in the function of p53 in other ways, such as in the production of p53-binding proteins or the enhanced degradation through ubiquitination. Most P53 mutations in ovarian cancer are missense,98 but specific mutations (ie, null mutations) may play a key role in producing a metastatic phenotype, in that they are seen much less frequently in stage I ovarian cancers.99 Interestingly, P53 mutations have been detected in ovarian inclusion cysts adjacent to cystadenocarcinomas, in microscopic ovarian cancer, and even in tubular intraepithelial carcinomas removed prophylactically from patients with BRCA1 mutations.13,100 The accumulation of evidence suggests that p53 inactivation may be a relatively early event in ovarian cancer pathogenesis. The PI3-kinase/AKT pathway is upregulated in approximately 30% of ovarian cancers.74 Activators of this pathway inhibit apoptosis, but they also have been shown to increase neovascularization, enhance invasion, and increase resistance to chemotherapeutic agents.101 Control 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.61
NF Limitless replicative potential. Normal cells can only divide a set number of times before they achieve senescence and undergo apoptosis. The clock for this pathway lies in telomere caps on the ends of chromosomes that are made up of DNA and associated proteins. Without the protection provided by telomeres, exposed chromosomes undergo massive defects, activating p53 and other policing proteins that propel a cell into an apoptotic pathway. Most cancer cells (75% to 90% of all types; 81% to 86% of those in ovarian cancer) maintain telomere length by production of telomerase, a reverse transcriptase composed of an RNA component (hTR) and a catalytic subunit (hTERT).104 The hTR subunit is expressed by all cells, but hTERT expression increases with increasing tumorigenicity, which suggests that it is the rate-limiting step in telomerase activity.105 Findings that P53 knockdown and hTERT expression alone can transform ovarian surface epithelial cells106 and that functional BRCA inhibits telomerase activity107 suggest that telomerase activation is an early and required event for carcinogenesis. Early events in the tumor microenvironment: angiogenesis, invasion, and metastasis. A growing body of evidence suggests that, although genetic events in the tumor cells themselves are certainly crucial, host and stromal factors in the tumor microenvironment are equally important. A clinically significant tumor includes not only tumor cells but also matrix components, stromal cells, and inflammatory cells. An interplay between tumor cells and surrounding normal tissue dictates the establishment of a vascular supply through angiogenesis, invasion into the surrounding stroma, penetration of lymphatic and vascular spaces, and adhesion and growth at metastatic sites. Although metastasis is thought of as a late event in carcinogenesis, emerging evidence in breast cancer suggests that early tumors may already hold the genetic profile needed for metastasis,108 which further suggests that factors other than the tumor cell itself may regulate metastasis. Similarly, in ovarian cancer, peritoneal and stromal alterations may be permissive for cancer spread.109 An understanding of these factors may provide additional insights into tumor pathogenesis and also may offer unique targets for therapy. No cells, cancerous or benign, can exist without oxygen and other nutrients. Cells must reside within 100 µm of a capillary in order to receive oxygen.110 Therefore, in order for a malignancy to grow beyond approximately 1 mm3, it must induce the growth of new vessels in or around itself. Regulation of angiogenesis is complex, which reflects a balance between pro- and antiangiogenic influences within the tumor microenvironment. The primary mediator of angiogenesis is VEGF-A,111,112 which is known to increase vascular permeability, stimulate endothelial cell proliferation and migration, alter endothelial cell gene expression, and protect endothelial cells from apoptosis.113,114 VEGF expression strongly correlates with ovarian cancer cell lines that induce ascites and carcinomatosis,115 and increased circulating and tumor VEGF levels are associated with the clinical outcome of ovarian cancer patients.116,117
Mediators of angiogenesis include tumor-derived factors and host stromal factors. Interleukin-8 plays a significant role in neovascularization and ovarian cancer growth118 and is elevated in patients with both early- and late-stage cancers.119 The The all-important first step in metastasis, and the primary feature that defines malignancy, is invasion through the basement membrane, which requires interplay between tumor cells and the permissive underlying 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 stimulate proliferation and induce release of VEGF.126 Ovarian tumors overexpress MMP-2 and MMP-9,127 and this increased expression correlates with clinical stage128 and patient survival.129 Interestingly, 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 invasion and metastasis.131,132 These mechanistic data support epidemiologic studies that show that patients with poor social support and increased stress are at greater risk for cancer progression.133 Inflammatory cells and associated cytokines play significant roles in the tumor microenvironment. Because tumor cells can produce proteins that are recognized as abnormal, they can induce an immune response 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 apoptosis134 and HLA-G secretion to inhibit natural-killer cell activity.76,135 Cytokine production by mesenchymal cells stimulates ovarian epithelium and activates processes that may participate in malignant transformation.136 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.139 Although the definition of an advanced stage requires metastatic spread of cancer cells, recent evidence suggests that metastasis is an earlier event than previously thought.108 However, few (< 0.01%) of shed malignant cells are capable of metastasizing, and even the persistent presence of cancer cells in the vasculature does not necessarily result in seeding to distant sites.140 The patterns of metastasis with EOC are different than those of most cancers. Release of malignant cells by early-stage cancers is difficult to assess, but positive peritoneal cytology is detected in approximately 30% of stage I cancers.141 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) and E-cadherin.142-145 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.146
Proposed Model of Ovarian Carcinogenesis
The authors indicated no potential conflicts of interest.
Conception and design: Charles N. Landen, Anil K. Sood Administrative support: Anil K. Sood Collection and assembly of data: Charles N. Landen, Michael J. Birrer, Anil K. Sood Data analysis and interpretation: Charles N. Landen, Anil K. Sood Manuscript writing: Charles N. Landen, Michael J. Birrer, Anil K. Sood Final approval of manuscript: Charles N. Landen, Michael J. Birrer, Anil K. Sood
published online ahead of print at www.jco.org on January 14, 2008. Supported in part by the Reproductive Scientist Development Program through NIH Grant No. 5K12HD00849 and the Ovarian Cancer Research Fund (C.N.L.); Grants No. CA 11079301 and CA 10929801 from the National Institutes of Health (A.K.S.); Grant No. P50 CA083639 from the M.D. Anderson Cancer Center Ovarian Cancer Specialized Program of Research Excellence; a Program Project Development Grant from the Ovarian Cancer Research Fund Inc; the Marcus Foundation (A.K.S.); and the Intramural Research Program of the National Institutes of Health, National Cancer Institute (M.J.B.). Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
B, have been implicated in carcinogenic pathways.
vβ3 integrin is primarily expressed on newly developing vascular endothelial cells, but it is also expressed on ovarian tumor cells.
