The Biology of Ovarian Cancer Development
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530 The Biology of Ovarian Cancer Development Andrew K. Godwin, Ph.D., Joseph R. Testa, Ph.D., and Thomas C. Hamilton, Ph.D. Background. In theory, all the cell types that com- strate independent growth, tumorigenicity in athymic prise the human ovary have the potential for malignant mice, and cytogenetic changes. transformation. The vast majority of malignant ovarian Conclusions. Our data support the involvement of tumors in the human, however, arise from the ovarian tumor suppressor genes in the development of ovarian surface epithelium. These cells have important functions cancer. Cancer 1993: 71:530-6. during reproductive life; they contribute to follicular rupture and by cell division repair the wound that accom- Key words: ovarian cancer, malignant transformation, panies ovulation. There has been much speculation that tumor suppressor genes, cytogenetics, surface epi- the rapid cycles of cell division associated with wound thelium. repair contribute significantly to the development of ovarian cancer. Such speculation is based on the obser- vation that ovarian cancer occurs most frequently a t the The etiology of ovarian cancer is unknown,'*2but there end of a woman's reproductive life and is associated with are some data that suggest that multiple factors may nulliparity. It is of potential significance that, unlike contribute to the initiation and progression of the dis- most epithelia, these cells are not replaced through re- ease. The vast majority of ovarian carcinomas arise as a plenishment stem cells with the development of one end- result of malignant transformation of the ovarian sur- stage cell and one cell with continued growth potential. face epitheli~rn.~-~ This simple epithelium, composed Rather, the division of an ovarian surface epithelial cell of a single layer of cells, often is described as modified yields two daughter cells with equal potential for subse- peritoneal mesothelium. quent growth. Thus, all potential mutations as they accu- This paper is divided into two parts. The first part mulate are passed on to near-exponentially expanding summarizes some of the information available on the subsequent generations of cells that can acquire addi- role of hormones and growth factors in regulation of tional mutations that could confer the malignant phe- notype. normal and malignant ovarian surface epithelium in Methods. We have developed a model to test the hy- the context of how regulatory substances may affect pothesis that repeated cell division by ovarian surface disease etiology and progression. The second part con- epithelial cells contributes to development of malig- tains experimental data supportive of the long-standing nancy. In this model, rat ovarian surface epithelial cells hypothesis that incessant or repetitious ovulation con- are isolated and subjected in vitro to repetitious cell divi- tributes to the initiation of ovarian cancer, sion to mimic in a simple way growth of the surface epi- thelium in vivo. Features of the Normal and Malignant Ovarian Results. These cells develop a malignant phenotype based on loss of contact inhibition, the ability for sub- Surface Epithelium In adult life, the ovarian surface epithelial cells are a single layer of nondescript cells that vary from squa- Presented at the Perspectives on Ovarian Cancer in Older-Aged mous to cuboidal and low col~mnar.~~'J'The generally Women: Current Knowledge and Recommendations for Research Working Conference, Bethesda, Maryland, November 20-21, 1991. unremarkable features of these cells suggest that they From the Department of Medical Oncology, Fox Chase Cancer might have little role in normal ovarian function, but Center, Philadelphia, Pennsylvania. this does not appear to be the case. The ovary has two Supported in part by grant CA 06927 from the National Cancer major functions: (1) the production of steroid hor- Institute, Bethesda, Maryland. mones, and (2) the timely release of ova. Based on data Address for repnnts: Thomas C.Hamilton, Ph.D., Department of Medical Oncology, Fox Chase Cancer Center, 7701 Burholme Ave- from several species, ovarian surface epithelial cells are nue, Philadelphia, PA 19111. believed to have a pivotal role in the latter p r o c e ~ s . * ~ ~ ~ ' ~ Accepted for publication July 16, 1992. As the time of ovulation approaches, ovarian sur-
Ovarian Cancer BiologylGodwin et al. 531 face epithelial cells (in the area of the ovulation fossa) cancer cell lines it recently has been shown that estro- produce large lysosomal bodies that migrate to the ba- gen is a strong m i t ~ g e n 'and~ , promotes ~ ~ ~ ~ ~the capacity sal region of the cells. These large bodies are excreted for substrate-independent growth.22It is possible that from the cells' basal surfaces befqre ovulation. It is be- these effects are mediated indirectly by transforming lieved the lysosomal bodies contain enzymes that partic- growth factor a and /3 prod~ction.'~ In the PE04 ovarian ipate in the breakdown of the tunica albuginea and thus cancer cell line, in which estrogen stimulated growth, it aid in follicular r ~ p t u r eThe . ~ process of ovulation re- was observed that the hormone did not induce proges- sults in a wound at the ovarian surface that is repaired terone receptor synthesis,22whereas in the OVCAR-3 by rapid growth of ovarian surface epithelial cells." ovarian cancer cell line estrogen induced progesterone These surface epithelial cells also may participate in the receptor but not growth.22t25 Thus,it is possible that the Production of a new tunica albuginea.12 The require- divergent signals that mediate these two markers of es- ment for regulation of both processes (i.e., lysosome trogen action are uncoupled readily in ovarian cancer. Production and wound repair) suggests that the func- This could explain why antiestrogen therapy is effective tions of ovarian surface epithelial cells are controlled in only in a small subset of patients with ovarian cancer.26 complex ways. The significance of progestagens and androgens to There is potential for a diverse range of regulatory the regulation of normal and malignant ovarian surface molecules to influence function and growth of ovarian epithelial cells is limited essentially to the findings of surface epithelial cells. These signals may reach their receptors for these two sex steroid hormone classes in target by autocrine, endocrine, or paracrine routes. The ovarian tumors.27Only very limited data suggestive of a latter of these mechanisms (i-e., paracrine) may have role for testosterone in ~ t i m u l a t i o nand ~ ~ , antiandro- ~~ special significance to the surface epithelium in that the gens on inhibition of g r o ~ t h ' of~ ,ovarian ~ ~ cancer cells ovarian surface is bathed by follicular fluid at the time are available. It is noteworthy that the postmenopausal of ovulation. Direct experimental evidence on the roles ovary is a net producer of androgens due to the contin- of various hormones and growth factors in control of ued formation of functional secondary interstitial tissue ovarian surface epithelial cells, however, is limited. The ~ ' thus, if androgens stimulate in the ~ r g a n , ~ ' ,and Potential for hormones and growth factors to regulate growth of either normal or malignant ovarian surface growth and function of these cells is suggested by the epithelialcells, they may well contribute to disease etiol- Presence of appropriate receptors for many of these reg- ogy or progression (see below). ulatory substances in both the normal and malignant The roles of peptide hormones and growth factors ovarian surface epithelial cells. Estrogen receptors, for in the regulation of the ovarian surface epithelium are example, have been detected in both normal and malig- not completely defined. It has been shown that the age- nant ovarian surface epithelial cell^."*'^-'^ Independent specific incidence of ovarian cancer increases abruptly laboratories have reported estrogen receptors in the at the time of the m e n o ~ a u s e . The ~ ~ , ~age-related ~ normal rat ovarian surface epithelium, whereas there is change in ovarian function results in loss of feedback less evidence for the presence of estrogen receptors in inhibition on pituitary peptide hormone synthesis such human ovarian surface epithelial cells." There have that the pituitary produces constant increased amounts been numerous studies, however, showing the pres- of follicle-stimulating hormone (FSH) and luteinizing ence of estrogen receptors in malignant tumors of ovar- hormone (LH) (15- and 5-fold normal levels, respec- ian surface epithelial cell rigi in.^^,'^^^ The presence of tively) for a number of years after the ~limacteric.~~ This estrogen receptors in the malignant counterpart of a suggests that FSH and LH may somehow contribute to given cell type generally is considered to result from the development of ovarian cancer. The potential for retention of a differentiated feature of the normal pro- direct effects of peptide hormones on the surface epithe- genitor cell, rather than de novo synthesis as a result of lium is shown by the existence of FSH and LH receptors malignant transformation. The complexity of ovarian in ovarian cancer specimens.3536In addition, peptide surfaceepithelial cell regulation is indicated by the find- hormones have been shown to stimulate growth of ing of estrogen production by ovarian cancer cell normal rabbit ovarian surface epithelial cells in vitro" line^.'^,^^ Thus, estrogen, which generally is considered and cell lines derived from ovarian cancer specimens.28 to mediate its effects through the endocrine route, may Receptors for epidermal growth factor (EGF; the also have effects by both paracrine mechanisms (i.e., best known of the peptide growth factors) have been estrogen in follicular fluid) and autocrine mechanisms. found in both the normal and malignant human ovar- The exact function of estrogen in ovarian surface epithe- ian surface Furthermore, EGF has been lial cell regulation is not known. Limited evidencein the shown to be weakly to moderately mitogenic in rat4' rat and mouse suggest estrogen is a weak mit~gen.'"~' and human ovarian surface epithelial cells.41 In some estrogen receptor-positive human ovarian It is of interest to consider how mitogens may come
532 CANCER Supplement january 25, 2993, Volume 71, No. 2 into the proximity of the surface epithelium. This tissue of antioncogene inactivation, where both alleles of the is avascular and normally is separated from the ovarian antioncogene must be inactivated to achieve malignant cortex by a well defined tunica albuginea. Ovarian transformation." If replication increases the pool of cancer is believed to arise most frequently in surface cells with one inactivated allele (first hit) and also in- epithelial inclusion cysts. These cysts result from the creases the likelihood of additional mutations (second proliferation of surface epithelial cells that either in- hit), the process of replication in generative stem cells vade the ovarian cortex or are trapped within the cortex becomes doubly (or perhaps exponentially) dangerous. during ovulation or remodeling of the ovarian sur- Thus, any growth-promoting stimuli could increase the Such cysts increase in number in relation to possibility to accumulate combinations of potentially ovulatory activity, and thus are more prevalent in devastating mutational events that eventually result in older-aged It should be noted that the sur- malignancy. face epithelial cells lining these inclusion cysts in the ovarian cortex are theoretically in close proximity to the Repetitious Ovulation and Ovarian mitogen-producing components of the ovary, including Cancer Etiology the functional secondary interstitial tissue of the older- aged women. The observation that ovarian cancer is more prevalent There is a reasonable amount of information sug- in nulliparous women served as the basis for the devel- gestive that diverse regulatory molecules have the po- opment of a hypothesis that repetitious ovulatory activ- tential to stimulate growth of both normal and malig- ity is a factor in malignant transformation of the ovarian nant ovarian surface epithelial cells. The question arises surface epithelium." Alternatively, it has been sug- as to how growth-stimulatory effects might relate to gested that an underlying hormonal imbalance might disease etiology or manifestation. The potential for be responsible for infertility and that this, rather than growth-stimulatory factors to influence disease mani- ovulatory activity, may be responsible for the increased festation appears straightforward. An alteration in the incidence of ovarian cancer observed in nulliparous concentrations or patterns of production of growth-re- women.46The fact that birth control pill use reduces gulatory substances could stimulate slowly growing ma- ovarian cancer risk supports the former, more widely lignant cells such that tumor rapidly becomes manifest touted It also is noteworthy that tumors clinically. Alternatively, malignant transformation of the ovary derived from the surface epithelium are might include an altered responsiveness to such sub- rare in animals. Germane to this, in nature animals stances and thus more rapid growth. ovulate seasonally and most frequently become preg- The issue of how hormones and growth factors nant shortly after ovulatory activity commences in the may directly influence the etiology of ovarian cancer is spring. Thus, the number of ovulations during life is more complex. The simplest explanation is that any in- quite low. The only exception to this is the incessantly crease in DNA replication increases the likelihood of a ovulating domestic hen, which has a high incidence of mutation. Such mutations could be dominant, activat- ovarian c a n ~ e r . ~ ' , ~ * ing a protooncogene or producing an altered antionco- It is tempting to speculate how ovulatory activity gene product. Alternatively, recessive mutations could could contribute to ovarian cancer etiology. If surface inactivate antioncogenes. Stimulation of mitotic activity epithelial inclusion cysts are important in disease etiol- may be of special significance in the ovarian surface ogy, it is obvious that there would be a greater opportu- epithelium. Ovarian surface epithelial cells, unlike most nity for such cysts to formin the more frequently ovu- epithelia, behave as generative stem cells.* Thus, the lating person. In addition, the surface epithelial cell mi- division of one of these cells is believed to yield two totic activity required to repair the wound created by cells with equivalent potential for fuhire growth. This is the follicular rupture accompanying ovulation may be a in contrast to replicative stem cells that simplistically factor in disease initiation. As noted above, mutations yield two cells, one with loss of growth potential (i.e., are more likely to occur in dividing as opposed to quies- destined for differentiation) and one stem cell with con- cent cells. Furthermore, because growth increases the tinued replicative potential. In the case of ovarian sur- pool of cells carrying a potential first mutation (first hit), face epithelial cells, a single mutation could be passed the probability of an additional mutation occurring in a on to exponentially expanding progeny, and since cell with a preexisting mutation is increased. It is of transformation is essentially a game of numbers, the interest to speculate whether certain mechanisms to vig- larger the number of cells available for additional mu- orously assure the fidelity of DNA replication, repair, tations, the more likely it is that a mutation of signifi- and of chromosomal segregation might be inactive in cance to transformation will occur. It is straightforward surface epithelial cells because these cells would have to apply this pattern of replication to the simple model been under little selective pressure from the standpoint
Ovarian Cancer Biology/Godwin et al. 533 of evolution. In nature, such cells have a very limited requirement for replication, in contrast to the selective Pressure placed on the skin or gastrointestinal mucosa, which during evolution might be expected to have been rigorously selected for the capacity for wound repair and lumenal replenishment, respectively. In fact, pro- teins have been identified that are believed to have a role in the fidelity of DNA replication and chromo- somal segregation and, thus, act to reduce the possibil- ity of recombination errors and malignan~y.~~-'~ Over the years, there has been a rather strong case made for the role of incessant ovulation in ovarian cancer etiology. Beside the recapitulation of the original hypothesis, however, previously there has been little more supportive epidemiologic data and even less bio- logic evidence. Recently, we have described a model in which ovarian surface epithelial cells from the rat un- dergo malignant transformation in association with Prolonged exposure to a growth-promoting environ- ment.2,40Surface epithelial cells isolated from the rat ovary by selective trypsin treatment are placed in cul- ture. These cells rapidly grow to cover the culture sur- face as if to cover the wound created by follicular mp- ture and, at confluence, mitotic activity ceases. These cells may then be repetitiously subcultured to mimic in Figure 2. Karyotype of a Giemsa-banded metaphase cell from late Vitro in a simple way the repeated requirement for passage clone 7. Clonal changes include an unbalanced 5;12 derivative chromosome (arrow) and an unidentified marker (mar). growth produced by incessant ovulation in vivo. This Inset: chromosome pairs 5 and 12 from another cell; der(5;12) is arrowed. prolonged growth results in the spontaneous acquisi- tion of multiple features consistent with malignant transformation. The cells show loss of contact inhibi- tion, acquisition of the capacity for substrate-indepen- dent growth, and, when injected intraperitoneally or subcutaneously into nude athymic mice, form tumors consistent with serous cystadenocarcinoma of ovarian origin. We have examined the karyotypes of two spontane- ously transformed clonal cell lines derived from ovarian surface epithelial cells and one spontaneously trans- formed mixed population surface epithelial cell line. In each cell line, the karyotypes revealed several cytoge- netic abnormalities that could be consistent with onco- gene activation or tumor suppressor gene inactivation. The most frequent changes involved chromosome 5 and chromosome 1." Figure1. Karyotype of a Giemsa-bandedmetaphase cell from early One of the clonal rat ovarian surface epithelial cell Passage clone 7. Clonal changes include loss of one chromosome lines, clone 7, compared for cytogenetic changes be- 5 and partial deletions of chromosomes 4 and X. Note that the tween early (normal phenotype) and late passage 'emaining copy of chromosome 5 appears normal cytogenetically. (transformed phenotype), showed cytogenetic changes but molecular analyses indicate that a small segment, including the interferon-alocus, is deleted from this chromosome(see Fig. 3). LOSS of theoretical interest (Figs. 1 and 2). This cell line in of a chromosome 11 is a nonclonal change seen in this cell only. early passage showed monosomy for chromosome 5 Arrows indicate structural alterations of 4 and X. (Fig. l),whereas late passage cells contained two copies
534 CANCER Supplement Iunuury 15, 2993, Volume 71, No. 2 of chromosome 5, one apparently normal homologue and one defective copy consisting of an unbalanced de- rivative between chromosomes 5 and 12 (Fig. 2). We interpret this observation to indicate that there has been P "5" 1 xq-, 4q- - 5 / 5 '5' / - "5"/ ded '5";1 2) +mar I 1 I I I I I I I I I 1 & & & 1oox SOX 1 oox (J/J*) (J1-j (J/J) A B 100% (B/B*) (inkbp) (in kbp) 1 oox (A/A*) 23.1- 9.4- Normal Surface Hypothetical Clone 7 Clone 7 Epithelium Earlg Late 4.2- 6.6- Figure 4. Schematic diagram illustrating proposed clonal evolution of ROVGE clone 7 cells. Normal surface epithelial cells (N)contain two normal copies of chromosome 5. We hypothesize that on in 4.4 vitro culture, a single cell loses one copy of chromosome 5; the second copy ("5") appears normal cytogenetically but has a microscopic deletion of a segment that include the interferon-n C locus. Early passage clone 7 cells also display deletions of X and 4 (Xq- and 4q-). Late passage clone 7 cells have duplicated the defective chromosome "5," and one of these copies participates in 2.3- a rearrangement with a chromosome 12, der("5";12). The DNA signal intensity and allelic constitution of three different genes 2.9- 2.0- residing on chromosome 5 (Lea,c-jun alleles J and J', the interferon-n gene locus [A/A*], and interferon-8 [B/B*]) are indicated. Both alleles of interferon-cu are lost in early and late passage clone 7 cells. Percent sign indicates the approximate gene dosage of the three genes as determined by Southern blot analysis; mar indicates the presence of an unknown marker chromosome. The existence of the hypothetical subpopulation of cells noted above D is suggested by the presence of late passage clone 7 cells that do not contain cytogenetic deletions of chromosome X and chromosome 4. This would indicate that the hypothetical population 9.6- 4.0- 9.2- ("5"/-) gave rise to the early passage clone 7 cells ("5"/-, Xq-, 4q-) and to another subpopulation with the features of late passage clone 7. This latter subpopulation (at the time of early passage cytogenetic analysis) must have been a very small component of the Figure 3. DNA blot analysis of early and late passage rat ovarian culture, and thus was not observed in the chromosomal preparations germinal epithelium (ROVGE) clone 7 cell lines for loss of specific examined and did not influence gene dosage. This latter loci of genes located on chromosome 5. High molecular DNA (10 subpopulation, however. apparently had a distinct growth rg per lane) from the early and late passage clone 7 cells (indicated advantage, and by late passage became dominant if not the entire above) was digested with EcoRI, electrophoresed on a 196 agarose population. gel, and transferred to nylon membrane filters. Filters were hybridized sequentially with the following [3ZP]-labelednick translated DNA probes: (A) interferon-& (6) interferon-a, (C) c-jun, and (D) EGF receptor. The rat EGF receptor cDNA probe detects duplication of the single chromosome 5 of early passage three bands (9.6,9.2, and 4.0 kilobase pairs [kbp]); the 4.0-kbp band cells. This view is supported by molecular data (see be- (left), which is closest in size to interferon-6 and c-jun, and the 9.6 low). It has been hypothesized by others that one mech- and 9.2 bands (right) are shown for comparison of DNA loading and anism by which predisposing recessive somatic or germ hansfer. Hind Ill-digested X phage D N A was used as molecular size markers. The fragment size is indicated in kilobase pairs to the line mutations could be unmasked is by the loss of a left. DNA from normal rat spleen and lung is included as a control normal (wild type) chromosome (by mitotic nondis- for normal gene dosage. junction) and reduplication of the remaining homo-
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