The Biology of Ovarian Cancer Development


                             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

                                                                        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
                                                                             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)
                                                                               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%

(inkbp)                               (in kbp)                                1 oox

                                          9.4-                            Normal Surface     Hypothetical     Clone 7           Clone 7
                                                                            Epithelium                         Earlg             Late
                                          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
      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-
Ovarian Cancer Biology/Godwin e t al.                                                                                                     535

lowe containing the aberrant allele.5'*58In our example,               5. Nicosia SV,Nicosia RF. Neoplasms of the ovarian mesothelium.
we examined the DNA of early and late passage clone 7                        In: Azar HA, editor. Pathology of human neoplasms. New York:
                                                                             Raven Press, 1988:435-86.
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apparently "normal" chromosome 5. A strong indica-                           phology of ovarian "germinal" epithelium during the reproduc-
                                                                             tive cycle and in some pathological conditions. 1Submicrosc Cy-
tion that the chromosome 5 portion of the unbalanced                         to/ 1980; 12~407-25.
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Process is summarized in Figure 4 along with the gene                        trogen binding in cultured rat ovarian surface epithelial cells. j
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