The Biology of Ovarian Cancer Development
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
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 come532 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 standpointOvarian 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 copies534 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-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.
cells for three genes that reside on the long arm of chro- 6. Bell DA. Ovarian surface epithelial-stromal tumors. Hum Puthol
mosome 5: the interferon-a family, interferon-& and 1991; 22~750-62.
c - j ~ n .It~would
~ * ~be~ anticipated in early passage clone 7. Papadaki L, Beilby JOW. The fine structure of the surface epithe-
7 cells, which had one cytogenetically normal chromo- lium of the human ovary. Cell Sci 1971; €2445-65.
Some 5, that there would be one-half the diploid dosage 8. Blaustein A, Lee H. Surface cells of the ovary and pelvic perito-
neum: a histochemical and ultrastructure comparison. Gynecol
for these genes. This was the case for c-jun and inter- Oncol 1979; 8:34-43.
feron-0(Fig. 3). Unexpectedly, all members of the inter- 9. Bjersing L, Cajander 5. Ovulation and the role of the ovarian
feron-a family were totally absent (Fig. 3). This indi- surface epithelium. Experienfia 1975; 31:605-8.
cates that there was a submicroscopic deletion in this 10. Motta P, Van Blerkom J, Makabe 5.Changes in the surface mor-
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.
5;12 derivative seen in late passage cells originated 11. Nicosia SV, Saunders BO, Acevedo-Duncan ME, Setrakian S,
from the defective chromosome 5 of early passage cells DeCregoria R. Biopathology of ovarian mesothelium. In: Fami-
is given by a doubling of the gene dosage for inter- liari G, Makabe S, Motta PM, editors. Ultrastructure of the
feron+ and c-jun and the continued total absence of ovary. Boston: Kluwers Academic Publishers, 1991:287-310.
12. Auersperg N, Maclaren IA, Kruk PA. Ovarian surface epithe-
the interferon-a family in DNA of late passage cells lium: autonomous production of connective tissue-type extra-
(Fig. 3). This is perhaps the first experimental proof by a cellular matrix. Biol Reprod 1991; 44:717-24.
combination of cytogenetic and molecular methods, 13. Hamilton TC, Davies P, Griffiths K. Androgen and oestrogen
that the process of reduplication that returns a cell to binding of cytosols of human ovarian tumors. 1Endocrinoll981;
90~421-31.
disomy does indeed occur in transformed cells, and the 14, Adams AT, Auersperg N. Autoradiographic investigation of es-
Process is summarized in Figure 4 along with the gene trogen binding in cultured rat ovarian surface epithelial cells. j
dosage evidence. Histochem Cytochem 1983; 31:1321-5.
The cytogenetic and molecular changes in rat chro- 15. Hamilton TC, Davies P, Griffiths K. Oestrogen receptor-like
mosome 5 we observe are in an area where a yet-to-be- binding in the surface germinal epithelium of the rat ovary. j
Endocrinol 1982; 95:377-85.
cloned gene for the suppression of anchorage-depen- 16. Slotman B, Rao B. Ovarian carcinoma [review]. Anticancer Res
dent (SAI) growth is proposed to reside.60Furthermore, 1988; 8:417-34.
this portion of rat chromosome 5 has synteny with the 17. Langdon SP, Hawkes MM, Lawrie SS, Hawkins RA, Tesdale
short arm of human chromosome 9159which reportedly AL, Crew AJ, et al. Oestrogen receptor expression and the ef-
shows frequent cytogenetic changes in human ovarian fects of oestrogen and tamoxifen on the growth of human ovar-
ian carcinoma cell lines. Br j Cancer 1990; 62:213-6.
Cancer61and has been proposed as the site of a tumor 18. Hamilton TC, Davies P. Hormonal relationships in ovarian
suppressor gene.62-64 cancer. Reviews on Endocrine-Related Cancer 1983; 1419-22.
In conclusion, much work remains to be done to 19. Wimalasena J, Meehan D, Cavallo C. Human epithelial ovarian
determine not only those genes involved in the develop- cancer cell steroid secretion and its control by gonadotropins.
ment of the growth-dependent acquisition of the trans- Gynecol Oncol 1991; 41:56-63.
20. Pwls LG, Jap PHK, Ramaekers FFCS, Scheres JMJC, Thomas
formed phenotype in our rat model, but also to show CMG, Vooijs PG, et al. Characterization of a hormone-produc-
the relationship of those findings to human ovarian ing ovarian carcinoma cell line. Gynecol Oncol 1989; 32:203-14.
neoplasms. Nonetheless, the development of this 21. Stein KF, Allen E. Attempts to stimulate proliferation of the ger-
model has provided the first experimental evidence to minal epithelium of the ovary. Anat Rec 1942; 821-9.
support a role for repetitious ovulation in ovarian 22, Nash JD, Ozols RF, Smyth JF, Hamilton TC. Estrogen and anti-
Cancer etiology, and has proved a starting point to ex- estrogen effects on the growth of human epithelial ovarian
cancer in vitro. Obstef Gynecol 1989; 73:1009-16.
perimentally unravel potential genes involved in dis- 23, Sawada M, Terada N, Wada A, Mori Y, Yamasaki M, Saga T, et
ease etiology. al. Estrogen- and androgen-responsive growth of human ovar-
ian adenwardnoma heterotransplanted into nude mice. Int 1
Cancer 1990; 45:359-63.
References 24. Nash J, Hall L, Ozols R, Young R, Smyth J, Hamilton TC. Estro-
genic regulation and growth factor expression in human ovarian
river MS, Baker TR,Piedmonte M, Sandecki AM. Epidemiology cancer in vitro [abstract]. Proc Am Assoc Cancer Res 1989;
and etiology of ovarian cancer. Semin Oncol 1991; 18177-85. 30:1189.
Hamilton, TC. Ovarian cancer: part I: biology. Curr Probl Cancer 25. Hamilton TC, Behrens BC, Louie KC, Ozols RF. Induction of
1992; 16:l-57. progesterone receptor with 178-estradiol in human ovarian
h l l y RE. Ovarian tumours: a review. Am Pafhol 1977; cancer. 1 Clin Endocrinol Mefub 1984; 59561-3.
87686-720. 26. Hatch KD, Beecham JB, Blessing]A, Creasman W. Responsive-
woodruff JD. History of ovarian neoplasia: facts and fancy. Ob- ness of patients with advanced ovarian carcinoma to tamoxifen.
stetrics and Gynecology Annual 1976; 5:331-44. Cancer 1991; 68:269-71.536 CANCER Supplement January 15, 2993, Volume 71, No. 2
27. Geisinger KR, Berens ME, Duckett Y, Morgan TM, Kute TE, We- cologic oncology: principles and practice. Philadelphia: JB Lip-
lander CE. The effects of estrogen, progesterone, and tamoxifen pincott, 1992237-1 16.
alone and in combination with cytotoxic agents against human 45. Fathalla MF. Incessant ovulation: a factor in ovarian neoplasia?
ovarian caranoma in vitro. Cancer 1990; 651055-61. Lancet 1971; 2:163.
28. Simon WE, Albrecht M, Hansel M, Dietel M, Holzel F. Cell lines 46. Whittemore AS, Wu ML, Paffenbarger RS, Sarles DL, Kampert
derived from human ovarian carcinomas: growth stimulation by JB, Grosser S, et al. Epithelial ovarian cancer and the ability to
gonadotropic and steroid hormones. J Natl Cancer lnsf 1983; conceive. Cancer Res 1989; 49:4047-52.
70:839-45. 49. Negri E, Franceschi S, Tzonou A, Booth M, LaVecchia C, Paraz-
29. Slotman BJ, Rao BR. Response to inhibition of androgen action zini F, et al. Pooled analysis of 3 European case-control studies:
of human ovarian cancer cells in vitro. Cancer Lett 1989; 45:213- I. reproductive factors and risk of epithelial ovarian cancer. Int j
20 Cancer 1991; 4950-6.
30. Guraya SS. Interstitial gland tissue of mammalian ovary. A ~ t n 48. Franceschi S, LaVecchia C, Booth M, Tzonou A, Negri E. Paraz-
Endocrind [Suppl] 1972; 171:5-27. zini F, et al. Pooled analysis of 3 European case-control studies
31. Guraya SS. Histochemical observations in the corpus luteum of ovarian cancer: 11. age at menarche and at menopause. Int ]
atreticum of the human postmenopausal ovary with reference to Cancer 1991; 49:57-60,
steroid hormone synthesis. Arch ital Anaf Embriol 1976; 81:189- 49. Franceschi S, Parazzini F, Negri E, Booth M, LaVecchia, Beral V,
202. et al. Pooled analysis of 3 European case-control studies of epi-
32. Anthony HM. Age-specific incidence of cancer of the endome- thelial ovarian cancer: 111. oral contraceptive use. Jnt ] Cancer
trium, ovary and breast in the United Kingdom and United 1991; 49:61-5.
States. Int ] Epidemiol 1976; 5:231-6. 50. Lowry 5, Russell H, Hickey I, Atkinson R. Incessant ovulation
33. Brinton LA, Hoover RN. Epidemiology of gynecologic cancers. and ovarian cancer. Lancet 1991; 1:1544-5.
In: Hoskins WJ, Perez CA, Young RC, editors. Gynecologic on- 51. Wilson JE. Adeno-carcinomata in hens kept in a constant envi-
cology: principles and practice. Philadelphia: JB Lippincott, ronment. Poult Sci 1958; 37:1253.
1992~3-26. 52. Fredrickson TN. Ovarian tumors of the hen. Environ Healfh Per-
34. Monroe SE, Menon KMJ. Changes in reproductive hormone se- spect 1987; 73:35-51.
cretion during the climacteric and postmenopausal periods. CIin 53. Weinert TA, Hartwell LH. Characterization of RAD9 of Sacchar-
Obstrt Gynecol 1977; 20:113-22. omyces cerevisiae and evidence that its function acts posttransla-
35 Rajaniemi H, Kauppila A, Ronnberg L, Selander K, Pystynen P. tionally in cell cycle arrest after DNA damage. Mol Cell B i d
LH(hCG) receptor in benign and malignant tumors of human 1990; 10:6554-64.
ovary. Actn Obstet Gynecol Scnnd [Suppl] 1981; 101:83. 54. Gerring SL, Spencer F, Hieter P. The CHLl (CTF 1) gene prod-
36. Stouffer RL, Grodin MS, Davis JR, Surivit EA. Investigation of uct of Saccharomyces cerevisiae is important for chromosome
binding sites for follicle-stimulatinghormone and chorionic go- transmission and normal cell cycle progression in G2/M. EMBO
nadotropin in human ovarian cancers. j Clin Endocrind Mefab 1 1990; 9~4347-58.
1984; 59:441-6 55. Murray AW, Kirschner MW. Dominoes and clocks: the union of
37 Nicosia SV, Johnson JH, Streibel EJ.Growth characteristics of two views of the cell cycle. Science 1989; 246:614-21.
rabbit ovarian mesothelial (surface epithelial) cells. Inf ] Gynecol 56. Murray AW, Kirschner MW. Cyclin synthesis drives the early
Pathol 1985; 4:58-74. embryonic cell cycle. Nature 1989; 339:275-80.
38 Berchuck A, Rodriguez CG, Kame1 A, Dodge RK, Soper IT, 57. Cavenee WK, Dryja TP, Phillips RA, Benedict WF, Godbout R,
Clark-Pearson DL, et al. Epidermal growth factor receptor ex- Gallie BL, et al. Expression of recessive alleles by chromosomal
pression in normal ovanan epithelium and ovarian cancer. Am J mechanisms in retinoblastoma. Nature 1983; 305:779-84.
Obsfet Gynecol 1991; 164:669-74. 58. Hansen MF, Cavenee WK. Retinoblastoma and the progression
of tumor genetics. Trends in Genetics 1988; 4:125-8.
39. Bauknecht T, Runge M, Schwa11 M, Pfeiderer A. Occurrence of
epidermal growth factor receptors in human adnexal tumors 59. Levan C, Szpirer J, Szpirer C, Klinga K, Hanson C, Islam Q. The
and their prognostic value in advanced ovarian carcinomas. gene map of the Norway rat (Rattus norvegicus) and comparative
mapping with mouse and human. Genomics 1991; 10:699-717.
Gynecol Oncol 1988; 2 9 147-57.
60. Islam MQ, Szpirer J, Szpirer C, Islam K,Dasnoy J-F,Levan G.A
40. Godwin AK, Testa JR, Handel LM, Liu Z, Vanderveer LA, Tra- gene for the suppression of anchorage independence is located
cey PA, et al. Spontaneous transformation of rat ovarian surface in rat chromosome 5 bands q22-23, and the rat alpha-interferon
epithelial cells: assoclation with cytogenetic changes and impli- locus maps at the same region. ] Cell Sci 1989; 92:147-62.
cations of repeated ovulation in the etiology of ovarian cancer.
61. Bello MI, Moreno 5, Rey JA. Involvement of 9p in metastatic
Nut1 Cancer Inst 1992; 84592-601.
ovarian adenocarcinomas. Cancer Genet Cytogenet 1990; 45:
41. Rodriguez CC, Berchuck A, Whitaker RS, Schlossman D, Clark- 223-9.
Pearson DL, Bast RC. Epidermal growth factor receptor expres- 62. Diaz MO, Ziemin s, Beau MM, Pitha P, Smith SD, Chilcote RR,
sion in normal ovarian epithelium and ovarian cancer: 11. rela- et al. Homozygous deletion of the a-and j3-interferon genes in
tionship between receptor expression and response to epidermal human leukemia and derived cell lines. Proc Natl Acad Sci USA
growth factor. Am Obsfet Gynecol 1991; 164:745-50. 1988; 85:5259-63.
42. Radisavljevic SV. The pathogenesis of ovarian inclusion cysts 63. Diaz MO, Rubin CM, Harden A, Ziemin S, Larson RA, LeBeau
and cystomas. Obstet Gynecol 1976; 49424-9. MM, et al. Deletions of interferon genes in acute lymphoblastic
43. Nicosia SV. Morphological changes of the human ovary leukemia. N Engl 1 Med 1990; 322:77-82.
throughout life. In: Serra CB, editor. TThe Ovary. New York, 64. Olopade 01, Jenkins R, Linnenbach A], Cowan JM, Pomykala
Raven Press, 198357-81. H, Rowley 1, et al. Molecular analysis of chromosome 9p dele-.
44. Godwin AK, Hamilton TC, Knudson AG. Oncogenes and anti- tion in human solid tumors. Proc Am Assoc Cancer Res 1990;
oncogenes. In: Hoskins WJ, Perez CA, Young RC, editors. Gyne- 31318.You can also read
