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Animal models of ovarian cancer
Reproductive Biology and Endocrinology volume 1, Article number: 67 (2003)
Ovarian cancer is the most lethal of all of the gynecological cancers and can arise from any cell type of the ovary, including germ cells, granulosa or stromal cells. However, the majority of ovarian cancers arise from the surface epithelium, a single layer of cells that covers the surface of the ovary. The lack of a reliable and specific method for the early detection of epithelial ovarian cancer results in diagnosis occurring most commonly at late clinical stages, when treatment is less effective. In part, the deficiency in diagnostic tools is due to the lack of markers for the detection of preneoplastic or early neoplastic changes in the epithelial cells, which reflects our rather poor understanding of this process. Animal models which accurately represent the cellular and molecular changes associated with the initiation and progression of human ovarian cancer have significant potential to facilitate the development of better methods for the early detection and treatment of ovarian cancer. This review describes some of the experimental animal models of ovarian tumorigenesis that have been reported, including those involving specific reproductive factors and environmental toxins. Consideration has also been given to the recent progress in modeling ovarian cancer using genetically engineered mice.
Despite improved knowledge of the etiology of ovarian cancer, aggressive cytoreductive surgery, and modern combination chemotherapy, there has been little change in the mortality statistics over the last 30 years, and approximately 60% of the women who develop ovarian cancer will die from their disease. Lack of an adequate screening test for early disease detection and the rapid progression to chemoresistance have prevented appreciable improvement in the five year survival rate of patients with ovarian cancer.
Experimental models for human diseases are of crucial importance not only to understand the biological and genetic factors that influence the phenotypic characteristics of the disease but to utilize as a basis for developing rational intervention strategies. Ovarian cancer cell lines derived from ascites or primary ovarian tumors have been used extensively and can be very effective for studying the processes controlling growth regulation and chemosensitivity. Our limited knowledge of the initiating events of ovarian cancer has restricted the development of models in which the early pathogenic events for ovarian cancer can be studied. However, there are a few animal models that develop ovarian tumors spontaneously, and others where the manipulation of various reproductive factors or exposure to environmental toxins have been shown to promote ovarian tumorigenesis. Finally, the recent identification of promoters that can drive gene expression in the ovarian surface epithelium is providing new opportunities for the generation of genetically engineered mouse models of ovarian cancer. Here we describe some of the models that have been developed to investigate ovarian cell transformation.
Spontaneous and Non-epithelial Ovarian Tumorigenesis
There are few animal models that develop ovarian tumors spontaneously. Hens maintained under intensive egg-laying conditions develop ovarian adenocarcinomas; however such tumors are uncommon in hens less than 2 years of age . Ovarian tumors will also arise spontaneously with age in some strains of mice , and in Wistar and Sprague-Dawley rats [3, 4]. These tumors show a wide variety of histologic sub-types, including tubular adenoma, adenocarcinoma, papillary cystadenoma, mesothelioma, granulosa cell tumor, and polycystic sex cord/stromal tumor. However, the low incidence and/or the length of time required for the appearance of tumors in all of these models render them poorly feasible for experimental studies of ovarian carcinogenesis.
Some strains of mice, including C3HeB/Fe and C3HeB/De, show a high incidence of spontaneously occurring granulosa cell tumors and tubular adenomas . Strain HAN:NMRI develop spontaneous Sertoli cell-like tumors and (DBA × Ce)F1 hybrids have a high incidence granulosa cell tumors . Granulosa cell tumors also appear spontaneously at 4–6 weeks of age in SWR/J and in SWR/Bm inbred strain mice, with a maximum incidence reached by 10 weeks . In some SWXJ strains, granulosa cell tumors occur spontaneously, and in others granulosa tumors can only be induced by treatment with dehydroepiandrosterone .
Spontaneous germ cell tumors are less common, but have been reported in LT/Sv and related strains of mice. These mice have a high frequency of spontaneous ovarian teratomas arising from follicular oocytes that undergo parthenogenetic activation. In some strains, this defect appears to be associated with an arrest of the oocytes at metaphase of meiosis I . Teratomas arising from parthenogenetic activation of oocytes also occur in c-mos-deficient oocytes, which fail to maintain meiotic arrest after oocyte maturation [9, 10].
Mice generated to be deficient in the tumor suppressor gene Lats1 exhibit a lack of mammary gland development, infertility and growth retardation. Accompanying these defects are hyperplastic changes in the pituitary and decreased serum hormone levels. The reproductive hormone defects of Lats1-/- mice are reminiscent of isolated LH-hypogonadotropic hypogonadism and corpus luteum insufficiency in humans. Lats1-/- mice develop soft-tissue sarcomas and ovarian stromal cell tumors .
The Ovarian Surface Epithelium
Although ovarian cancer in humans can arise from any of the cell types found in the ovary, almost 90% are derived from the ovarian surface epithelium (OSE) . The OSE covers the entire ovarian surface, and varies morphologically from simple squamous to cuboidal to low pseudostratified columnar [13, 14]. Embryologically derived from the mesodermal epithelium of the gonadal ridges, OSE cells are continuous with the flattened mesothelium of the peritoneum  and are separated from the underlying stromal compartment of the ovary by a basement membrane. Immunohistochemical staining has shown that OSE cells express cytokeratin, desmoplakin, transforming growth factor-α (TGF-α) and receptors for estrogen, progesterone and epidermal growth factor (EGF) [16–20]. Despite their rather unremarkable appearance in vivo, it is believed that OSE cells actively participate in the ovulatory process. Studies in rabbits and sheep have shown that OSE release proteolytic enzymes that degrade the basement membrane and the underlying apical follicular wall, weakening the ovarian surface to the point of rupture . The OSE cells directly over the point of rupture undergo apoptotic cell death before ovulation  and the wound created at the ovulatory site surface is repaired by rapid proliferation of OSE cells from the perimeter of the ruptured follicle . The biology, endocrinology and pathology of the ovarian surface epithelium have recently been reviewed in detail .
Although the ovarian surface is generally smooth in early reproductive life, with aging the ovary becomes more convoluted. Invaginations of the epithelium result in crypts or gland-like structures that can become pinched off to form epithelial inclusion cysts within the underlying stromal compartment . This may occur following the postovulatory proliferation of OSE, follicular attrition, and/or from inflammation caused by carcinogens or chemical irritants like talcum powder . The incidence of inclusion cysts increases with advancing age and are common in postmenopausal women. Although generally benign in nature, these epithelial rearrangements are widely thought to be the potential origin of many epithelial cancers. The more frequent appearance of epithelial invaginations and inclusion cysts in women with hereditary risk of ovarian cancer has strengthened this hypothesis . In addition, some microscopic borderline and malignant tumors have been observed to arise directly within these sites, and they are often associated with dysplasia in similar sites elsewhere in the same or contralateral ovary [28, 29].
Xenografts of OSE Cells Transformed in vitro
OSE cells have been implicated as the cell of origin for the majority of ovarian cancers based primarily on histological and immunohistochemical analyses of patient samples, but several recent experimental models manipulating these cells in vitro have provided additional support for this concept. Primary culture of human OSE was first reported by Auersperg et al. in 1984 , and her group has since developed several in vitro models of ovarian epithelial carcinogenesis. Introduction of Kirsten murine sarcoma virus into rat OSE cells results in endometrioid tumors following subcutaneous or intraperitoneal injection into immunosuppressed rats . Transfection of SV40 T antigen early genes induces immortalization of human OSE cells that delays, but does not prevent, the senescence that normally occurs after a few passages . Introduction of E-cadherin into these T antigen-immortalized cells induces epithelial differentiation  and the cells formed transplantable, invasive adenocarcinomas when injected into SCID mice . In contrast to T antigen-immortalized cells, introduction of the human papilloma virus E6 and E7 genes into human OSE cells results in the spontaneous progression from a benign to invasive phenotype .
Unlike human OSE, rat and mouse OSE do not senesce. Rat OSE cells that have spontaneously immortalized but are not tumorigenic (eg. ROSE 199 cells; ) have been used in a variety of experiments, including some to characterize the cellular features when SV40 T antigen or H-ras is introduced into immortalized cells and following the formation of tumors when these cells are xenografted into nude mice . Repeated subculture of rat and mouse OSE cells to maintain continued proliferation results in spontaneous malignant transformation, as characterized by loss of contact inhibition, substrate-independent growth and the ability to form tumors in nude mice [38, 39]. In a variation of the above in vitro transformation approaches, Orsulic and colleagues used the RCAS retroviral vector to introduce oncogenes into OSE cells from transgenic mice bearing the RCAS receptor TVA and the cells were evaluated for tumorigenicity by injection into immune-deficient or syngeneic animals . The investigators found that p53 deficiency in combination with two oncogenes from among C-MYC, K-RAS or AKT were required to achieve transformation.
While these models allow an evaluation of oncogenes whose activation may contribute to the development of epithelial ovarian cancer, this approach does not allow the investigation of the early events in ovarian tumorigenesis inherent in mice when the tumors arise in situ. However, the establishment of in vitro models of normal and transformed OSE cells has provided the opportunity to use molecular approaches such as microarray or suppression subtractive hybridization to identify differential gene expression patterns that can distinguish normal OSE and ovarian cancer cells [41, 42]. These data will be useful for the elucidation of molecular events associated with OSE cell transformation.
Xenografts of Cancer Cells
Xenograft models, where ovarian cancer cells have been injected either subcutaneously or into the peritoneal cavity have been used extensively for the testing of novel therapeutics or modified regimens for administration of standard chemotherapeutic drugs [43–45]. Some mouse models take advantage of the presence of a bursa, a sac-like structure that envelops rodent ovaries. For decades, researchers have used the intra-bursal space for transplants of xenografted ovaries, or to facilitate direct exposure of the ovary to various factors. For the generation of mouse models of ovarian cancer, the injection of ovarian cancer cells into the intra-bursal space results in tumor formation that can perhaps be viewed as more physiological (Figure 1), as the cancer cells are placed directly in the environment where ovarian tumors normally arise .
Reproductive Factors and Ovarian Tumorigenesis
Unlike most other cancers, the series of events involved in the initiation, progression and metastasis of ovarian cancer is not yet established. It is not clear if malignancies arise from benign or borderline tumors or if they develop de novo from the surface epithelium or inclusion cysts, as there is evidence for both . The incidence of ovarian cancer climbs dramatically in women around the age at which they reach menopause. The reason for this is not clear, but two of the major changes associated with menopause form the foundation for hypotheses regarding the origin of ovarian tumors: 1) the depletion of oocytes or germ cells, which is the underlying cause of menopause, and 2) a significant increase in the pituitary's production of the gonadotropic hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), that arises as a consequence of the reduced follicular estrogen levels. In addition to the loss of germ cells and the associated alterations in hormone levels which normally occur at menopause, there are a number of non-menopausal factors that have been shown to have physiological relevance in epithelial ovarian tumorigenesis, including ovulation. Each of these will be discussed in the context of the animal models that have resulted from the experimental manipulations of these factors.
The "incessant ovulation hypothesis" proposes that continuous ovulation, with its successive rounds of surface rupture and OSE cell mitosis to repair the wound, renders the cells susceptible to malignant transformation . Anecdotal support for this hypothesis comes from the observation that intensive egg-laying domestic hens frequently develop peritoneal carcinomata that is presumably of ovarian origin . Epidemiological studies indicate that circumstances that decrease the number of ovulations, i.e., pregnancy, oral contraceptive usage, duration of lactation and early menopause, all substantially reduce the risk of ovarian cancer [49, 50].
Inherent in the incessant ovulation hypothesis for ovarian cancer risk is the premise that repetitive damage of the OSE at ovulation and/or the subsequent mitotic repair following ovulation increases the risk of developing ovarian cancer. Experimental evidence to support the susceptibility of OSE cells to mutagenic events during mitosis is provided by studies showing that primary cultures of normal rat and mouse OSE cells which have been repeatedly subcultured to maintain continued proliferation acquire features associated with malignant transformation, including loss of contact inhibition, substrate-independent growth and the ability to form tumors in nude mice [38, 39].
The risk generated by incessant ovulation may also be associated with the formation of epithelial cell-lined inclusion cysts that are frequently found in the ovarian stroma of perimenopausal women. As noted above, these inclusion cysts may form as a result of the process of ovulation and the pinching off of deep clefts . In mice, the lifetime total number of ovulations is associated with a marked increase in OSE invagination and stratification , although the incidence of inclusion cysts was more related to age than to number of ovulations. Therefore, unlike in humans, an association between number of ovulations and ovarian cancer risk has not been demonstrated in rodents.
An alternative, but not mutually exclusive, hypothesis for the mechanism of ovarian carcinogenesis proposes that the development of ovarian tumors is related to excessive gonadotropin production associated with the onset of menopause or premature ovarian failure . The median age for epithelial ovarian cancer is 60–65 years, with only 10–15% of the tumors appearing in premenopausal women . Serum FSH and LH levels reach their peak during perimenopausal and postmenopausal years and remain elevated thereafter . High circulating levels of pituitary gonadotropins may increase the risk of ovarian cancer by stimulating the growth of ovarian epithelial cells, since normal human OSE cells and epithelial inclusions have been found to express receptors for FSH  and LH/hCG . Enhanced cell proliferation in response to FSH and/or LH/hCG has been reported for primary cultures of rabbit , mouse  and human  OSE cells. Schiffenbauer and colleagues  found that human epithelial ovarian cancers progressed faster in ovariectomized mice due to elevated FSH and LH levels, which promoted increased vascular endothelial growth factor expression and tumor neovascularization.
The gonadotropin theory of ovarian tumorigenesis suggests that elevated gonadotropin concentrations contribute to the development of ovarian tumors. This theory is based on the initial observation of Biskind and Biskind in 1944  who reported that transplantation of ovaries into the splenic pulp of adult rats led to the development of ovarian tumors. The tumorigenesis was attributed to inactivation of estrogen in the liver, and the consequent elevation of gonadotropin levels due to the lack of steroid feedback on the pituitary. Several transgenic or knockout animal models in which gonadotropin levels are elevated also result in ovarian tumorigenesis. For example, when inhibin, the ovarian protein that inhibits the production of FSH, is made deficient in mice, gonadal stromal tumors arise . Transgenic mice generated to have chronic LH hypersecretion develop granulosa cell tumors or luteomas, depending on the background strain [62, 63]. Mice with disruption of the FSH receptor are acyclic and sterile, with very small, underdeveloped ovaries; they exhibit hypergonadotropic-hypogonadism with high levels of circulating FSH and LH similar to the postmenopausal state in women. By 12 months, more than 92% of these animals developed various kinds of ovarian pathology, including neoplasms of sex cord-stromal type as well as cysts, suggesting that FSH receptor insensitivity in the face of prolonged elevated levels of gonadotropins may be contributing to the development of ovarian granulosa or stromal tumors . None of the animal models with targeted manipulation of gonadotropin secretion or action appear to promote ovarian epithelial tumorigenesis.
In the developing fetal ovary, marked OSE cell proliferation occurs at 16 to 20 weeks of gestation, coincident with the appearance of steroid-producing cells in the ovarian cortex . Adult human OSE cells express receptors for estrogen, progesterone and androgens [66, 67], and human OSE cell proliferation can be stimulated by androgens . In contrast, human OSE cells in culture are reportedly unaffected by estradiol or progesterone , which would suggest that these steroid hormones do not have a significant role in ovarian tumorigenesis. However, a recent study has found that menopausal women who have taken hormone replacement therapy using estrogen only are at an increased risk of ovarian cancer . In animals, continuous exposure to estradiol stimulates sheep OSE cell proliferation , while in guinea pigs and rabbits, it results in the formation of a papillary ovarian surface resembling human serous neoplasms of low malignant potential [71, 72]. The mechanisms by which estrogen may contribute to ovarian cancer risk is unknown, but could be direct action on the OSE cells, or may be indirect, as estrogen reduces GnRH receptor expression in both OSE and ovarian cancer cells, thereby suppressing the growth inhibitory effects of GnRH . Estrogen also modulates levels of hepatocyte growth factor which stimulates OSE cell growth .
A number of studies, largely epidemiological, provide support for the hypothesis that androgens are involved in ovarian carcinogenesis. Over 80% of tumors express AR  and an increased risk of ovarian cancer was found in women with elevated circulating levels of androgens . Testosterone-stimulated growth of OSE cells in guinea pigs caused the formation of benign cysts, small adenomas in the ovarian parenchyma, and papillomas on the ovarian surface . Androgens may promote ovarian tumorigenesis in part by decreasing TGF-β receptor levels, thereby allowing ovarian cancer cells to escape TGF-β growth inhibition .
Germ cell deficiency/depletion
Aging and hereditary risk are associated with a more frequent incidence of epithelial invaginations and inclusion cysts, putative preneoplastic precursor lesions, but the underlying mechanisms for these epithelial-stromal rearrangements are unknown. OSE cell hyperplasia with stromal invasion has been reported in a diverse array of experimental situations, all of them involving loss of germ cells and consequent failure of follicle development. For example, mutations at the W (Kit) or Sl (Kitl) loci result in sterility by preventing the normal proliferation and migration of germ cells during fetal development . Germ cell deficiency in vivo, as is found in Wx/Wvmice, results in bilateral ovarian tubular adenomas in more than 95% of the animals by 5 months of age [80, 81]. The tumors arise from interstitial cell hyperplasia, with proliferation and invasion of the ovarian surface epithelium into the stromal compartment of the ovary. Invasive epithelial tubules are also found in Sl/Sltgerm cell deficient mice by 7 months of age , and mice heterozygous for the Sldmutation, which carries a splicing defect, develop papillary structures and epithelial invaginations (Figure 2), similar to that seen in women . Likewise, female mice homozygous for the germ cell deficient (gcd) mutation enter reproductive senescence prematurely due to a dearth of germ cells. By one year of age, 56% of homozygotes have developed ovarian tubulostromal adenomas while wild-type littermates are phenotypically normal . Therefore, it appears that oocyte depletion is associated with formation of epithelial structures that resemble the preneoplastic lesions in human ovaries.
Experimental ovarian tumorigenesis has been investigated in inbred and hybrid strains of mice and induced by a diversity of mechanisms including X-irradiation, oocytotoxic xenobiotic chemicals, ovarian grafting to ectopic or orthotopic sites, neonatal thymectomy, genetic defects reducing germ cell populations, and aging [reviewed in ]. While germ cell deficiency seems to be a required element for the development of epithelium-derived adenomas, the mechanisms by which germ cell loss contributes to tumorigenesis in these models remain unclear. Ovarian follicles do not develop in the absence of oocytes, indicating that the oocyte directs the development of follicles. Pathogenetic factors that prematurely destroy or diminish the numbers of germ cells lead to failure in follicle development and a resulting decrease in sex steroid hormone secretion (notably estradiol) leading to a compensatory over-production of pituitary gonadotropins, which places the ovary at an increased risk to develop tumors. Therefore oocyte depletion, similar to that which occurs naturally by the time of menopause, may be a contributing factor to the oncogenic behavior of the surface epithelial cells.
The intense proliferation of OSE and stromal (interstitial) cells with the development of unique tubular adenomas in response to sterility seems to require both the lack of germ cells/follicles and the increased production of gonadotropins. Elevated gonadotropins alone resulted in granulosa cell tumors or luteomas [62, 63]. Oocyte destruction by gamma irradiation in hypogonadal mice deficient in gonadotropins did not result in the development of tubular adenomas . Similarly, the experimental suppression of gonadotropin levels in Wx/Wvmice was sufficient to prevent the development of ovarian tubular adenomas from the surface epithelium , suggesting that both oocyte loss/destruction and elevated gonadotropins are necessary for epithelial tumorigenesis.
Although the more established hypotheses that have been proposed to explain increased risk of developing ovarian cancer are related to the number of ovulations or to increased hormone levels, there are additional risk factors that have been identified, including a number of environmental carcinogens. While these factors have been reported to have effects on the ovarian surface epithelium, they are usually also associated with follicular destruction and/or ovotoxicity, so indirect actions due to altered gonadotropin levels cannot be eliminated. Use of perineal talc has been identified as a risk factor, possibly due to its ability to ascend the genital tract and affect the ovarian surface . Indeed, direct exposure of rat ovaries to talc results in focal areas of papillary change in the ovarian surface epithelium, as well as ovarian cysts . Exposure of rhesus and cynomolgus monkeys to the environmental pollutant, hexachlorobenzene results in both reproductive failure and notable alterations in the size, shape and degree of stratification of the OSE cell layer . More recent studies have shown that the insecticide methoxychlor increases both the height of the OSE cell layer and the percentage of atretic follicles in exposed mice . In rodent studies, ovarian toxicity and/or carcinogenicity has been documented for at least eight chemicals that result in follicular necrosis, tubular hyperplasia, granulosa cell tumors and benign mixed tumors [91, 92]. N-ethyl-N-nitrosourea administered to rats intraperitoneally or transplacentally increases the incidence of ovarian tubular adenomas . The mechanisms by which these environmental carcinogens enhance the risk of ovarian tumors remain unexplored.
Transgenics and Targeted Approaches to Transform the Ovarian Epithelium
The ideal model to investigate the pathogenic events associated with early ovarian tumorigenesis would be a mouse model in which the tumor arises directly from the OSE cells. This model would differ from current xenograft models in that transgenic mice with defined genetic lesions could be studied at various stages as they inevitably develop ovarian cancer in situ. In addition, the development of a genetic model would permit the direct testing of oncogenes and tumor suppressors for their contribution to the initiation and progression of overt malignancies in the mouse ovary. Finally, a number of different factors could be altered such as the genetic background of the mouse strain, the frequency of ovulation and the levels of various hormones to determine their impact on the development of tumors in the susceptible transgenic mouse line.
One approach to alter gene expression directly in the OSE cells would be to take advantage of the fact that these cells readily take up and express genes delivered by intra-bursal injection of adenoviruses [94, 95]. This method has the potential advantage of mimicking somatic mutations that contribute to early ovarian tumorigenesis. One recent report used intra-bursal adenovirus delivery and Cre-loxP mediated gene inactivation to render OSE cells deficient in two key tumor suppressor genes: p53 and Rb . The p53 tumor suppressor gene is the most frequently mutated gene in human neoplasms. Mutations and/or over-expression of p53 have been described in 26–62% of ovarian cancers, particularly serous ovarian carcinomas [reviewed in ]. Aberrations in the Rb pathway have been reported ; however, direct evidence for their contribution to ovarian epithelial tumorigenesis is lacking. In this model, recombinant adenovirus expressing Cre was injected under the ovarian bursal membrane of double transgenic mice bearing floxed copies of p53 and Rb. Concurrent inactivation of p53 and Rb was sufficient for reproducible induction of ovarian epithelial carcinogenesis in mice homozygous for the conditional alleles. While less than 15% of mice with inactivation of either Rb or p53 developed tumors, 33 of 34 mice with deficiencies in both genes succumbed to their ovarian cancers at a median of 227 days, with 24% having abdominal ascites.
The major impediment to the development of transgenic models of ovarian cancer is the lack of specific promoters able to direct gene expression to OSE cells. Previous models of ovarian cancer have resulted in granulosa cell tumors using promoters, such as inhibin-alpha subunit promoter, that are active in this cell type to drive the expression of the large T antigen of SV40 [98, 99]. Recent studies have identified two other promoters that may prove to be useful for the generation of transgenic models of ovarian cancer. The Ovarian Specific Promoter (OSP-1) was developed from a retrovirus-like element specifically expressed in the rat ovary. The promoter drives gene expression specifically in normal and neoplastic ovarian epithelial cells  and expression of lacZ driven by OSP-1 in transgenic mice was restricted to the ovary as determined by X-gal staining of multiple organs . Immunohistochemical detection of β-galactosidase showed lacZ expression mainly in the granulosa cells and ovarian surface epithelial cells. However, transgenic mice in which OSP-1 drives the expression of the early region of SV40 virus developed tumors in a variety of tissues, including unilateral granulosa cell tumors in two of three female founder mice. Thus, although transcription from the OSP-1 promoter occurs predominantly in the ovary, this promoter is sufficiently "leaky" in cells in other tissues to permit their tumorigenic conversion by SV40 TAg.
The first transgenic model of epithelial ovarian cancer was recently reported and used the upstream region of the Mullerian inhibitory substance type II receptor (MISIIR) gene to drive tissue-specific expression . MISIIR is a single transmembrane serine/threonine kinase that shares homology with the TGFβ-receptor [103, 104]. Expression of MISIIR has been reported to be restricted to mesenchymal cells surrounding the Mullerian duct during embryogenesis, tubular and follicular structures of fetal gonads, Sertoli and Leydig cells of adult testis, and granulosa cells of adult ovary [103, 105, 106]. More recently, expression of MISIIR in established human ovarian cancer cell lines as well as cell lines derived from the ascites of patients with ovarian carcinomas has been demonstrated . Transgenic mice in which the 5' upstream regulatory sequences of the mouse MISIIR gene were used to target expression of the SV40 TAg specifically to the epithelium of the female mouse reproductive tract, including the OSE, developed ovarian carcinomas with metastatic spread to peritoneal organs by 3 months of age. Female transgenic mice developed bilateral ovarian tumors in ~50% percent of cases. Histologically, these tumors were poorly differentiated carcinomas with occasional cysts and papillary structures present at the surface of the ovary. These tumors disseminated intraperitoneally, invaded the omentum and formed ascites in a manner that resembles human ovarian carcinomas. The demonstration that the MISIIR promoter can be used successfully to drive gynecological tissue-specific transgene expression in mice and that this often results in the formation of ovarian carcinoma offers very promising opportunities for testing the efficacy of chemotherapeutic and chemopreventive agents in a heritable model of epithelial ovarian cancer.
The two most pressing problems in the management of ovarian cancer are the lack of adequate diagnostic or screening strategies, and the recurrence of disease that is often chemoresistant. In part, the deficiency in diagnostic tools is due to the lack of markers for the detection of preneoplastic or early neoplastic changes in the OSE cells. The generation of animal models in which OSE cells undergo neoplastic transformation in vivo will provide much-needed opportunities to investigate the cellular and molecular changes associated with the initiation of OSE cell transformation, as well as to provide models in which prevention, diagnostic, screening and therapeutic strategies can be developed.
Fredrickson TN: Ovarian tumors of the hen. Environ Health Perspect. 1987, 73: 35-51.
Tillmann T, Kamino K, Mohr U: Incidence and spectrum of spontaneous neoplasms in male and female CBA/J mice. Exp Toxicol Pathol. 2000, 52: 221-225.
Walsh KM, Poteracki J: Spontaneous neoplasms in control Wistar rats. Fundam Appl Toxicol. 1994, 22: 65-72. 10.1006/faat.1994.1009.
Gregson RL, Lewis DJ, Abbott DP: Spontaneous ovarian neoplasms of the laboratory rat. Vet Pathol. 1984, 21: 292-299.
Liebelt AG, Sass B, Lombard LS: Mouse ovarian tumors – a review including classification and induction of neoplastic lesions and description of several previously unreported types. J Exp Pathol. 1987, 3: 115-145.
Beamer WG, Hoppe PC, Whitten WK: Spontaneous malignant granulosa cell tumors in ovaries of young SWR mice. Cancer Res. 1985, 45: 5575-5581.
Tennent BJ, Shultz KL, Beamer WG: Genetic susceptibility for C19 androgen induction of ovarian granulosa cell tumorigenesis in SWXJ strains of mice. Cancer Res. 1993, 53: 1059-1063.
Eppig JJ, Wigglesworth K, Varnum DS, Nadeau JH: Genetic regulation of traits essential for spontaneous ovarian teratocarcinogenesis in strain LT/Sv mice: aberrant meiotic cell cycle, oocyte activation, and parthenogenetic development. Cancer Res. 1996, 56: 5047-5054.
Colledge WH, Carlton MB, Udy GB, Evans MJ: Disruption of c-mos causes parthenogenetic development of unfertilized mouse eggs. Nature. 1994, 370: 65-68. 10.1038/370065a0.
Hashimoto N, Watanabe N, Furuta Y, Tamemoto H, Sagata N, Yokoyama M, Okazaki K, Nagayoshi M, Takeda N, Ikawa Y et al.: Parthenogenetic activation of oocytes in c-mos-deficient mice. Nature. 1994, 370: 68-71. 10.1038/370068a0.
St John MA, Tao W, Fei X, Fukumoto R, Carcangiu ML, Brownstein DG, Parlow AF, McGrath J, Xu T: Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nat Genet. 1999, 21: 182-186. 10.1038/5965.
Weiss NS, Homonchuk T, Young JLJ: Incidence of the histologic types of ovarian cancer: the US Third National Cancer Survey, 1969–1971. Gynecol Oncol. 1977, 5: 161-167.
Papadaki L, Beilby JO: The fine structure of the surface epithelium of the human ovary. J Cell Sci. 1971, 8: 445-465.
Blaustein A, Lee H: Surface cells of the ovary and pelvic peritoneum: a histochemical and ultrastructure comparison. Gynecol Oncol. 1979, 8: 34-43.
Moore KL: The pelvis and perineum. In: Clinically oriented anatomy. Edited by: Satterfield TS, Napora L, Lumpkin K. 1992, Baltimore, Williams & Williams, 281-289.
Benjamin E, Law S, Bobrow LG: Intermediate filaments, cytokeratin and vimentin in ovarian sex cord-stromal tumours with correlative studies in adult and fetal ovaries. J Pathol. 1987, 152: 253-263.
Isola J, Kallioniemi OP, Korte JM, Wahlstrom T, Aine R, Helle M, Helin H: Steroid receptors and Ki-67 reactivity in ovarian cancer and in normal ovary: correlation with DNA flow cytometry, biochemical receptor assay, and patient survival. J Pathol. 1990, 162: 295-301.
Czernobilsky B, Moll R, Levy R, Franke WW: Co-expression of cytokeratin and vimentin filaments in mesothelial, granulosa and rete ovarii cells of the human ovary. Eur J Cell Biol. 1985, 37: 175-190.
Jindal SK, Ishii E, Letarte M, Vera S, Teerds K, Dorrington JH: Regulation of transforming growth factor-α gene expression in an ovarian surface epithelial cell line derived from a human carcinoma. Biol Reprod. 1995, 52: 1027-1037.
Rodriguez GC, Berchuck A, Whitaker RS, Schlossman D, Clarke-Pearson DL, Bast RCJ: Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer. II. Relationship between receptor expression and response to epidermal growth factor. Am J Obstet Gynecol. 1991, 164: 745-750.
Bjersing L, Cajander S: Ovulation and the mechanism of follicle rupture. V. Ultrastructure of tunica albuginea and theca externa of rabbit graafian follicles prior to induced ovulation. Cell Tissue Res. 1974, 153: 15-30.
Ackerman RC, Murdoch WJ: Prostaglandin-induced apoptosis of ovarian surface epithelial cells. Prostaglandins. 1993, 45: 475-485. 10.1016/0090-6980(93)90123-O.
Osterholzer HO, Johnson JH, Nicosia SV: An autoradiographic study of rabbit ovarian surface epithelium before and after ovulation. Biol Reprod. 1985, 33: 729-738.
Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC: Ovarian surface epithelium: biology, endocrinology, and pathology. Endocr Rev. 2001, 22: 255-288. 10.1210/er.22.2.255.
Nicosia SV: The aging ovary. Med Clin North Am. 1987, 71: 1-9.
Hamilton TC: Ovarian cancer, Part I: Biology. Curr Probl Cancer. 1992, 16: 1-57.
Salazar H, Godwin AK, Daly MB, Laub PB, Hogan WM, Rosenblum N, Boente MP, Lynch HT, Hamilton TC: Microscopic benign and invasive malignant neoplasms and a cancer-prone phenotype in prophylactic oophorectomies. J Natl Cancer Inst. 1996, 88: 1810-1820.
Deligdisch L, Gil J: Characterization of ovarian dysplasia by interactive morphometry. Cancer. 1989, 63: 748-755.
Scully RE: Early de novo ovarian cancer and cancer developing in benign ovarian lesions. Int J Gynaecol Obstet. 1995, 49 (Suppl): S9-15. 10.1016/0020-7292(95)02404-Z.
Auersperg N, Siemens CH, Myrdal SE: Human ovarian surface epithelium in primary culture. In Vitro. 1984, 20: 743-755.
Adams AT, Auersperg N: Transformation of cultured rat ovarian surface epithelial cells by Kirsten murine sarcoma virus. Cancer Res. 1981, 41: 2063-2072.
Leung EH, Leung PC, Auersperg N: Differentiation and growth potential of human ovarian surface epithelial cells expressing temperature-sensitive SV40 T antigen. In Vitro Cell Dev Biol Anim. 2001, 37: 515-521. 10.1290/1071-2690(2001)037<0515:DAGPOH>2.0.CO;2.
Auersperg N, Pan J, Grove BD, Peterson T, Fisher J, Maines-Bandiera S, Somasiri A, Roskelley CD: E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium. Proc Natl Acad Sci USA. 1999, 96: 6249-6254. 10.1073/pnas.96.11.6249.
Ong A, Maines-Bandiera SL, Roskelley CD, Auersperg N: An ovarian adenocarcinoma line derived from SV40/E-cadherin-transfected normal human ovarian surface epithelium. Int J Cancer. 2000, 85: 430-437. 10.1002/(SICI)1097-0215(20000201)85:3<430::AID-IJC21>3.3.CO;2-H.
Gregoire L, Rabah R, Schmelz EM, Munkarah A, Roberts PC, Lancaster WD: Spontaneous malignant transformation of human ovarian surface epithelial cells in vitro. Clin Cancer Res. 2001, 7: 4280-4287.
Adams AT, Auersperg N: A cell line, ROSE 199, derived from normal rat ovarian surface epithelium. Exp Cell Biol. 1985, 53: 181-188.
Hoffman AG, Burghardt RC, Tilley R, Auersperg N: An in vitro model of ovarian epithelial carcinogenesis: changes in cell-cell communication and adhesion occuring during neoplastic progression. Int J Cancer. 1993, 54: 828-838.
Godwin AK, Testa JR, Handel LM, Liu Z, Vanderveer LA, Tracey PA, Hamilton TC: Spontaneous transformation of rat ovarian surface epithelial cells: association with cytogenetic changes and implications of repeated ovulation in the etiology of ovarian cancer. J Natl Cancer Inst. 1992, 84: 592-601.
Roby KF, Taylor CC, Sweetwood JP, Cheng Y, Pace JL, Tawfik O, Persons DL, Smith PG, Terranova PF: Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogenesis. 2000, 21: 585-591. 10.1093/carcin/21.4.585.
Orsulic S, Li Y, Soslow RA, Vitale-Cross LA, Gutkind JS, Varmus HE: Induction of ovarian cancer by defined multiple genetic changes in a mouse model system. Cancer Cell. 2002, 1: 53-62. 10.1016/S1535-6108(01)00002-2.
Tonin PN, Hudson TJ, Rodier F, Bossolasco M, Lee PD, Novak J, Manderson EN, Provencher D, Mes-Masson AM: Microarray analysis of gene expression mirrors the biology of an ovarian cancer model. Oncogene. 2001, 20: 6617-6626. 10.1038/sj.onc.1204804.
Roberts D, Williams SJ, Cvetkovic D, Weinstein JK, Godwin AK, Johnson SW, Hamilton TC: Decreased expression of retinol-binding proteins is associated with malignant transformation of the ovarian surface epithelium. DNA Cell Biol. 2002, 21: 11-19. 10.1089/10445490252810276.
Ward BG, Wallace K: Localization of the monoclonal antibody HMFG2 after intravenous and intraperitoneal injection into nude mice bearing subcutaneous and intraperitoneal human ovarian cancer xenografts. Cancer Res. 1987, 47: 4714-4718.
Hamilton TC, Young RC, Louie KG, Behrens BC, McKoy WM, Grotzinger KR, Ozols RF: Characterization of a xenograft model of human ovarian carcinoma which produces ascites and intraabdominal carcinomatosis in mice. Cancer Res. 1984, 44: 5286-5290.
Massazza G, Tomasoni A, Lucchini V, Allavena P, Erba E, Colombo N, Mantovani A, D'Incalci M, Mangioni C, Giavazzi R: Intraperitoneal and subcutaneous xenografts of human ovarian carcinoma in nude mice and their potential in experimental therapy. Int J Cancer. 1989, 44: 494-500.
Fu X, Hoffman RM: Human ovarian carcinoma metastatic models constructed in nude mice by orthotopic transplantation of histologically-intact patient specimens. Anticancer Res. 1993, 13: 283-286.
Scully RE, Young RH, Clement PB: Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. 1996, Washington DC, Armed Forces Institute of Pathology
Fathalla MF: Incessant ovulation – a factor in ovarian neoplasia?. Lancet. 1971, 2: 163-
Whittemore AS, Harris R, Itnyre J: Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. IV. The pathogenesis of epithelial ovarian cancer Collaborative Ovarian Cancer Group. Am J Epidemiol. 1992, 136: 1212-1220.
La Vecchia C, Franceschi S: Oral contraceptives and ovarian cancer. Eur J Cancer Prev. 1999, 8: 297-304.
Clow OL, Hurst PR, Fleming JS: Changes in the mouse ovarian surface epithelium with age and ovulation number. Mol Cell Endocrinol. 2002, 191: 105-111. 10.1016/S0303-7207(02)00061-8.
Cramer DW, Welch WR: Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis. J Natl Cancer Inst. 1983, 71: 717-721.
Sell A, Bertelsen K, Andersen JE, Stroyer I, Panduro J: Randomized study of whole-abdomen irradiation versus pelvic irradiation plus cyclophosphamide in treatment of early ovarian cancer. Gynecol Oncol. 1990, 37: 367-373.
Chakravarti S, Collins WP, Forecast JD, Newton JR, Oram DH, Studd JW: Hormonal profiles after the menopause. Br Med J. 1976, 2: 784-787.
Zheng WX, Magid MS, Kramer EE, Chen YT: Follicle-stimulating hormone receptor is expressed in human ovarian surface epithelium and fallopian tube. Am J Pathol. 1996, 148: 47-53.
Konishi I, Kuroda H, Mandai M: Review: gonadotropins and development of ovarian cancer. Oncology. 1999, 57 (Suppl 2): 45-48. 10.1159/000055274.
Osterholzer HO, Streibel EJ, Nicosia SV: Growth effects of protein hormones on cultured rabbit ovarian surface epithelial cells. Biol Reprod. 1985, 33: 247-258.
Davies BR, Finnigan DS, Smith SK, Ponder BA: Administration of gonadotropins stimulates proliferation of normal mouse ovarian surface epithelium. Gynecol Endocrinol. 1999, 13: 75-81.
Schiffenbauer YS, Abramovitch R, Meir G, Nevo N, Holzinger M, Itin A, Keshet E, Neeman M: Loss of ovarian function promotes angiogenesis in human ovarian carcinoma. Proc Natl Acad Sci U S A. 1997, 94: 13203-13208. 10.1073/pnas.94.24.13203.
Biskind MS, Biskind GS: Development of tumors in the rat ovary after transplantation into the spleen. Proc Soc Exp Biol Med. 1944, 55: 176-179.
Matzuk MM, Finegold MJ, Su JG, Hsueh AJ, Bradley A: Alpha-inhibin is a tumor-suppressor gene with gonadal specificity in mice. Nature. 1992, 360: 313-319. 10.1038/360313a0.
Nilson JH, Abbud RA, Keri RA, Quirk CC: Chronic hypersecretion of luteinizing hormone in transgenic mice disrupts both ovarian and pituitary function, with some effects modified by the genetic background. Recent Prog Horm Res. 2000, 55: 69-89.
Keri RA, Lozada KL, Abdul-Karim FW, Nadeau JH, Nilson JH: Luteinizing hormone induction of ovarian tumors: oligogenic differences between mouse strains dictates tumor disposition. Proc Natl Acad Sci USA. 2000, 97: 383-387. 10.1073/pnas.97.1.383.
Danilovich N, Roy I, Sairam MR: Ovarian pathology and high incidence of sex cord tumors in follitropin receptor knockout (FORKO) mice. Endocrinology. 2001, 142: 3673-3684. 10.1210/en.142.8.3673.
Gondos B: Surface epithelium of the developing ovary. Possible correlation with ovarian neoplasia. Am J Pathol. 1975, 81: 303-321.
Karlan BY, Jones J, Greenwald M, Lagasse LD: Steroid hormone effects on the proliferation of human ovarian surface epithelium in vitro. Am J Obstet Gynecol. 1995, 173: 97-104.
Lau KM, Mok SC, Ho SM: Expression of human estrogen receptor-alpha and -beta, progesterone receptor, and androgen receptor mRNA in normal and malignant ovarian epithelial cells. Proc Natl Acad Sci USA. 1999, 96: 5722-5727. 10.1073/pnas.96.10.5722.
Hamilton TC, Davies P, Criffiths K: Steroid hormone receptor status of the normal and neoplastic ovarian surface germinal epithelium. In Factors regulating ovarian function. Edited by: Greenwald GS, Terranova PF. 1983, New York, Raven Press, 81-85.
Lacey JV Jr, Mink PJ, Lubin JH, Sherman ME, Troisi R, Hartge P, Schatzkin A, Schairer C: Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA. 2002, 288: 334-341.
Murdoch WJ, Van Kirk EA: Steroid hormonal regulation of proliferative, p53 tumor suppressor, and apoptotic responses of sheep ovarian surface epithelial cells. Mol Cell Endocrinol. 2002, 186: 61-67. 10.1016/S0303-7207(01)00675-X.
Silva EG, Tornos C, Deavers M, Kaisman K, Gray K, Gershenson D: Induction of epithelial neoplasms in the ovaries of guinea pigs by estrogenic stimulation. Gynecol Oncol. 1998, 71: 240-246. 10.1006/gyno.1998.5153.
Bai W, Oliveros-Saunders B, Wang Q, Acevedo-Duncan ME, Nicosia SV: Estrogen stimulation of ovarian surface epithelial cell proliferation. In Vitro Cell Dev Biol Anim. 2000, 36: 657-666. 10.1290/1071-2690(2000)036<0657:ESOOSE>2.0.CO;2.
Kang SK, Choi KC, Tai CJ, Auersperg N, Leung PC: Estradiol regulates gonadotropin-releasing hormone (GnRH) and its receptor gene expression and antagonizes the growth inhibitory effects of GnRH in human ovarian surface epithelial and ovarian cancer cells. Endocrinology. 2001, 142: 580-588. 10.1210/en.142.2.580.
Liu Y, Lin L, Zarnegar R: Modulation of hepatocyte growth factor gene expression by estrogen in mouse ovary. Mol Cell Endocrinol. 1994, 104: 173-181. 10.1016/0303-7207(94)90120-1.
Ilekis JV, Connor JP, Prins GS, Ferrer K, Niederberger C, Scoccia B: Expression of epidermal growth factor and androgen receptors in ovarian cancer. Gynecol Oncol. 1997, 66: 250-254. 10.1006/gyno.1997.4764.
Helzlsouer KJ, Alberg AJ, Gordon GB, Longcope C, Bush TL, Hoffman SC, Comstock GW: Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA. 1995, 274: 1926-1930. 10.1001/jama.274.24.1926.
Silva EG, Tornos C, Fritsche HAJ, el-Naggar A, Gray K, Ordonez NG, Luna M, Gershenson D: The induction of benign epithelial neoplasms of the ovaries of guinea pigs by testosterone stimulation: a potential animal model. Mod Pathol. 1997, 10: 879-883.
Evangelou A, Jindal SK, Brown TJ, Letarte M: Down-regulation of transforming growth factor beta receptors by androgen in ovarian cancer cells. Cancer Res. 2000, 60: 929-935.
Mintz B, Russell ES: Gene-induced embryological modifications of primordial germ cells in the mouse. J Exp Zool. 1957, 134: 207-237.
Murphy ED: Hyperplastic and early neoplastic changes in the ovaries of mice after genic deletion of germ cells. J Natl Cancer Inst. 1972, 48: 1283-1295.
Murphy ED, Beamer WG: Plasma gonadotropin levels during early stages of ovarian tumorigenesis in mice of the Wx/Wv genotype. Cancer Res. 1973, 33: 721-723.
Ishimura K, Matsuda H, Tatsumi H, Fujita H, Terada N, Kitamura Y: Ultrastructural changes in the ovaries of Sl/Slt mutant mice, showing developmental deficiency of follicles and tubular adenomas. Arch Histol Jpn. 1986, 49: 379-389.
Duncan MK, Chada KK: Incidence of tubulostromal adenoma of the ovary in aged germ cell-deficient mice. J Comp Pathol. 1993, 109: 13-19.
Capen CC, Beamer WG, Tennent BJ, Stitzel KA: Mechanisms of hormone-mediated carcinogenesis of the ovary in mice. Mutat Res. 1995, 333: 143-151. 10.1016/0027-5107(95)00140-9.
Tennent BJ, Beamer WG: Ovarian tumors not induced by irradiation and gonadotropins in hypogonadal (hpg) mice. Biol Reprod. 1986, 34: 751-760.
Blaakaer J, Baeksted M, Micic S, Albrectsen P, Rygaard J, Bock J: Gonadotropin-releasing hormone agonist suppression of ovarian tumorigenesis in mice of the Wx/Wv genotype. Biol Reprod. 1995, 53: 775-779.
Gertig DM, Hunter DJ, Cramer DW, Colditz GA, Speizer FE, Willett WC, Hankinson SE: Prospective study of talc use and ovarian cancer. J Natl Cancer Inst. 2000, 92: 249-252. 10.1093/jnci/92.3.249.
Hamilton TC, Fox H, Buckley CH, Henderson WJ, Griffiths K: Effects of talc on the rat ovary. Br J Exp Pathol. 1984, 65: 101-106.
Sims DE, Singh A, Donald A, Jarrell J, Villeneuve DC: Alteration of primate ovary surface epithelium by exposure to hexachlorobenzene: a quantitative study. Histol Histopathol. 1991, 6: 525-529.
Borgeest C, Symonds D, Mayer LP, Hoyer PB, Flaws JA: Methoxychlor may cause ovarian follicular atresia and proliferation of the ovarian epithelium in the mouse. Toxicol Sci. 2002, 68: 473-478. 10.1093/toxsci/68.2.473.
Maronpot RR: Ovarian toxicity and carcinogenicity in eight recent National Toxicology Program studies. Environ Health Perspect. 1987, 73: 125-130.
Collins JJ, Montali RJ, Manus AG: Toxicological evaluation of 4-vinylcyclohexene. II. Induction of ovarian tumors in female B6C3F1 mice by chronic oral administration of 4-vinylcyclohexene. J Toxicol Environ Health. 1987, 21: 507-524.
Stoica G, Koestner A, Capen CC: Testicular (Sertoli's cell)-like tumors of the ovary induced by N-ethyl-N-nitrosourea (ENU) in rats. Vet Pathol. 1985, 22: 483-491.
Vanderhyden BC, Shaw TJ, Garson K, Tonary AM: Ovarian Carcinogenesis. In: The Ovary. Edited by: Leung PCK, Adashi EY. 2003, San Diego, Elsevier Science
Flesken-Nikitin A, Choi K-C, Eng JP, Shmidt EN, Nikitin AY: Induction of carcinogenesis by concurrent inactivation of p53 and Rb1 in the mouse ovarian surface epithelium. Cancer Res. 2003
Aunoble B, Sanches R, Didier E, Bignon Y-J: Major oncogenes and tumor suppressor genes involved in epithelial ovarian cancer. Int J Oncol. 2000, 16: 567-576.
Gras E, Pons C, Machin P, Matias-Guiu X, Prat J: Loss of heterozygosity at the RB-1 locus and pRB immunostaining in epithelial ovarian tumors: a molecular, immunohistochemical, and clinicopathologic study. Int J Gynecol Pathol. 2001, 20: 335-340. 10.1097/00004347-200110000-00004.
Kananen K, Markkula M, Rainio E, Su JG, Hsueh AJ, Huhtaniemi IT: Gonadal tumorigenesis in transgenic mice bearing the mouse inhibin alpha-subunit promoter/simian virus T-antigen fusion gene: characterization of ovarian tumors and establishment of gonadotropin-responsive granulosa cell lines. Mol Endocrinol. 1995, 9: 616-627. 10.1210/me.9.5.616.
Dutertre M, Gouedard L, Xavier F, Long WQ, di Clemente N, Picard JY, Rey R: Ovarian granulosa cell tumors express a functional membrane receptor for anti-Mullerian hormone in transgenic mice. Endocrinology. 2001, 142: 4040-4046. 10.1210/en.142.9.4040.
Selvakumaran M, Bao R, Crijns AP, Connolly DC, Weinstein JK, Hamilton TC: Ovarian epithelial cell lineage-specific gene expression using the promoter of a retrovirus-like element. Cancer Res. 2001, 61: 1291-1295.
Garson K, Macdonald E, Dube M, Bao R, Hamilton TC, Vanderhyden BC: Generation of tumors in transgenic mice expressing the SV40 T antigen under the control of ovarian-specific promoter 1. J Soc Gynecol Investig. 2003, 10: 244-250. 10.1016/S1071-5576(03)00073-X.
Connolly DC, Bao R, Nikitin AY, Stephens KC, Poole TW, Hua X, Harris SS, Vanderhyden BC, Hamilton TC: Female mice chimeric for expression of the simian virus 40 TAg under control of the MISIIR promoter develop epithelial ovarian cancer. Cancer Res. 2003, 63: 1389-1397.
di Clemente N, Wilson C, Faure E, Boussin L, Carmillo P, Tizard R, Picard JY, Vigier B, Josso N, Cate R: Cloning, expression, and alternative splicing of the receptor for anti-Mullerian hormone. Mol Endocrinol. 1994, 8: 1006-1020. 10.1210/me.8.8.1006.
Baarends WM, Uilenbroek JT, Kramer P, Hoogerbrugge JW, van Leeuwen EC, Themmen AP, Grootegoed JA: Anti-mullerian hormone and anti-mullerian hormone type II receptor messenger ribonucleic acid expression in rat ovaries during postnatal development, the estrous cycle, and gonadotropin-induced follicle growth. Endocrinology. 1995, 136: 4951-4962. 10.1210/en.136.11.4951.
Baarends WM, van Helmond MJ, Post M, van der Schoot PJ, Hoogerbrugge JW, de Winter JP, Uilenbroek JT, Karels B, Wilming LG, Meijers JH et al.: A novel member of the transmembrane serine/threonine kinase receptor family is specifically expressed in the gonads and in mesenchymal cells adjacent to the mullerian duct. Development. 1994, 120: 189-197.
Teixeira J, He WW, Shah PC, Morikawa N, Lee MM, Catlin EA, Hudson PL, Wing J, Maclaughlin DT, Donahoe PK: Developmental expression of a candidate mullerian inhibiting substance type II receptor. Endocrinology. 1996, 137: 160-165. 10.1210/en.137.1.160.
Masiakos PT, MacLaughlin DT, Maheswaran S, Teixeira J, Fuller AF Jr, Shah PC, Kehas DJ, Kenneally MK, Dombkowski DM, Ha TU, Preffer FI, Donahoe PK: Human ovarian cancer, cell lines, and primary ascites cells express the human Mullerian inhibiting substance (MIS) type II receptor, bind, and are responsive to MIS. Clin Cancer Res. 1999, 5: 3488-3499.
The authors wish to thank Dr. Ken Garson for critical review of this manuscript and Dr. Thomas Hamilton, Fox Chase Cancer Center, for providing the photograph showing human papillomatosis. Research was supported by grants from the National Cancer Institute of Canada (BCV) and the National Institutes of Health (BCV; Dr. Thomas Hamilton, Principal Investigator), a scholarship from the Canadian Institutes of Health Research (TJS) and a fellowship from a partnership of the Mitchell Family Fund, the National Ovarian Cancer Association and Cancer Care Ontario (JFE).
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Vanderhyden, B.C., Shaw, T.J. & Ethier, J. Animal models of ovarian cancer. Reprod Biol Endocrinol 1, 67 (2003). https://doi.org/10.1186/1477-7827-1-67
- Ovarian Cancer
- Epithelial Ovarian Cancer
- Ovarian Surface Epithelium
- Ovarian Cancer Risk
- Granulosa Cell Tumor