Ovarian surface epithelium (OSE) cells, derived from mesodermal epithelium of gonadal ridges, are flattened mesothelium of peritoneum separated from underneath ovarian stroma by a basement membrane and a connective tissue layer, tunica albuginea (Leung & Choi, 2007). OSE occupies the entire ovarian lining and varies in morphology from simple squamous to cuboidal to low pseudostratified columnar. OSE participates in transporting and exchanging nutrients and other bioactive metabolites from the peritoneal cavity and ovary.
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Despite their inconspicuous appearance, OSE actively participates in the ovulatory cycle. Studies in rabbits and sheep have revealed that OSE produces proteolytic enzymes that degrade the basement membrane and apical follicular wall thereby softening the ovarian surface and facilitating ovulation. At pre-ovulation, OSE in proximity to the rupture site undergoes apoptotic cell death, and the wound caused by ovulation is repaired by highly proliferating OSE cells from the surroundings of the ruptured follicle. OSE cell proliferation also occurs at the post-ovulatory phase especially in a post-menopausal woman when due to aging of the ovary; the epithelial line invaginates, producing crypts and glands, which eventually develop into cysts within the stromal compartment.
Although mostly benign, these cysts can turn malignant and initiate epithelial cancerous growth. Approximately 90% of human ovarian cancer origin from OSE, whereas follicular granulosa cells (GC’s), stroma, or germ cells account for the rest of the incidences (Vanderhyden, Shaw & Ethier, 2003). Epithelial ovarian cancer is the fourth most common cancer in females around the world and the most lethal gynecological malignancy. It has been hypothesized that repeated cycles of ovulation-induced trauma and repair of the OSE at the site of ovulation contribute to malignancy. A host of tumorigenesis factors, viz. cytokeratin, desmoplakin, transforming growth factor-α (TGF-α) and receptors for estrogen, progesterone and epidermal growth factor (EGF) are expressed by OSE.
The “incessant ovulation hypothesis” proposes that repeated ovulations and concomitant ovarian surface rupture and OSE mitosis to heal the wound, makes the OSE susceptible to mitogenic factors and other genotoxic radicals. It is well known that pregnancy and use of oral contraceptives can reduce the risk of epithelial ovarian cancer (EOC) development. Additionally, it has been reported that EOC is absent in animal species where seasonal ovulation and multiple pregnancies take place. Suppression of ovulation and steroid production by the pre-ovulatory follicles are the main significant alteration that occurs within the ovary during pregnancy.
Although pregnancy is proposed as protective factor against ovarian cancer, the mechanism by which it may enhance this effect is not elucidated. Rodent’s isolated OSE cells, continuously maintained in proliferative conditions, after several rounds of subcultures acquired malignant features including loss of contact inhibition, substrate-independent growth and the ability to form tumors in nude mice. Suitable animal models in which OSE undergoes in vivo transformation to neoplastic state would be highly useful for investigating cellular changes attributed to this phenomenon, as well as for developing diagnostic, preventive and even curative measures.
According to Fortune (1994) senescent ovary, like the one during pregnancy or postnatal period, maintains oocytes in “resting” or primordial follicles. Growing follicles either ovulate to release oocytes for fertilization, or degenerate through into atretia. Differentiated follicles also provide steroidal hormones to maintain the ovarian cycle and prepare uterus for implant, and CL produces hormones for establishing and maintaining pregnancy. Gondotropins and estrogens are vital for maintaining ovarian cycle until antral stage just before ovulation. Early follicular growth and development occur readily in the presence of normal basal concentrations of gonadotropins.
In cycling mammals upon reaching 8-9 GC stage the primordial follicles start to grow to large antral follicles in two different patterns – in rats, primates and pigs, in follicular phase only one follicle grows and others in cohort regress, and in cattle, sheep and horses, a wave of 3-6 follicles continue to grow in follicular as well as luteal phases and one of them slightly larger than others continues to grow while the other subordinate follicles regress. Recent evidences suggest that FSH in combination with TGF-β1 mediates follicular progression and associated proliferative activities in GC’s beyond primary and preantral stages, and this involves an increase in apoptosis and suppression of subordinate follicle development (Findlay et al. 2009).
In this study, we have examined proliferative activity of OSE and granulosa cells of the ovarian follicles by immunohistochemistry (IHC) of proliferating cell nuclear antigen (PCNA) and Ki67 proteins, which is a standard method for detecting proliferating cells in tissue sections. Additionally, a histomorphological study was done to identify the stages of follicular development at different phases of the reproductive cycle, including the quiescence phases (anoestrous and pregnancy).
We have selected sheep as in vivo model for two reasons: a) sheep is a mono-ovular and seasonally polyoestrous animal, with ewes being short-day breeders. Ovulatory cycles in most sheep breeds in the northern hemisphere, occur in a regular pattern between autumn and winter with oestrous cycle that ranges in length from 14 to 18 days. Ewes exhibit an anoestrous phase that starts from the end of spring until the start of summer, and b) as research material more than one differentiated follicles of the intermediate stages like primary, preantral and antral follicles can be obtained in estrous phase, which is not possible in case of human ovaries.
Findlay, J.K., Kerr, J.B., Britt, K., Liew, S.H. Simpson, E.R. Rosairo, D. & Drummond, A. (2009). Ovarian physiology: follicle development, oocyte and hormone relationships. Animal Reproduction, 6(1), 16-19.
Fortune, J.E. (1994). Ovarian Follicular Growth and Development in Mammals. Biology of Reproduction, 50, 225-232.
Leung, P.C.K. & Choi, J-H. (2007). Endocrine signaling in ovarian surface epithelium and cancer. Human Reproduction Update, 13(2), 143–162.
Vanderhyden, B.C., Shaw, T.J. & Ethier, J.F. (2003). Animal models of ovarian cancer. Reproductive Biology and Endocrinology, 1:67. Web.