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Influences of endocrine and autocrine factors in normal and neoplastic ovarian surface epithelium

University of British Columbia

The common epithelial ovarian tumors appear to arise from the ovarian surface epithelium (OSE), which is a simple squamous-to-cuboidal meso^helium covering the ovary. The exact mechanism of ovarian tumorigenesis is not well known even though this disease is the most frequent cause of cancer death in gynecological malignancies. Repeated ovulation contributes to neoplastic transformation of OSE, indicating that the process of healing ruptured OSE may contribute to the disease. Therefore, it has been hypothesized that endocrine and autocrine factors may influence the occurrence of ovarian tumors in women. Recently, non-tumorigenic and tumorigenic immortalized OSE (IOSE) cells were generated by sequentially introducing simian virus 40 (SV40)-large T antigen (IOSE-29) and E-cadherin (IOSE-29EC) into normal OSE. These IOSE-29EC cells were found to be anchorage independent and formed transplantable, invasive subcutaneous and intraperitoneal adenocarcinomas in SCID mice. Thus, two additional cell lines, designated IOSE-29EC/T4 and IOSE-29EC/T5 were established from tumors that arose in IOSE-29EC-inoculated SCID mice. This experimental culture model provides a unique system to examine the influences of endocrine and autocrine factors in OSE at progressive stages of neoplastic transformation. In the present study, the effects of activin, transforming growth factor (TGF)-(3, estradiol (E2), follicle-stimulating hormone (FSFf) and gonadotropin-releasing hormone-II (GnRH-II) were investigated in the growth-stimulation or -inhibition and regulation of apoptosis in normal and neoplastic OSE cells. Different levels of activin/inhibin and activin receptor isoforms were expressed in normal and neoplastic OSE cells. In addition, the altered expression of the activin/inhibin subunits, as well as the cell proliferative effect of activin observed in OVCAR-3 but not in normal OSE cells, indicate that activin may act as an autocrine regulator of neoplastic OSE progression. Interestingly, activin and TGF-(3 inhibited growth and induced apoptosis in early neoplastic (IOSE-29) and tumorigenic OSE (IOSE-29EC) cells. Furthermore, the antiapoptotic bcl-2 protein was down-regulated by TGF-p\ whereas no difference was observed in bax protein by activin or TGF-(3 treatment and in bcl-2 protein by activin. These results suggest that activin and TGF-P may play a role in growth inhibition and induction of apoptosis in early neoplastic and tumorigenic stages of ovarian cancer. In terms of regulation of apoptosis by E2, it has been demonstrated that IOSE cell lines expressed both ERoc and ERp at the mRNA and protein levels. In addition, treatment with E2 prevented tamoxifen induced-apoptosis through ERs. The mechanism of E2 action may be associated with up-regulation of bcl-2 gene at the mRNA and protein levels in IOSE-29EC cells. These results suggest that estrogen may play a role in ovarian tumorigenesis by preventing apoptosis in tumorigenic OSE cells. In addition, FSH receptor (FSH-R) was expressed and FSH induced a growth-stimulation in normal and neoplastic OSE cells. Interestingly, FSH stimulated the activation of the MAPK cascade and activated MAPK phosphorylated Elk-1 in neoplastic OSE cells. These results suggest that the MAPK cascade may be involved in cellular function such as growth stimulation in response to FSH in neoplastic OSE cells. GnRH-II mRNA is expressed in normal OSE, immortalized OSE (IOSE), ovarian tumors from the patients and ovarian cancer cell lines, suggesting that GnRH-II Q 7 exerts an autocrine/paracrine effect in these cells. Treatments with increasing doses (10" - 10" M) of GnRH-I and -II resulted in growth-inhibition and induction of apoptosis in IOSE-29 and IOSE-29EC cells. These results suggest that GnRH-II may be an integral regulator similar to GnRH-I in normal OSE physiology and may play a role in the induction of a growth-inhibitory response in neoplastic OSE cells. Taken together, these results suggest that these endocrine and autocrine factors may play a role in ovarian tumorigenesis in the regulation of growthstimulation or -inhibition and/or apoptosis of normal and neoplastic OSE cells via their specific receptors.

Thesis/Dissertation

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2009-10-07

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http://hdl.handle.net/2429/13688

Reproductive and Developmental Sciences

University of British Columbia

UBCV

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