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Key Event Title
Promotion, Ovarian Cancer
|Level of Biological Organization|
|female reproductive organ|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Hypothalamic estrogen receptors inhibition leading to ovarian cancer||AdverseOutcome||Cataia Ives (send email)||Under development: Not open for comment. Do not cite||Under Development|
Key Event Description
Biological state: Ovarian cancer is fatal gynecological malignancy and ranked as fifth most commonly diagnosed cancer among women. Generally, mortality rate is highest (~ 50 %) from this cancer as there is lack of proper diagnosis at early stage(Siegel et al. 2019). Ovarian cancers are broadly categorised into three types based on origin of cells namely epithelial, stromal and germ cell cancers (Gilks and Prat 2009). Recent research efforts revealed that numbers of molecular level (genome, transcriptome and proteome level) perturbations are responsible for the development and progression of ovarian cancer (Cheng and Zhan 2017). There is need to develop a molecular level biomarker for early detection, treatment and development of personalized medicine. Understanding of molecular level interactions in large and complex biological networks using systems biology approach will be key factors to identify the major regulatory motifs (Zhang et al. 2018). This approach not only reduces the animal experiments substantially, but will able to quick detect of key perturbations
Biological compartments: Recent studies have suggested that FSH stimulates the proliferation and invasion of ovarian cancer cells, inhibits apoptosis and facilitates neovascularisation (Tao et al. 2013). Earlier studies also have established that the estrogen (ER) and progesterone (PR) receptors are important prognostic indicators of breast and endometrial cancers, and epithelial ovarian cancer. Despite acceptance regarding the influence of reproductive hormones on ovarian cancer risk and considerable advances in the understanding of epithelial ovarian carcinogenesis on a molecular level, complete understanding of the biologic processes underlying malignant transformation of ovarian surface epithelium is still lacking (Gharwan et al. 2015).
General role in biology: Malfunctioning of sex hormones (e.g., estradiol, estrone and progesterone) may result ovarian cancer (Fooladi et al. 2020, Meehan and Sadar 2003). Exposure to endocrine-disrupting chemicals (EDCs) in the form of occupational usage of pesticides, fungicides, herbicides, plasticizers, cosmetics, etc. are the cause of ovarian cancer (Samtani et al. 2018). Clomiphene which is used as drug to treat infertility and it is reported that this chemical increases the risk of ovarian cancer (McLemore et al. 2009). Clomiphene (molecular initiating event, MIE) stimulates the releasing of gonadotropin-releasing hormone (GnRH) from hypothalamic. Also, it stimulates the secretion of the Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from pituitary (Cassidenti et al. 1992, Mungenast and Thalhammer 2014, Tomao et al. 2014). These hormones regulate the synthesis of sex hormons (e.g., estrogen) level (Shoemaker et al. 2010, Tomao et al. 2014). These sex hormones are primarily produced in the gonads through a series of enzyme-mediated reactions from cholesterol (precursor) and control through complex signalling pathway along hypothalamus – pituitary - gonadal (HPG) axis (Perkins et al. 2019, Shoemaker et al. 2010). The series of complex signalling pathways in ovary include G-protein cycle, G-protein activation, adenylate cyclase (AC) activation, cyclic AMP (cAMP) activation, protein kinase A (PKA) activation, steroidogenic factor 1 (SF1) and StAR transcription. Ultimately, this signalling pathway activates the StAR protein which regulates the intake of cholesterol into the inner mitochondria where synthesis of sex hormones takes place. It may be noted that cholesterol is the precursor of the sex hormones synthesis. Again, releasing of LH is regulated by estradiol and testosterone level resulting complex signalling pathway that includes genes, transcritome, proteome and metabolites (Perkins et al. 2019, Shoemaker et al. 2010). Under clomiphene exposure, synthesis of estrogen level becomes high resulting risk of ovarian cancer (McLemore et al. 2009, Tomao et al. 2014). Therefore, perturbations of GnRH, FSH and LH can result adverse phenotype as ovarian cancer.
How It Is Measured or Detected
Gossmann et al., had shown the effects of angiogenesis inhibition on tumor microvascular permeability was monitored with the help of magnetic resonance imaging (MRI) technique in a rat model of human ovarian cancer (Gossmann et al. 2000).
Gitsch et al., had developed gamma-ray detection probe for overcoming the conventional radio-immunoscintigraphy problems for the detection of ovarian cancer in female patients (Gitsch and Pateisky 1989).
Kim et al., had used the detection of magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) for the detection of ovarian tumor in human patient. Sensitivity and accuracy of the PET/CT technique for detecting the ovarian tumor was reported 73% and 91%. Whereas, the sensitivity and accuracy of the MRI technique was reported 81% and 89% (Kim et al. 2007).
Harrington et al., had used immunotechniques (Anti-CDCP1 immuno-conjugates) for detection of the ovarian cancer. Expression and binding properties of the cell surface protein was detected in ovarian cancer cell (in vitro) using flow cytometry and western blot technique (Harrington et al.).
Domain of Applicability
It is applicable in ovary for reproductive matured female.
Regulatory Significance of the Adverse Outcome
Informations related with ovarian cancer will be helpful for the regulatory authorities to develop monographs, frame the rules of assesments and monitoring of the process.
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Cheng, T. and Zhan, X. (2017) Pattern recognition for predictive, preventive, and personalized medicine in cancer. EPMA J 8(1), 51-60.
Fooladi, S., Akbari, H., Abolhassani, M., Sadeghi, E. and Fallah, H. (2020) Estradiol, des-acylated, and total ghrelin levels might be associated with epithelial ovarian cancer in postmenopausal women. medRxiv.
Gharwan, H., Bunch, K.P. and Annunziata, C.M. (2015) The role of reproductive hormones in epithelial ovarian carcinogenesis. Endocr Relat Cancer 22(6), R339-363.
Gilks, C.B. and Prat, J. (2009) Ovarian carcinoma pathology and genetics: recent advances. Hum Pathol 40(9), 1213-1223.
Gitsch, E. and Pateisky, N. (1989) Radio-immunoscintigraphy and intraoperative tumour detection by means of anti-tumour antibodies in patients with ovarian cancer. Baillieres Clin Obstet Gynaecol 3(1), 31-36.
Gossmann, A., Helbich, T.H., Mesiano, S., Shames, D.M., Wendland, M.F., Roberts, T.P., Ferrara, N., Jaffe, R.B. and Brasch, R.C. (2000) Magnetic resonance imaging in an experimental model of human ovarian cancer demonstrating altered microvascular permeability after inhibition of vascular endothelial growth factor. Am J Obstet Gynecol 183(4), 956-963.
Harrington, B.S., He, Y., Khan, T., Puttick, S., Conroy, P.J., Kryza, T., Cuda, T., Sokolowski, K.A., Tse, B.W., Robbins, K.K., Arachchige, B.J., Stehbens, S.J., Pollock, P.M., Reed, S., Weroha, S.J., Haluska, P., Salomon, C., Lourie, R., Perrin, L.C., Law, R.H.P., Whisstock, J.C. and Hooper, J.D. Anti-CDCP1 immuno-conjugates for detection and inhibition of ovarian cancer. Theranostics 10(5), 2095-2114.
Hollis, R.L.J.C.L. (2023) Molecular characteristics and clinical behaviour of epithelial ovarian cancers. 216057.
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Kim, C.K., Park, B.K., Choi, J.Y., Kim, B.G. and Han, H. (2007) Detection of recurrent ovarian cancer at MRI: comparison with integrated PET/CT. J Comput Assist Tomogr 31(6), 868-875.
Liu, Y., Lin, X., Bao, T., Ni, P., Xie, C., Shen, H., Xu, W., Xu, H. and Su, Z. (2015) [Detection and correlation analysis of miRNAs and myeloid-derived suppressor cells in ovarian cancer-bearing mice]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 31(4), 467-469, 473.
McLemore, M.R., Miaskowski, C., Aouizerat, B.E., Chen, L.M. and Dodd, M.J. (2009) Epidemiological and genetic factors associated with ovarian cancer. Cancer Nurs 32(4), 281-288; quiz 289-290.
Meehan, K.L. and Sadar, M.D. (2003) Androgens and androgen receptor in prostate and ovarian malignancies. Front Biosci 8, d780-800.
Mortlock, S., Corona, R.I., Kho, P.F., Pharoah, P., Seo, J.-H., Freedman, M.L., Gayther, S.A., Siedhoff, M.T., Rogers, P.A. and Leuchter, R.J.C.R.M. (2022) A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes. 3(3), 100542.
Mungenast, F. and Thalhammer, T. (2014) Estrogen biosynthesis and action in ovarian cancer. Front Endocrinol (Lausanne) 5, 192.
Perkins, E.J., Gayen, K., Shoemaker, J.E., Antczak, P., Burgoon, L., Falciani, F., Gutsell, S., Hodges, G., Kienzler, A., Knapen, D., McBride, M., Willett, C., Doyle, F.J. and Garcia-Reyero, N. (2019) Chemical hazard prediction and hypothesis testing using quantitative adverse outcome pathways. ALTEX 36(1), 91-102.
Samtani, R., Sharma, N. and Garg, D. (2018) Effects of Endocrine-Disrupting Chemicals and Epigenetic Modifications in Ovarian Cancer: A Review. Reprod Sci 25(1), 7-18.
Schneider, J., Jimenez, E., Marenbach, K., Romero, H., Marx, D. and Meden, H. (1999) Immunohistochemical detection of HSP60-expression in human ovarian cancer. Correlation with survival in a series of 247 patients. Anticancer Res 19(3A), 2141-2146.
Shoemaker, J.E., Gayen, K., Garcia-Reyero, N., Perkins, E.J., Villeneuve, D.L., Liu, L. and Doyle, F.J. (2010) Fathead minnow steroidogenesis: in silico analyses reveals tradeoffs between nominal target efficacy and robustness to cross-talk. BMC Systems Biology 4(1), 89.
Siegel, R.L., Miller, K.D. and Jemal, A. (2019) Cancer statistics, 2019. CA Cancer J Clin 69(1), 7-34.
Tao, X., Zhao, N., Jin, H., Zhang, Z., Liu, Y., Wu, J., Bast, R.C., Jr., Yu, Y. and Feng, Y. (2013) FSH enhances the proliferation of ovarian cancer cells by activating transient receptor potential channel C3. Endocr Relat Cancer 20(3), 415-429.
Tomao, F., Lo Russo, G., Spinelli, G.P., Stati, V., Prete, A.A., Prinzi, N., Sinjari, M., Vici, P., Papa, A., Chiotti, M.S., Benedetti Panici, P. and Tomao, S. (2014) Fertility drugs, reproductive strategies and ovarian cancer risk. J Ovarian Res 7, 51.
Zhang, T., Xu, J., Deng, S., Zhou, F., Li, J., Zhang, L., Li, L., Wang, Q.-E. and Li, F. (2018) Core signaling pathways in ovarian cancer stem cell revealed by integrative analysis of multi-marker genomics data. PLOS ONE 13(5), e0196351.