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Event: 2092

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Promotion, Ovarian Cancer

Short name

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Organ

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term
female reproductive organ

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
endocrine signaling	estrone	increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

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

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	High	NCBI
rat	Rattus norvegicus	High	NCBI
mice	Mus sp.	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Adult	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Female	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

It is applicable in ovary for reproductive matured female.

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

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.

References

List of the literature that was cited for this KE description. More help

Cassidenti, D.L., Paulson, R.J., Lobo, R.A. and Sauer, M.V. (1992) The synergistic effects of clomiphene citrate and human menopausal gonadotrophin in the folliculogenesis of stimulated cycles as assessed by the gonadotrophin-releasing hormone antagonist Nal-Glu. Hum Reprod 7(3), 344-348.

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.

Jokerst, J.V., Cole, A.J., Van de Sompel, D. and Gambhir, S.S. (2012) Gold nanorods for ovarian cancer detection with photoacoustic imaging and resection guidance via Raman imaging in living mice. ACS Nano 6(11), 10366-10377.

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.