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      IGF-axis confers transformation and regeneration of fallopian tube fimbria epithelium upon ovulation

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          Abstract

          Background

          The fallopian tube fimbria is regarded as the main tissue of origin and incessant ovulation as the main risk factor of ovarian high-grade serous carcinoma. Previously, we discovered the tumorigenesis activity of human ovulatory follicular fluid (FF) upon injection to the mammary fat pad of Trp53-null mice. We also found a mutagenesis activity of FF-ROS and a apoptosis-rescuing activity of Hb from retrograde menstruation. However, neither of them can explain the tumorigenesis activities of FF.

          Methods

          From two cohorts of ovulatory FF retrieved from IVF patients, the main growth factor responsible for the transformation of human fimbrial epithelial cells was identified. Mechanism of activation, ways of signal transduction of the growth factor, as well as the cellular and genetic phenotypes of the malignant transformation was characterized.

          Findings

          In this study, we showed that insulin-like growth factor (IGF)-axis proteins, including IGFBP-bound IGF2 as well as the IGFBP-lytic enzyme PAPP-A, are abundantly present in FF. Upon engaging with glycosaminoglycans on the membrane of fimbrial epithelial cells, PAPP-A cleaves IGFBPs and releases IGF2 to bind with IGF-1R. Through the IGF-1R/AKT/mTOR and IGF-1R/AKT/NANOG pathways, FF-IGF leads to stemness and survival, and in the case of TP53/Rb or TP53/CCNE1 loss, to clonal expansion and malignant transformation of fimbrial epithelial cells. By depleting each IGF axis component from FF, we proved that IGF2, IGFBP2/6, and PAPP-A are all essential and confer the majority of the transformation and regeneration activities.

          Interpretation

          This study revealed that the FF–IGF axis functions to regenerate tissue damage after ovulation and promote the transformation of fimbrial epithelial cells that have been initiated by p53- and Rb-pathway disruptions.

          Fund

          The study was supported by grants of the Ministry of Science and Technology, Taiwan (MOST 106-2314-B-303-001-MY2; MOST 105-2314-B-303-017-MY2; MOST 107-2314-B-303-013-MY3), and Buddhist Tzu Chi General Hospital, Taiwan (TCMMP104-04-01).

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          Most cited references43

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          Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours.

          L A Donehower, M. Harvey, B Slagle … (1992)
          Mutations in the p53 tumour-suppressor gene are the most frequently observed genetic lesions in human cancers. To investigate the role of the p53 gene in mammalian development and tumorigenesis, a null mutation was introduced into the gene by homologous recombination in murine embryonic stem cells. Mice homozygous for the null allele appear normal but are prone to the spontaneous development of a variety of neoplasms by 6 months of age. These observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.
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            Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls.

            Elisabete Weiderpass (2008)
            Oral contraceptives were introduced almost 50 years ago, and over 100 million women currently use them. Oral contraceptives can reduce the risk of ovarian cancer, but the eventual public-health effects of this reduction will depend on how long the protection lasts after use ceases. We aimed to assess these effects. Individual data for 23,257 women with ovarian cancer (cases) and 87,303 without ovarian cancer (controls) from 45 epidemiological studies in 21 countries were checked and analysed centrally. The relative risk of ovarian cancer in relation to oral contraceptive use was estimated, stratifying by study, age, parity, and hysterectomy. Overall 7308 (31%) cases and 32,717 (37%) controls had ever used oral contraceptives, for average durations among users of 4.4 and 5.0 years, respectively. The median year of cancer diagnosis was 1993, when cases were aged an average of 56 years. The longer that women had used oral contraceptives, the greater the reduction in ovarian cancer risk (p<0.0001). This reduction in risk persisted for more than 30 years after oral contraceptive use had ceased but became somewhat attenuated over time-the proportional risk reductions per 5 years of use were 29% (95% CI 23-34%) for use that had ceased less than 10 years previously, 19% (14-24%) for use that had ceased 10-19 years previously, and 15% (9-21%) for use that had ceased 20-29 years previously. Use during the 1960s, 1970s, and 1980s was associated with similar proportional risk reductions, although typical oestrogen doses in the 1960s were more than double those in the 1980s. The incidence of mucinous tumours (12% of the total) seemed little affected by oral contraceptives, but otherwise the proportional risk reduction did not vary much between different histological types. In high-income countries, 10 years use of oral contraceptives was estimated to reduce ovarian cancer incidence before age 75 from 1.2 to 0.8 per 100 users and mortality from 0.7 to 0.5 per 100; for every 5000 woman-years of use, about two ovarian cancers and one death from the disease before age 75 are prevented. Use of oral contraceptives confers long-term protection against ovarian cancer. These findings suggest that oral contraceptives have already prevented some 200,000 ovarian cancers and 100,000 deaths from the disease, and that over the next few decades the number of cancers prevented will rise to at least 30,000 per year.
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              Incessant ovulation--a factor in ovarian neoplasia?

              Mohamed Fathalla (1971)
              Article 0 comments Cited 140 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Tang-Yuan Chu
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 07 March 2019
                Publication date Collection: March 2019
                Publication date (Electronic): 07 March 2019
                Volume: 41
                Pages: 597-609
                Affiliations
                [a ]Center for Prevention and Therapy of Gynecological Cancers, Department of Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan, ROC
                [b ]Department of Obstetrics & Gynecology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan, ROC
                [c ]Institute of Medical Science, Tzu Chi University, Hualien, Taiwan, ROC
                [d ]Department of Life Science, Institute of Biotechnology National Dong Hwa University, Hualien, Taiwan
                Author notes
                [* ]Corresponding author at: Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, 707, Section 3, Chung-Yang Road, Hualien 970, Taiwan. hidrchu@ 123456gmail.com
                [1]

                Equal contribution.

                Article
                Publisher ID: S2352-3964(19)30067-2
                DOI: 10.1016/j.ebiom.2019.01.061
                PMC ID: 6441876
                PubMed ID: 30852161
                SO-VID: 759dbdda-9f9a-4192-8bda-427f97cb17c3
                Copyright © © 2019 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 11 December 2018
                Date revision received : 26 January 2019
                Date accepted : 31 January 2019
                Categories
                Subject: Research paper

                Keywords: ovarian high-grade serous carcinoma,follicular fluid,fallopian tube fimbriae,igf axis,stemness
                Data availability:
                Keywords: ovarian high-grade serous carcinoma, follicular fluid, fallopian tube fimbriae, igf axis, stemness

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