Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Role of activin C in normal ovaries and granulosa cell tumours of mice and humans

Karen L. Reader A D , Francesco E. Marino A C , Helen D. Nicholson A , Gail P. Risbridger B and Elspeth J. Gold A
+ Author Affiliations
- Author Affiliations

A Department of Anatomy, University of Otago, Dunedin 9054, New Zealand.

B Consortium and Cancer Program Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Vic. 3800, Australia.

C Present address: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, PA, USA.

D Corresponding author. Email: karen.reader@otago.ac.nz

Reproduction, Fertility and Development - https://doi.org/10.1071/RD17250
Submitted: 30 June 2017  Accepted: 8 November 2017   Published online: 6 December 2017

Abstract

Activins and inhibins play important roles in the development, growth and function of the ovary. Mice lacking inhibin develop granulosa cell tumours in their ovaries that secrete activin A, and these tumours are modulated by increased activin C expression. The aim of the present study was to identify where activin C is expressed in mouse and human ovaries and whether overexpression of activin C modulates normal follicular development in mice. Immunohistochemical staining for the activin βC subunit was performed on sections from mouse and human ovaries and human adult granulosa cell tumours. Stereology techniques were used to quantify oocyte and follicular diameters, and the percentage of different follicular types in ovaries from wild-type mice and those underexpressing inhibin α and/or overexpressing activin C. Staining for activin βC was observed in the oocytes, granulosa cells, thecal cells and surface epithelium of mouse and human ovaries, and in the granulosa-like cells of adult granulosa cell tumours. Overexpression of activin C in mice did not alter follicular development compared with wild-type mice, but it did modulate the development of abnormal early stage follicles in inhibin α-null mice. These results provide further evidence of a role for activin C in the ovary.

Additional keywords: follicle development, ovarian cancer, ovary.


References

Arora, D. S., Cooke, I. E., Ganesan, T. S., Ramsdale, J., Manek, S., Charnock, F. M., Groome, N. P., and Wells, M. (1997). Immunohistochemical expression of inhibin/activin subunits in epithelial and granulosa cell tumours of the ovary. J. Pathol. 181, 413–418.
Immunohistochemical expression of inhibin/activin subunits in epithelial and granulosa cell tumours of the ovary.CrossRef | 1:STN:280:DyaK2szjvFyrtw%3D%3D&md5=b23e8a22d0b2fdcbf14596c91136bfeeCAS |

Bi, X., Xia, X., Fan, D., Mu, T., Zhang, Q., Iozzo, R. D., and Yang, W. (2016). Oncogenic activin C interacts with decorin in colorectal cancer in vivo and in vitro. Mol. Carcinog. 55, 1786–1795.
Oncogenic activin C interacts with decorin in colorectal cancer in vivo and in vitro.CrossRef | 1:CAS:528:DC%2BC2MXhslamsrrL&md5=5602707a0bbda298981caccbc5b3734eCAS |

Braw-Tal, R., McNatty, K. P., Smith, P., Heath, D. A., Hudson, N. L., Phillips, D. J., McLeod, B. J., and Davis, G. H. (1993). Ovaries of ewes homozygous for the X-linked Inverdale gene (FecXI) are devoid of secondary and tertiary follicles but contain many abnormal structures. Biol. Reprod. 49, 895–907.
Ovaries of ewes homozygous for the X-linked Inverdale gene (FecXI) are devoid of secondary and tertiary follicles but contain many abnormal structures.CrossRef | 1:STN:280:DyaK2c7hsVOmsA%3D%3D&md5=76e73f7e312a409d55a905db9827427eCAS |

Bristol-Gould, S. K., Kreeger, P. K., Selkirk, C. G., Kilen, S. M., Cook, R. W., Kipp, J. L., Shea, L. D., Mayo, K. E., and Woodruff, T. K. (2006). Postnatal regulation of germ cells by activin: the establishment of the initial follicle pool. Dev. Biol. 298, 132–148.
Postnatal regulation of germ cells by activin: the establishment of the initial follicle pool.CrossRef | 1:CAS:528:DC%2BD28XpvFeksL4%3D&md5=a03c5c9b3964bb98eceee53615ceba80CAS |

Gold, E. J., O’Bryan, M. K., Mellor, S. L., Cranfield, M., Risbridger, G. P., Groome, N. P., and Fleming, J. S. (2004). Cell-specific expression of betaC-activin in the rat reproductive tract, adrenal and liver. Mol. Cell. Endocrinol. 222, 61–69.
Cell-specific expression of betaC-activin in the rat reproductive tract, adrenal and liver.CrossRef | 1:CAS:528:DC%2BD2cXlsFOqs7k%3D&md5=f41f34795937d54ee1890dafbbfc7592CAS |

Gold, E., Jetly, N., O’Bryan, M. K., Meachem, S., Srinivasan, D., Behuria, S., Sanchez-Partida, L. G., Woodruff, T., Hedwards, S., Wang, H., McDougall, H., Casey, V., Niranjan, B., Patella, S., and Risbridger, G. (2009). Activin C antagonizes activin A in vitro and overexpression leads to pathologies in vivo. Am. J. Pathol. 174, 184–195.
Activin C antagonizes activin A in vitro and overexpression leads to pathologies in vivo.CrossRef | 1:CAS:528:DC%2BD1MXhslOksr0%3D&md5=743a6959ac06ff3d0fb0442f2580ad43CAS |

Gold, E., Marino, F. E., Harrison, C., Makanji, Y., and Risbridger, G. (2013). Activin-beta(c) reduces reproductive tumour progression and abolishes cancer-associated cachexia in inhibin-deficient mice. J. Pathol. 229, 599–607.
Activin-beta(c) reduces reproductive tumour progression and abolishes cancer-associated cachexia in inhibin-deficient mice.CrossRef | 1:CAS:528:DC%2BC3sXivFaqu7k%3D&md5=4400d464e74a965442f30e157484dbb0CAS |

Hotten, G., Neidhardt, H., Schneider, C., and Pohl, J. (1995). Cloning of a new member of the TGF-beta family: a putative new activin beta C chain. Biochem. Biophys. Res. Commun. 206, 608–613.
Cloning of a new member of the TGF-beta family: a putative new activin beta C chain.CrossRef |

Juengel, J. L., Quirke, L. D., Tisdall, D. J., Smith, P., Hudson, N. L., and McNatty, K. P. (2000). Gene expression in abnormal ovarian structures of ewes homozygous for the Inverdale prolificacy gene. Biol. Reprod. 62, 1467–1478.
Gene expression in abnormal ovarian structures of ewes homozygous for the Inverdale prolificacy gene.CrossRef | 1:CAS:528:DC%2BD3cXjsF2hsr0%3D&md5=69c1b629fc1eff2724044b661c27d412CAS |

Käufl, S. D., Makovitzky, J., Kuhn, C., Kunze, S., Jeschke, U., and Mylonas, I. (2010). Inhibin/activin-betaC subunit in human endometrial adenocarcinomas and HEC-1a adenocarcinoma cell line. In Vivo 24, 695–698.

Kimmich, T., Bruning, A., Kaufl, S. D., Makovitzky, J., Kuhn, C., Jeschke, U., Friese, K., and Mylonas, I. (2010). Inhibin/activin-betaC and -betaE subunits in the Ishikawa human endometrial adenocarcinoma cell line. Arch. Gynecol. Obstet. 282, 185–191.
Inhibin/activin-betaC and -betaE subunits in the Ishikawa human endometrial adenocarcinoma cell line.CrossRef | 1:CAS:528:DC%2BC3cXotlygtrg%3D&md5=961b251e48bfa2f89aabad1d17afd353CAS |

Knight, P. G., Satchell, L., and Glister, C. (2012). Intra-ovarian roles of activins and inhibins. Mol. Cell. Endocrinol. 359, 53–65.
Intra-ovarian roles of activins and inhibins.CrossRef | 1:CAS:528:DC%2BC38XnslOjurw%3D&md5=34543b596c4f37a9f22ac50d500ed9c4CAS |

Lau, A. L., Kumar, T. R., Nishimori, K., Bonadio, J., and Matzuk, M. M. (2000). Activin betaC and betaE genes are not essential for mouse liver growth, differentiation, and regeneration. Mol. Cell. Biol. 20, 6127–6137.
Activin betaC and betaE genes are not essential for mouse liver growth, differentiation, and regeneration.CrossRef | 1:CAS:528:DC%2BD3cXlsl2gtrk%3D&md5=4059e02ff0ff7a016eb8b0c9eef46b76CAS |

Li, R., Phillips, D. M., and Mather, J. P. (1995). Activin promotes ovarian follicle development in vitro. Endocrinology 136, 849–856.
Activin promotes ovarian follicle development in vitro.CrossRef | 1:CAS:528:DyaK2MXjvFCjs7g%3D&md5=75df33a5c68e306c0e81295e7924a6bdCAS |

Li, Q., Wu, H., Chen, B., Hu, G., Huang, L., Qin, K., Chen, Y., Yuan, X., and Liao, Z. (2012). SNPs in the TGF-beta signaling pathway are associated with increased risk of brain metastasis in patients with non-small-cell lung cancer. PLoS One 7, e51713.
SNPs in the TGF-beta signaling pathway are associated with increased risk of brain metastasis in patients with non-small-cell lung cancer.CrossRef | 1:CAS:528:DC%2BC3sXht1KrtA%3D%3D&md5=1bcbb09fbffd96db737aa7ccf1a583d3CAS |

Loveland, K. L., McFarlane, J. R., and de Kretser, D. M. (1996). Expression of activin beta C subunit mRNA in reproductive tissues. J. Mol. Endocrinol. 17, 61–65.
Expression of activin beta C subunit mRNA in reproductive tissues.CrossRef | 1:CAS:528:DyaK28XltV2ru7w%3D&md5=7594d688c1124ea3ffd7cb9a57d31977CAS |

Marino, F. E., Risbridger, G., and Gold, E. (2014). The inhibin/activin signalling pathway in human gonadal and adrenal cancers. Mol. Hum. Reprod. 20, 1223–1237.
The inhibin/activin signalling pathway in human gonadal and adrenal cancers.CrossRef | 1:CAS:528:DC%2BC28XitVyhtrbF&md5=fe57baffb6918e170254cbef4f759ddfCAS |

Marino, F. E., Risbridger, G., and Gold, E. (2015). Activin-beta modulates gonadal, but not adrenal tumorigenesis in the inhibin deficient mice. Mol. Cell. Endocrinol. 409, 41–50.
Activin-beta modulates gonadal, but not adrenal tumorigenesis in the inhibin deficient mice.CrossRef | 1:CAS:528:DC%2BC2MXmslehs70%3D&md5=3dc69a13cb625045dd8ad87751cf2bb7CAS |

Martins da Silva, S. J., Bayne, R. A., Cambray, N., Hartley, P. S., McNeilly, A. S., and Anderson, R. A. (2004). Expression of activin subunits and receptors in the developing human ovary: activin A promotes germ cell survival and proliferation before primordial follicle formation. Dev. Biol. 266, 334–345.
Expression of activin subunits and receptors in the developing human ovary: activin A promotes germ cell survival and proliferation before primordial follicle formation.CrossRef | 1:CAS:528:DC%2BD2cXltF2qsg%3D%3D&md5=4aa6e030aed96ad0230127588e3b3898CAS |

Matzuk, M. M., Finegold, M. J., Su, J. G., Hsueh, A. J., and Bradley, A. (1992). Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice. Nature 360, 313–319.
Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice.CrossRef | 1:CAS:528:DyaK3sXhs1Gitw%3D%3D&md5=5224e336731a07a087eb70559e19383cCAS |

Matzuk, M. M., Finegold, M. J., Mather, J. P., Krummen, L., Lu, H., and Bradley, A. (1994). Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice. Proc. Natl Acad. Sci. USA 91, 8817–8821.
Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice.CrossRef | 1:CAS:528:DyaK2cXmtVajtL0%3D&md5=f2bba03212dd4e2b8998b822f12ceec2CAS |

Mayhew, T. M. (1991). The new stereological methods for interpreting functional morphology from slices of cells and organs. Exp. Physiol. 76, 639–665.
The new stereological methods for interpreting functional morphology from slices of cells and organs.CrossRef | 1:STN:280:DyaK38%2FnsFanuw%3D%3D&md5=ce3f3db4ebb723b787039eb326183483CAS |

McNatty, K. P., Juengel, J. L., Reader, K. L., Lun, S., Myllymaa, S., Lawrence, S. B., Western, A., Meerasahib, M. F., Mottershead, D. G., Groome, N. P., Ritvos, O., and Laitinen, M. P. (2005a). Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function. Reproduction 129, 473–480.
Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function.CrossRef | 1:CAS:528:DC%2BD2MXjs1ertbw%3D&md5=698d4bb3635d4f323c02035ed7581e7fCAS |

McNatty, K. P., Juengel, J. L., Reader, K. L., Lun, S., Myllymaa, S., Lawrence, S. B., Western, A., Meerasahib, M. F., Mottershead, D. G., Groome, N. P., Ritvos, O., and Laitinen, M. P. (2005b). Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function in ruminants. Reproduction 129, 481–487.
Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function in ruminants.CrossRef | 1:CAS:528:DC%2BD2MXjs1ertb0%3D&md5=9c65f05ea6df797e903d5598c808bc1bCAS |

Mellor, S. L., Cranfield, M., Ries, R., Pedersen, J., Cancilla, B., de Kretser, D., Groome, N. P., Mason, A. J., and Risbridger, G. P. (2000). Localization of activin beta(A)-, beta(B)-, and beta(C)-subunits in human prostate and evidence for formation of new activin heterodimers of beta(C)-subunit. J. Clin. Endocrinol. Metab. 85, 4851–4858.
| 1:CAS:528:DC%2BD3MXis1Gjuw%3D%3D&md5=a62bdf4548e4caa050510bf0a1a8cb31CAS |

Mellor, S. L., Ball, E. M., O’Connor, A. E., Ethier, J. F., Cranfield, M., Schmitt, J. F., Phillips, D. J., Groome, N. P., and Risbridger, G. P. (2003). Activin betaC-subunit heterodimers provide a new mechanism of regulating activin levels in the prostate. Endocrinology 144, 4410–4419.
Activin betaC-subunit heterodimers provide a new mechanism of regulating activin levels in the prostate.CrossRef | 1:CAS:528:DC%2BD3sXns1Srtbk%3D&md5=83e4222940a7e638a4943c2cef90d7a3CAS |

Myers, M., Middlebrook, B. S., Matzuk, M. M., and Pangas, S. A. (2009). Loss of inhibin alpha uncouples oocyte–granulosa cell dynamics and disrupts postnatal folliculogenesis. Dev. Biol. 334, 458–467.
Loss of inhibin alpha uncouples oocyte–granulosa cell dynamics and disrupts postnatal folliculogenesis.CrossRef | 1:CAS:528:DC%2BD1MXhtFyqsbvO&md5=b286781770190594c9b19daf7447a5a3CAS |

Pangas, S. A., Rademaker, A. W., Fishman, D. A., and Woodruff, T. K. (2002). Localization of the activin signal transduction components in normal human ovarian follicles: implications for autocrine and paracrine signaling in the ovary. J. Clin. Endocrinol. Metab. 87, 2644–2657.
Localization of the activin signal transduction components in normal human ovarian follicles: implications for autocrine and paracrine signaling in the ovary.CrossRef | 1:CAS:528:DC%2BD38XkvFartLk%3D&md5=ab0f9ed30bece88f08ecfd3535d4ae13CAS |

Pitman, J. L., McNeilly, A. S., McNeilly, J. R., Hays, L. E., Bagby, G. C., Sawyer, H. R., and McNatty, K. P. (2012). The fate of granulosa cells following premature oocyte loss and the development of ovarian cancers. Int. J. Dev. Biol. 56, 949–958.
The fate of granulosa cells following premature oocyte loss and the development of ovarian cancers.CrossRef | 1:CAS:528:DC%2BC3sXmvVyqsbs%3D&md5=0ad8ef06c60f3f15055168cef0da00ebCAS |

Rabinovici, J., Goldsmith, P. C., Roberts, V. J., Vaughan, J., Vale, W., and Jaffe, R. B. (1991). Localization and secretion of inhibin/activin subunits in the human and subhuman primate fetal gonads. J. Clin. Endocrinol. Metab. 73, 1141–1149.
Localization and secretion of inhibin/activin subunits in the human and subhuman primate fetal gonads.CrossRef | 1:CAS:528:DyaK38XltFOkuw%3D%3D&md5=7d3dde6f471484c3527790b17ab1c7f0CAS |

Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., Tinevez, J. Y., White, D. J., Hartenstein, V., Eliceiri, K., Tomancak, P., and Cardona, A. (2012). Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682.
Fiji: an open-source platform for biological-image analysis.CrossRef | 1:CAS:528:DC%2BC38XhtVKnurbJ&md5=63b94b92bb9f0da66a6ccfd027ffe962CAS |

Thévenaz, P., and Unser, M. (2007). User-friendly semiautomated assembly of accurate image mosaics in microscopy. Microsc. Res. Tech. 70, 135–146.
User-friendly semiautomated assembly of accurate image mosaics in microscopy.CrossRef |

Vejda, S., Cranfield, M., Peter, B., Mellor, S. L., Groome, N., Schulte-Hermann, R., and Rossmanith, W. (2002). Expression and dimerization of the rat activin subunits betaC and betaE: evidence for the formation of novel activin dimers. J. Mol. Endocrinol. 28, 137–148.
Expression and dimerization of the rat activin subunits betaC and betaE: evidence for the formation of novel activin dimers.CrossRef | 1:CAS:528:DC%2BD38Xjt1GrsLk%3D&md5=370678e84bf6916118ae9eb3f9737307CAS |

Weng, Q., Wang, H., Medan, M. S., Jin, W., Xia, G., Watanabe, G., and Taya, K. (2006). Expression of inhibin/activin subunits in the ovaries of fetal and neonatal mice. J. Reprod. Dev. 52, 607–616.
Expression of inhibin/activin subunits in the ovaries of fetal and neonatal mice.CrossRef | 1:CAS:528:DC%2BD2sXmtl2luw%3D%3D&md5=783fbf5758b8e5437c658773e9b30b92CAS |

Williams, M. (1977). ‘Quantitative Methods in Biology.’ (Elsevier/North-Holland Biomedical Press: Amsterdam.)

Yin, J., Lu, K., Lin, J., Wu, L., Hildebrandt, M. A. T., Chang, D. W., Meyer, L., Wu, X., and Liang, D. (2011). Genetic variants in TGF-β pathway are associated with ovarian cancer risk. PLoS One 6, e25559.
Genetic variants in TGF-β pathway are associated with ovarian cancer risk.CrossRef | 1:CAS:528:DC%2BC3MXhtlGmt7vP&md5=3e24bbaaed8e5c5a9eafe000bd5df66bCAS |

Young, R. H. (2011). Sex cord-stromal, steroid cell, and other ovarian tumors with endocrine, paraendocrine, and paraneoplastic manifestations. In ‘Blaustein’s Pathology of the Female Genital Tract’, 6th edn. (Eds R. J. Kurman, L. H. Ellenson, and B. M. Ronnett.) pp. 785–846. (Springer: New York, NY.)



Supplementary MaterialSupplementary Material (901 KB) Export Citation