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Cancer Res. 2016 Jul 1;76(13):3851-61. doi: 10.1158/0008-5472.CAN-15-3358. Epub 2016 May 9.

Constitutive Activation of PI3K in Oocyte Induces Ovarian Granulosa Cell Tumors.

Author information

1
Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. takeshi.kurita@osumc.edu so-youn-kim@northwestern.edu.
2
Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
3
Department of Pathology, The Comprehensive Cancer Center, Ohio State University, Columbus, Ohio.
4
Department of Molecular Virology, Immunology and Medical Genetics, The Comprehensive Cancer Center, Ohio State University, Columbus, Ohio. takeshi.kurita@osumc.edu so-youn-kim@northwestern.edu.

Abstract

Cell-cell interactions play crucial roles in the maintenance of tissue homeostasis, a loss of which often leads to varying diseases, including cancer. Here, we report that uncontrolled PI3K activity within oocytes irreversibly transforms granulosa cells (GC), causing GC tumors (GCT) through perturbed local cell communication. Previously, we reported reproductive phenotypes of transgenic mice, in which expression of constitutively active mutant PI3K was induced in primordial oocytes by Gdf9-iCre. The transgenic mice (Cre(+)) demonstrated severe ovarian phenotypes, including the overgrowth of excess ovarian follicles and anovulation. Surprisingly, the Cre(+) mice became cachectic by postnatal day 80 due to bilateral GCT. Although GCT cells proliferated independently of oocytes, local interactions with mutant PI3K-positive oocytes during early folliculogenesis were essential for the GC transformation. Growing GCT cells expressed high levels of inhibin βA and nuclear SMAD3, and the proliferation rate was positively correlated with a high activin A to inhibin A ratio. These results suggested that the tumor cells stimulated their growth through an activin A autocrine signaling pathway, a hypothesis confirmed by activin A secretion in cultured GCT cells, which proliferated in response. Although communication between the oocyte and surrounding somatic cells is critical for the normal development of ovarian follicles, perturbations in oocyte-GC communication during early folliculogenesis can induce GCT by activating an autocrine growth circuit program in GC. Cancer Res; 76(13); 3851-61.

PMID:
27197196
PMCID:
PMC5081136
DOI:
10.1158/0008-5472.CAN-15-3358
[Indexed for MEDLINE]
Free PMC Article

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