Role of the inositol polyphosphate-4-phosphatase type II Inpp4b in the generation of ovarian teratomas

Teratomas are a unique class of tumors composed of ecto-, meso- and endodermal tissues, all foreign to the site of origin. In humans, the most common teratoma is the ovarian teratoma. Not much is known about the molecular and genetic etiologies of these tumors. Female carriers of the Tgkd transgene are highly susceptible to developing teratomas. Ovaries of Tgkd/+ hemizygous female mice exhibit defects in luteinization, with numerous corpora lutea, some of which contain central trapped, fully-grown oocytes. Genetically, Tgkd teratomas originate from mature oocytes that have completed meiosis I, suggesting that Tgkd teratomas originate from these trapped oocytes. The insertion of Tgkd 3' of the Inpp4b gene is associated with decreased expression of Inpp4b and changes in intracellular PI3 Kinase/AKT signaling in follicular granulosa cells. Because Inpp4b is not expressed in fully-grown wild-type or Tgkd oocytes, these findings suggest that hyperactivation of the PI3K/AKT pathway caused by the decrease in INPP4B in granulosa cells promotes an ovarian environment defective in folliculogenesis and conducive to teratoma formation.

► A random Tgkd transgene insertion lowers inositol phosphatase Inpp4b levels. ► Decreased Inpp4b in granulosa cells linked to hyperactive PI3-kinase/AKT signaling. ► Granulosa cell proliferation/apoptosis ratio increases in FVB-Tgkd ovaries. ► Follicular defects such as trapped oocytes in corpora lutea seen in FVB-Tgkd ovaries. ► Teratomas develop from meiotically mature oocytes in Tgkd follicles. ► Trapped oocyte phenotype and high oocyte parthenogenesis may cause ovarian teratomas.