Follicle-stimulating hormone drives Sertoli cell tumor development by regulating proliferation (#139)
Testicular cancer is the most common malignancy amongst men aged 15-35. A serum marker of this disease is inhibin alpha, and when deleted in mice (Inha KO) causes Sertoli cell tumours. Interestingly, this phenotype is repressed in mice lacking both inhibin alpha and follicle stimulating hormone (FSH), however the developmental timepoint in which FSH impacts Sertoli cell tumour development is unknown. Therefore, we aimed to i) identify the developmental window(s) sensitive to FSH, and ii) determine the cellular mechanism (proliferation/survival) via which FSH stimulates tumourigenesis. To test this, we used a model of FSH immunoneutralisation in WT and KO Inha mice (n=5/group), which were given subcutaneous daily injections of anti-rat FSH antibody (Ab) or non-specific Ab (3mg/kg) during 0-7, 7-14 or 21-28 postnatal days of age and culled at 35d. Fresh Sertoli cells were analysed by flow cytometry for proliferation (EdU) and apoptosis (cleaved caspase-3). WT mice treated with non-specific Ab at 0-7, 7-14 and 21-28d showed 2.9% EdU-positive Sertoli cells, suggesting a subset of adult Sertoli cells retain proliferative ability. In comparison, KO mice treated with non-specific Ab showed an increase (P<0.001) in EdU-positive cells at all time-points to 6.0-7.2%, as expected due to tumourigenesis. KO mice treated with FSH antibody compared to non-specific Ab showed a 2.5-fold reduction (P<0.001) in EdU-positive Sertoli cells at 0-7d, and a 1.7-fold reduction (P<0.001) at 21-28d, however the greatest reduction of 3.8-fold was seen at 7-14d (P<0.001). In support, qualitative histological assessment of testes from FSH Ab-treated mice showed fewer and smaller tumours. A 2-fold increase (P<0.05) in cleaved caspase-3 positive cells were observed in FSH-Ab treated KO mice at 21-28d, but not 7-14d or 0-7d. In conclusion, i) pre- and post-pubertal Sertoli cells are sensitive to FSH tumourigenic action, however the 7-14d developmental window is most sensitive, and ii) FSH promotes Sertoli cell tumourigenesis by stimulation of both proliferation and apoptosis. These data implicate a role for altered FSH signalling in testicular tumour development in men.