Expression of TGF-ß signaling proteins in normal placenta and gestational trophoblastic disease

Abstract

The transforming growth factor ß (TGF-ß) is a vital regulator of placental development and functions. TGF-ß exerts several modulatory effects on trophoblast cells, such as inhibition of proliferation and invasiveness, and stimulation of differentiation by inducing multinucleated cell formation. In this study, we determine the expression patterns of TGF-ß signaling molecules in normal trophoblast, various hydatidiform mole types and choriocarcinoma. A total of 132 cases, including 51 normal placenta (20 first trimester, 11 second trimester, and 20 third trimester) and 81 gestational trophoblastic diseases (17 choriocarcinoma, and 64 hydatidiform moles: 39 complete, 6 partial, and 19 invasive) were immunohistochemically analyzed with anti-TGF ß1/2, TGF-ß receptor type I (TßRI), TßRII, Smad 2/3, and Smad 4 antibodies on paraffin blocks. In the case of normal placenta, maximal levels of all TGF-ß signaling molecules were observed in villous trophoblast in the first trimester, which decreased with gestational age. Expression of all the TGF-ß signaling proteins except Smad2/3, was significantly enhanced in various moles, relative to normal trophoblast. Moreover, TGF-ß signaling molecules were significantly downregulated in choriocarcinoma, compared to moles. In particular, TßRI and Smad2/3 levels were lower in choriocarcinoma than normal villous trophoblast (TßRI: p<0.025, Smad2/3: p<0.001). In conclusion, the TGF-ß signaling pathway plays an important role in the pathogenesis and progression of gestational trophoblastic disease, and may thus be employed as a potential therapeutic target and a diagnostic biomarker