The PSTT is a relatively uncommon form of trophoblastic tumors that is made up of neoplastic implantation site intermediate trophoblastic cells (8,24,37,38). In contrast to the normal implantation site in which invasion of IT is tightly regulated and is confined to the inner third of the myometrium, the tumor cells of PSTT are highly invasive and infiltrate deeply into the myometrium occasionally penetrating to the serosa.
Microscopically, PSTT resembles the trophoblastic infiltration of the endometrium and myometrium of the placental site during early pregnancy. The predominant cell type in PSTT is implantation site IT (Table 1). PSTT is diffusely positive for HLA-G, hPL, and CD146 (Mel-CAM), but rarely positive for p-hCG, PlAP, p63, or HNK-1, an immunophenotype consistent with implantation site IT (Table 1) (5,24). PSTT is associated with abnormal expression of cell-cycle regulatory gene products including cyclins, cyclin-dependent kinases, and p53 (39). At the molecular genetic level, most PSTTs are diploid based on flow cytometric DNA analysis. The trophoblastic origin of PSTT has been confirmed by molecular genetic studies showing that they contain a Y chromosomal locus and/or new (paternal) alleles not present in adjacent normal uterine tissue in all informative cases (37,40,41). PSTTs express the activated (phosphorylated) form of mitogen activated protein kinase (MAPK) in 84% of cases; whereas normal intermediate trophoblastic cells do not (42). The RAS/RAF/MEK (MAPK/ERK Kinase)/MAPK signaling pathway is known to play a major role in various cellular activities including proliferation, differentiation, apoptosis, angiogenesis, and migration (43-49). In order to characterize the role of MAPK activation in PSTT, Kobel et al. (42) established the first PSTT cell culture, IST-2, from a surgically resected PSTT. IST-2 cells expressed HLA-G and Mel-CAM, but not E-cadherin, an immunophenotype characteristic of PSTT. IST-2 cells are highly motile and invasive in culture. Treatment with MEK inhibitors, CI-1040 and PD59089, which prevents activation of MAPK significantly, reduces the motility and invasion of IST-2 based on wound assay, cell tracking by time-lapse videomicroscopy, and invasion chamber assays. In contrast, neither of the compounds has an effect on normal intermediate trophoblastic cells in the implantation site. These findings demonstrate a functional role of MAPK activation in the motility and invasion of PSTT.
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