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Differentiation of first trimester human placental cytotrophoblast (CTB) from an anchorage-dependent epithelial phenotype into the mesenchymal-like invasive extravillous trophoblast (EVT) is crucial in the development of the maternal-fetal interface. We showed previously that differentiation of first trimester CTB to EVT involves an epithelial-mesenchymal transition (EMT). Here we compare the epithelial-mesenchymal characteristics of CTB and EVT derived from normal third trimester placenta or placenta previa versus abnormally invasive placenta (AIP). CTB and EVT were isolated from normal term placenta or placenta previa following Caesarean section and EVT from AIP following Caesarean hysterectomy. Cell identity was validated by measurement of cytokeratin-7 and HLA-G. Comparing normal term CTB with EVT from normal term placenta or placenta previa for differential expression analysis of genes associated with the EMT showed changes in >70% of the genes probed. While demonstrating a mesenchymal phenotype relative to CTB, many of the gene expression changes in third trimester EVT were reduced relative to the first trimester EVT. We suggest that third trimester EVT are in a more constrained, metastable state compared to first trimester equivalents. By contrast, EVT from AIP demonstrate characteristics that are more mesenchymal than normal third trimester EVT, placing them closer to first trimester EVT on the EMT spectrum, consistent with a more invasive phenotype.

Field cancerization refers to areas of grossly normal epithelium that exhibit increased risk for tumor occurrence. Unfortunately, elucidation of the locoregional changes that contribute to increased tumor risk is difficult due to the inability to visualize the field. In this study, we use a non-invasive optical-based imaging approach to detail spatiotemporal changes in subclinical hyperemia that occur during experimental cutaneous carcinogenesis. After acute inflammation from 10 weeks of ultraviolet B (UVB) irradiation subsides, small areas of focal hyperemia form and were seen to persist and expand long after cessation of UVB irradiation. We show that these persistent early hyperemic foci reliably predict sites of angiogenesis and overlying tumor formation. Over 96% of tumors (57 of 59) that developed following UVB or DMBA/PMA treatment developed in sites of preexisting hyperemic foci. Hyperemic foci were multifocal and heterogeneously distributed and represented a minor fraction of the carcinogen-treated skin surface (10.3% of the imaging area in vehicle treated animals). Finally, we also assessed the ability of the anti-inflammatory agent celecoxib to suppress hyperemia formation during photocarcinogenesis. The chemopreventive activity of celecoxib was shown to correlate with its ability to reduce the area of skin that exhibit these hyperemic foci, reducing the area of imaged skin containing hyperemic foci by 49.1%. Thus, we propose that a hyperemic switch can be exploited to visualize the cancerization field very early in the course of cutaneous carcinogenesis and provides insight into the chemopreventive activity of the anti-inflammatory agent celecoxib.

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