No abstract

During pregnancy, fetal cells enter the maternal circulation. These may be mesenchymal stem cells, haematopoietic or endothelial progenitors, which may persist for decades and be recruited to damaged maternal tissues. Recently, fetal cells were also identified in tumour tissues such as cervical cancer and breast carcinomas. However, the timing of malignant tumour infiltration was not demonstrated. In this study, we used two step carcinogenesis to assess the presence of fetal cells in early phases of skin tumour formation in previously pregnant mice. Wild-type female C57/BL6 mice were bred to transgenic mice for EGFP. After delivery, skin papillomas were induced by two-step carcinogenesis. The tumours were dissected 9 months after gestation. Fetal cells were identified in 75% of cutaneous papillomas (9/12 tumours), but never in normal skin from the same mice. Fetal cells expressed von-Willebrand factor, and less frequently CD45 or cytokeratin but did not express the tumoral epidermal keratins. Our study shows that long-term engrafted fetal cells home to early stage skin tumours where they participate in formation of the stroma. ' 2008 Wiley-Liss, Inc.Key words: two step carcinogenesis; pregnancy; fetal cells; microchimerism In a relatively frequent number of situations, a low number of donor cells are found in the peripheral blood or the tissues of a genetically different recipient. This phenomenon, called microchimerism, results mainly from pregnancy. Indeed, during gestation, fetal cells cross the placenta, enter the maternal circulation and persist after delivery in 20-50% of women.1 Solid organ transplantation, red blood cell transfusion or exchange between twins also lead to a similar microchimerism. The fetal cells transferred to the mothers include hematopoietic progenitors in humans 3,4 and mouse models 5 as well as mesenchymal stem cells.6 Several studies have shown that fetal cells are able to migrate to damaged maternal tissues such as thyroid, liver, intestine or cervix in humans 7,8 and liver, kidney, skin or brain in mouse models. [9][10][11][12] In these tissues, fetal cells may adopt the phenotype of the affected organ. 13 The participation of microchimeric cells in tumours developing in the recipient has been a subject of interest in the past years. Indeed, Kaposi sarcomas developing after kidney transplantation have been shown to derive mainly from donor cells.14 We have recently described the participation of donor derived cells in malignant skin tumours developing after organ transplantation. 15 In one case, the tumour was composed of donor derived keratinocytes suggesting that progenitor cells of donor origin had engrafted in the recipient skin and underwent transformation upon exposure to carcinogenic stimuli. However, in most cases of this study, skin tumours contained chimeric cells but did not originate from these. Besides, the participation of fetal cells in maternal tumour stroma has also been suggested in breast cancer during gestation. 16 However, to date, only few studies have consi...

The phenotype of perivascular placental cells has previously been studied using tissue sections from the fetal villi. The examination of these cells in culture by scanning electron microscopy gives us the opportunity to observe their three-dimensional phenotypes and associations outside their normal constraints. Human umbilical endothelial cells, which have a phenotype comparable to that observed in other studies, seem more flattened in culture than in their usual environment. Microvascular endothelial cells did not attain an epithelioid phenotype with close contacts between cells but formed a network of branched, elongated cells with phagocytotic activity. Some circular associations were observed when using a gelatinized matrix. Microvascular pericytes were large, flattened cells with an irregular border that pushed up nodular associations on a gelatin matrix. Chorioplacental myocytes adopted a network template comparable to that developed by microvascular endothelial cells. However, these elongated cells were thicker, without microvilli, and superficial filaments could be observed. In culture, confluent endothelial cells from the umbilical cord or microvascular pericytes associated as nodules reached a cell phenotype close to their in vivo counter-parts. This attainment of an in vivo phenotype remains questionable for chorioplacental myocytes. Microvascular endothelial cells, however, though there was sparse formation of circular associations, remained far from their in vivo phenotype.