Syncytiotrophoblastic giant cells in teratocarcinoma-like tumors derived from Parp-disrupted mouse embryonic stem cells

The enzyme poly(ADP-ribose) polymerase (Parp) catalyzes poly(ADP-ribosyl)at ion reaction and is involved in DNA repair and cell death induction upon DN A damages. Meanwhile, poly(ADP-ribosyl)ation of chromosome-associated prote ins is suggested to be implicated in the regulation of gene expression and cellular differentiation, both of which are important in tumorigenesis. To investigate directly the role of Parp deficiency in tumorigenicity and diff erentiation of embryonic stem (Es) cells during tumor formation, studies we re conducted by using wild-type J1 (Parp(+/+)) ES cells and Parp(+/+) and P arp(-/-) ES clones generated by disrupting Parp exon 1. These ES cells, irr espective of the Parp genotype, produced tumors phenotypically similar to t eratocarcinoma when injected s.c, into nude mice. Remarkably, all tumors de rived from Parp(-/-) clones contained syncytiotrophoblastic giant cells (ST GCs), which possess single or multiple megalo-nuclei. The STGCs were presen t within large areas of intratumoral hemorrhage. In contrast, neither STGC nor hemorrhage was observed in tumors of both wild-type J1 cells and Parp(/-) clones. Electron microscopic examination showed that the STGCs possess microvilli on the cell surface and contained secretory granules in the cyto plasm. Furthermore, the cytoplasms of STGCs were strongly stained with anti body against mouse prolactin, which could similarly stain trophoblasts in p lacenta. These morphological and histochemical features indicate that the S TGCs in teratocarcinoma-like tumors derived from Parp(-/-) clones belong to the trophoblast cell lineage. Our findings thus suggest that differentiati on of ES cells into STGCs was possibly induced by the lack of Parp during t he development of teratocarcinoma.