Parp-1 deficiency in ES cells promotes invasive and metastatic lesions accompanying induction of trophoblast giant cells during tumorigenesis in uterine environment.

Embryonic stem (ES) cells deficient in poly(ADP-ribose) polymerase-1 (Parp-1) develop into teratocarcinomas with the appearance of trophoblast giant cells (TGCs) when injected subcutaneously into nude mice. Because the uterus is one of the original organs in which germ cell tumors develop with induction of trophoblast lineage, here we investigated whether Parp-1 deficiency in ES cells affects teratocarcinoma formation processes by grafting ES cells into the horns of uteri. Teratocarcinomas developed from both wild-type (Parp-1(+/+) ) and Parp-1(-/-) ES cells. The weights of the tumors derived from Parp-1(-/-) ES cells were lower than those of the tumors derived from Parp-1(+/+) ES cells (P < 0.05). The Parp-1(-/-) tumors showed the appearance of TGCs. Notably, organ metastasis to the lung and liver was observed for the Parp-1(-/-) tumors, but not for the Parp-1(+/+) tumors (P < 0.05). Invasions were more frequently observed with the Parp-1(-/-) tumors compared with the Parp-1(+/+) tumors (P < 0.05). Since TGCs are known to have invasive properties, the appearance of TGCs may have supported the metastatic process. The present findings suggest that loss of Parp-1 during teratocarcinoma formation might augment invasive and metastatic properties of the tumors in the uterine environment.