Stromal resistance to placental invasion is a derived trait in ruminants.

Placentation exhibits remarkable diversity among mammals, with reported correlations in cancer malignancy and invasiveness of placenta. Challenging the antagonistic pleiotropy hypothesis, which links evolution of invasive placentation to cancer malignancy, we had proposed the Evolved Levels of Invasability (ELI) framework for species with non-invasive epitheliochorial placentation. ELI posits that maternal stromal fibroblasts in epitheliochorial species evolved resistance to trophoblast invasion, secondarily limiting cancer dissemination in other tissues. Recent experiments with even-toed ungulate endometrial fibroblasts (ESFs) revealed that ESFs from ruminants (bovine and sheep) strongly resist trophoblast invasion, whereas porcine fibroblasts exhibit low resistance to invasion. Ruminants display synepitheliochorial placentation, formation of fetal-maternal hybrid epithelial cells are positioned to be in direct contact with maternal stroma. The ruminant condition, however, is evolutionarily derived from epitheliochorial placentation, as seen in pigs, where the trophoblast does not breach the luminal epithelium at all and the trophoblast is never in contact with the stroma. This experimental finding is consistent with our refined ELI hypothesis positing evolution of stromal resistance to invasion in synepitheliochorial placentation, where maternal stroma and trophoblasts are in direct contact with each other, but less resistance in pigs where the stroma does not directly interact with the trophoblast. The non-assortative sorting of placental types across clades offers opportunities to uncover mechanistic processes governing cellular invasion and tissue homeostasis.