Placental pseudo-malignancy from a DNA methylation perspective: unanswered questions and future directions

Abstract

The growing fetus is dependent on adequate placental function for delivery of essential nutrients and oxygen, and for waste removal. The placenta also plays an important protective role; shielding the developing baby from the maternal immune system and adverse environmental exposures. Fundamental to these processes is correct invasion of the decidua and remodeling of maternal vasculature, each of which show remarkable parallels to tumorogenesis, with the obvious exception that the former is usually a tightly controlled process. It is not surprising that these physiological similarities are mirrored in gene expression and epigenetic parallels, many not found in any other aspect of human development. In this perspective, we summarize known DNA methylation similarities between placenta and human tumors, and discuss the implications and knowledge gaps associated with these findings. We also speculate on the potential origin of common DNA methylation features in these two disparate aspects of human physiology.

Association of Aberrant Methylation at Promoter Regions of Tumor Suppressor Genes with Placental Pathologies

“…These observations highlight the importance of epigenetic regulation in mediating differential mRNA expression of RASSF1A and APC during advancing gestation in normal pregnancy. The observed hypermethylated pattern of APC and RASSF1A is consistent with the earlier studies [21,25,45,46] and supports the similar pattern of epigenetic regulations between placentation and tumorigenesis [47].…”

Epigenetic modifications at DMRs of placental genes are subjected to variations in normal gestation, pathological conditions and folate supplementation

“…The most prominent physiological resemblances between placentation and cancer development is the proliferation and invasion of cells into surrounding tissue. Such resemblances are attributed to similar expression of various growth factors and tumor like methylome in placenta34. However, unlike cancer development the proliferation and invasion processes exhibited by placental trophoblasts are tightly regulated during normal placentation.…”

“…There are many shared molecular mechanisms between invasive placentation and metastasis, especially in terms of the factors which enhance growth123. These similarities also appear at key epigenetic mechanisms4. Additionally the placental growth seems to be enhanced by paternally expressed genes, which are known to show growth promoting phenotype5.…”

ITPKA Gene Body Methylation Regulates Gene Expression and Serves as an Early Diagnostic Marker in Lung and Other Cancers

“…Placental tissues include cytotrophoblast and syncytiotrophoblast, and the extravillous trophoblast cells in the placenta have been demonstrated to migrate, invade, and remodel the maternal decidua and develop a vascular supply in a manner similar to cancers. 38 In addition, many tumor suppressor genes and oncogenes are thought to play important roles in normal placental development, and the epigenetic program of the placenta shows some similarities to those of cancer cells. 39,40 These findings support the concept that the placenta may be regarded as a self-limited malignancy.…”