Placental Development and Cancer Pathways

The early steps of placentation are reminiscent of the invasive properties of malignant tumors. Studies on DNA methylation in cancer cells and placental cells have highlighted similarities in their epigenomes, particularly, a widespread hypomethylation throughout the genome and focal hypermethylation at CpG islands. Hypomethylation within the placenta is not uniform but occurs in large domains (>100 kb) called partially methylated domains (PMDs) which are regions of reduced DNA methylation that cover approximately 40% of the placental genome [51]. PMDs are unique to a few di fferent tissue types that include the placenta, cultured and cancer cells [50,51,87]. Placental genes within PMDs tend to be tissue-specific and show higher promoter DNA methylation and reduced expression as compared with somatic tissues [51]. A genome-wide comparison of DNA methylation changes in placental tissues during pregnancy and in 13 types of tumor tissues during neoplastic transformation revealed that megabase-scale patterns of hypomethylation distinguish first from third trimester chorionic villi in the placenta [52]. These patterns mirror those that distinguish many tumors from the corresponding normal tissues. The genomic regions a ffected by this hypomethylation encompass genes involved in pathways related to EMT, immune response and inflammation, all of them associated to cancer phenotypes. Moreover, the authors observed that hypomethylated blocks distinguish vCTs before 8–10 weeks of gestation and after 12–14 weeks of gestation. The analogy between early placentation and malignant tumors at the epigenetic level is further stressed by studies analyzing the methylation status of the promoters of several tumor suppressor genes (RASSF1A, SERPINB5 also known as APC and Maspin, respectively) in the developing placenta and human choriocarcinoma cell lines (JAR and JEG3) [25,49]. These studies show that promoter DNA-methylation regulates the expression of these tumor suppressor genes which in turn a ffects the migration and invasive capacities of the trophoblastic cells (As summarized in Table 1).

#### 2.3.2. Non-coding RNAs and Epigenetic Regulation of Placenta Development
