In many mammals, including humans, the placenta invades the wall of the uterus during pregnancy in the same way that cancer cells invade surrounding tissues. An animal study by researchers from the University of Connecticut (UConn) Health and Yale University has made new advances connecting the evolution of pregnancy and cancer metastasis.

Their study is published in the journal Proceedings of the National Academy of Sciences, in a paper titled, “Tracing the cis-regulatory changes underlying the endometrial control of placental invasion.”

“Among eutherian (placental) mammals, placental embedding into the maternal endometrium exhibits great differences, from being deeply invasive (e.g., humans) to noninvasive (e.g., cattle),” the researchers wrote. “The degree of invasion of placental trophoblasts is positively correlated with the rate of cancer malignancy. Previously, we have shown that fibroblasts from different species offer different levels of resistance to the invading trophoblasts as well as to cancer cell invasion. Here we present a comparative genomic investigation revealing cis-regulatory elements underlying these interspecies differences in invasibility.”

Yasir Suhail, PhD, a postdoctoral researcher working alongside Kshitiz, PhD, assistant professor in the department of biomedical engineering, uncovered regulatory sequences in the genomes of mammals including cows, pigs, horses, and humans that explain how endometrium is invaded by the placenta, and how normal tissue is invaded by cancer.

“When you look at a picture of placentation, it looks eerily similar to cancer in any other part of the body,” said Kshitiz. “Even the molecular mechanisms are quite similar. This is quite a contrast from cows and horses, where the placenta does not invade into the mother. In these mammals, cancer cells also do not invade into their surroundings as they do in humans.”

Looking at cells from the endometrium of various species, the researchers observed that in order to resist invasion of the placenta, certain species have evolved over time to make their stromal cells—the connective tissue cells in an organ—highly resistant to any invasion.

“Our new framework identifies key transcription factors and examines how their targets differ from cows, pigs, and horses to humans,” said Suhail. “What we learned from other species has direct applications in advancing our understanding of human cancer.”

Suhail used the genomic sequences and gene expression information to predict specific signaling proteins that drive the expression of genes that decrease the susceptibility of invasion in human cells. Using a custom fabricated bio chip, the researchers were able to confirm that these predicted proteins did in fact decrease the invasion of both cancer and placental cells. Evolutionary predictions across species are difficult to test experimentally, so confirmation of the theory experimentally is very satisfying to the researchers.

“We all think about human cancers are an outcome of cancer cells themselves. But what we’ve proposed is that mammals have very different mechanisms to resist cancer spread, and that these mechanisms have actually been derived to resist fetal invasion into the mother,” Kshitiz said. “To be vulnerable to malignancy may partly be an evolutionary compromise to allow an invasive pregnancy.”

While other researchers are targeting cancer and immune cells, Kshitiz’s approach can help change the way cancer therapies are usually approached.

“This study identifies specific genetic regulatory mechanisms which explain these differences, and point us towards many directions to rethink about anticancer therapy, from those that kill cancer to creating new therapies which ‘contain’ cancer within its boundaries.”