Insights into the cellular origin of cervical cancer

Cervical cancer is the fourth most common type of cancer in women and is almost always caused by infection with human papillomavirus (HPV), for which a vaccine is now available. Over 90% of these cancers occur in the transition zone between the outer cervix and the inner cervix – a critical region that is evidently prone to infections. Cancer development at this site is often preceded by so-called metaplasia – a process during which the cell types normally present in the tissue are replaced by other cell types. Despite their importance for cancerogenesis, it has so far remained unclear how exactly metaplasias arise. Prof. Thomas F. Meyer, emeritus-director at the Max Planck Institute for Infection Biology in Berlin and now senior professor at the Christian-Albrechts University of Kiel, together with his former research team, has now published important new insights into metaplasia development in the renowned scientific journal Nature Cell Biology.

The cell types of the neighbouring tissues meet in the transition zone

“We first analyzed the transition zone between the inner and the outer cervix in detail at the cellular level. So far, it has been scientifically controversial which cell types make up this transition zone,“ says Thomas F. Meyer, whose team completed the majority of the work while still in Berlin. To this end, they used stem cells from the original tissue to essentially reconstruct the tissue in culture, in the form of so-called organoids. “We were able to show that the transition zone does not consist of a separate cell type, as has been widely assumed, but rather that the two cell types of the neighbouring areas meet here,” explains Meyer. Specifically, this means the squamous epithelial cells that cover the outer cervix, and the columnar epithelial cells that cover the inner cervix.

Opposing signals regulate which cell type is active where

„In order to understand how these two cell types give rise to metaplasias and ultimately to cancers, it is important to find out how these cells and their respective development are regulated,“ explains first author Dr. Cindrilla Chumduri, who is now a group leader at the Biocenter of the University of Würzburg. „Here we made a surprising discovery: The neighbouring epithelial cell types that meet at the transition zone are dependent on opposing cellular signals.” Accordingly, the columnar epithelial cells of the inner cervix require a specific signal to survive, which is sent via the so-called Wnt pathway, and which plays an important role in the maintenance of many tissues. By contrast, the squamous epithelial cells of the outer cervix are suppressed by precisely this signal.

Shifting of the signals leads to metaplasia

„We were able to show that a concentration gradient of these signals in the immediate environment of the cells is responsible for maintaining the two cell types that meet here. If this gradient shifts into one direction, then one cell type also shifts into the territory of the other – giving rise to metaplasia,“ according to first author Dr. Rajendra Gurumurthy, also formerly at the Max Planck Institute of Infection Biology in Berlin. The researchers were able to show in a mouse model that vitamin A deficiency, for example, leads to such a signal shift. As a result, squamous epithelial cells became activated in the inner cervix, and replaced the columnar epithelial cells normally present in this area.

 „The model we developed now enables investigations of the biological behaviour of transition zones in the lab for the first time, so we can begin to understand metaplastic changes. In particular, even though we know that HPV virus plays a causative role in the development of cervical cancer, it has remained unclear so far how the virus is able to reach and infect its target cells – the basal cells that are “buried” under several layers of squamous epithelial cells. Nor do we know how infection promotes the development of metaplasia. Ultimately, our findings will help to improve early detection of cervical cancer, and to develop precise strategies for prevention and improved treatments” says Meyer, who as senior professor in Kiel is now also part of the Cluster of Excellence Precision Medicine in Chronic Inflammation (PMI). "As the next step, we can now try to better understand the external influences and processes that lead to a signal change in the immediate cell environment, and thus to metaplasia formation. Preliminary findings also suggest a possible role of inflammation in this context. We can investigate this in future studies, also together with our colleagues at the PMI Cluster of Excellence," adds Meyer.