The study, published in the Sept. 18 online issue of the Journal of Cell Biology, helps illuminate the very first steps involved in metastasis, the spread of cancer that makes the disease difficult to treat, and suggests that a future designer drug might be able to block the beginning of this dangerous process, or stop it once it starts.
"Our data show that this one protein, p120 catenin, is a key player in both suppressing invasion and promoting it," says the study's senior author, Panos Anastasiadis, Ph.D., a Mayo Clinic cancer researcher. "This is very exciting, because the findings open up a whole new field of discovery for novel therapeutics that should be applicable to most types of tumors."
Their laboratory study looks at how p120 catenin interacts with different cadherin cell adhesion proteins in cancer cells. Cadherin proteins go through a cell membrane, and on the outside, they act like Velcro, sticking to other cadherin proteins on adjacent cells. On the inside of the cell membrane, cadherins bind, chain-like, to catenins, and catenins, in turn, regulate a cell's shape and function.
The best understood cadherin is E-cadherin, which provides tight connections between epithelial cells, forming a strong barrier-like layer covering the inside of organs and body cavities and the outside skin of humans. "E-cadherin holds a human's cells and tissues together," Anastasiadis says.
The other cadherins featured in this study belong to a group that collectively is called "mesenchymal" cadherins, which provide a looser bond between the cells that sparsely populate the connective tissue. "Collagen usually provides the strength to the connective tissue, so tight cell-cell adhesion is not that important," he says.
Sometimes, such as during human development or wound repair, epithelial cells need to travel to other areas, and to do this, they undergo a process known as "epithelial-mesenchymal transition" (EMT). The cell reduces its production of E-cadherin proteins and increases expression of mesenchymal cadherins, thus effectively loosening the anchors that keep the cell bound to its neighbors.
Cancer, unfortunately, has adopted this strategy in order to spread, Anastasiadis says. "When the function of E-cadherin is lost in a cell, it can break free from its neighbors and travel to settle elsewhere," he says. "This means that E-cadherin normally helps suppress invasion."
But researchers have noted that the p120 catenin protein seems mysteriously two-faced: while it normally strengthens cell-cell bonding, in some cases it can also negatively affect cell adhesion. They also have found that over production of p120 increases a cell's ability to move. But the significance of these observations had eluded scientists.
In this study, Masahiro Yanagisawa, M.D., Ph.D., a research fellow in Anastasiadis' laboratory, and Anastasiadis provide an answer as to why p120 acts this way, which helps explain how the EMT shift between E-cadherin and mesenchymal cadherins allows cancer cells to break away from tissue and spread.
They found that p120 "prefers" to bind to E-cadherin, rather than to mesenchymal cadherins. So in normal epithelial cells p120 always associates with the more abundant E-cadherins. But when E-cadherin production is lost during the progression of cancer, p120 catenins begin binding to mesenchymal cadherins. And when that happens, the researchers found that p120 unexpectedly switches on a cascade of events that promote cell movement.
"We show that E-cadherin suppresses invasion, at least in part, by binding to p120 protein in the cell," Anastasiadis says. "If E-cadherin is missing, p120 is free to bind to mesenchymal cadherins, setting off a process that leads to metastasis."
Thus, p120 acts as a "rheostat" that promotes either stability when associated with E-cadherin or motility when it interacts with mesenchymal cadherins, he says.
The investigators say that further research is needed to see if p120 functions the same way in living tissue as it does in laboratory cell culture, and they add that other "pathways" are likely involved in the transition to metastasis. But if the results continue to hold up, "it might be therapeutically possible to selectively shut down the pro-invasive function of p120 on mesenchymal cadherins while keeping the pro-adhesion function of p120 in normal epithelial cells.
"We have provided a better understanding of the processes involved in the initiation of tumor spread, and it is this process that we all seek to shut down," Anastasiadis says.
Christine Leon | EurekAlert!
Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz
Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences