Although tumor metastasis causes about 90 percent of cancer deaths, the exact mechanism that allows cancer cells to spread from one part of the body to another is not well understood. One key question is how tumor cells detach from the structural elements that normally hold tissues in place, then reattach themselves in a new site.
A microscopic image of cancer cells adhering to a spot coated with molecules found in the extracellular matrix.
Image: Nathan Reticker-Flynn
A new study from MIT cancer researchers reveals some of the cellular adhesion molecules that are critical to this process. The findings, published Oct. 9 in Nature Communications, offer potential new cancer drug targets, says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, and leader of the research team.
“As cancer cells become more metastatic, there can be a loss of adhesion to normal tissue structures. Then, as they become more aggressive, they gain the ability to stick to, and grow on, molecules that are not normally found in healthy tissues but are found in sites of tumor metastases,” says Bhatia, who is also a member of the David H. Koch Institute for Integrative Cancer Research at MIT. “If we can prevent them from growing at these new sites, we may be able to interfere with metastatic disease.”
Lead author of the paper is Nathan Reticker-Flynn, a PhD student in Bhatia’s lab. Other authors are former students David Braga Malta and Mary Xu, postdocs Monte Winslow and John Lamar, and research scientist Gregory Underhill. In addition, Richard Hynes, the D.K. Ludwig Professor of Biology and a member of the Koch Institute, and Tyler Jacks, director of the Koch Institute, are contributing authors on this study.
Losing and gaining adhesion
Cells inside the human body are usually tethered to a structural support system known as the extracellular matrix, which also helps regulate cellular behavior. Proteins called integrins, located on cell surfaces, form the anchors that hold the cells in place. When cancer cells metastasize, these anchors let go.
In this study, the researchers compared the adhesion properties of four types of cancer cells, taken from mice genetically engineered to develop lung cancer: primary lung tumors that later metastasized, primary lung tumors that did not metastasize, metastatic tumors that migrated from the lungs to nearby lymph nodes, and metastatic tumors that travelled to more distant locations such as the liver.
Building on a system they first described in 2005, the scientists developed technology allowing them to expose each type of cell to about 800 different pairs of molecules found in the extracellular matrix. After depositing cells onto a microscope slide in tiny spots — each containing two different extracellular matrix proteins — the researchers could measure how well cells from each tumor type bound to the protein pairs.
The new technology is a huge step forward from current experimental methods for studying cellular adhesion, which are limited to much smaller numbers of cells and adhesion molecules, says Jan Pilch, an assistant professor at the University of Pittsburgh School of Medicine.
“They’ve not only scaled this up dramatically, they’re able to study the adhesion proteins in combination, which allows them to identify adhesion synergies,” says Pilch, who was not part of the research team.
The researchers were surprised to find that adhesion tendencies of metastatic cells from different primary tumors were much more similar to each other than to those of the primary tumor from which they originally came. One pair of extracellular matrix molecules that metastatic tumors stuck to especially well was fibronectin and galectin-3, both made of proteins that contain or bind to sugars.
Although metastatic tumor cells share adhesion traits, they may take different pathways to get there, Reticker-Flynn says. Some tumor cells alter the combination of integrins that they express, while others vary the types of sugars found on their surfaces. All of these changes can result in higher or lower affinities for certain molecules found in the extracellular matrix of different tissues.
In an analysis of human tumor samples, both primary and metastatic, the researchers saw similar patterns. Specifically, they found that the more aggressive the metastasis, the more galectin-3 was present.
Previous studies have suggested that tumors pave the way for metastasis by secreting molecules that promote the development of environments hospitable to new cancer growth. Accumulation of galectin-3 and other molecules that help tumor cells colonize new sites may be part of this process, the researchers say.
“There’s a lot of evidence to suggest that a hospitable niche for the tumor cells is being established prior to the cells even arriving and establishing a home there,” Reticker-Flynn says.
Preventing cancer spreadThe findings offer potential new ways to block metastasis by focusing on a specific protein-protein or protein-sugar interaction, rather than a particular gene mutation, Reticker-Flynn says. “If those changes do confer a lot of metastatic potential, we can start thinking about how you target that interaction specifically,” he says.
To help with efforts to develop such drugs, the research team is now trying to figure out the details of tumor cells’ interactions with galectin-3 and is developing new candidate therapeutics aimed at inhibiting those interactions.
The research was funded by Stand Up to Cancer, the Koch Institute Circulating Tumor Cell Project, the Harvard Stem Cell Institute, the National Cancer Institute, the Howard Hughes Medical Institute and the Ludwig Center at MIT.
Sarah McDonnell | EurekAlert!
The importance of biodiversity in forests could increase due to climate change
17.11.2017 | Deutsches Zentrum für integrative Biodiversitätsforschung (iDiv) Halle-Jena-Leipzig
Win-win strategies for climate and food security
02.10.2017 | International Institute for Applied Systems Analysis (IIASA)
Heat from the friction of rocks caused by tidal forces could be the “engine” for the hydrothermal activity on Saturn's moon Enceladus. This presupposes that...
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
23.11.2017 | Information Technology
23.11.2017 | Physics and Astronomy
23.11.2017 | Life Sciences