INVASION OF THE CELL SNATCHERS
HOW CELLS CONTROL EACH OTHER.
Imagine a colony of identical individuals. From the outside, they all look the same – peaceful and docile. But inside one, a revolution is stirring: changes to the instruction code are being made and this individual is about to break from the tracks. As part of this betrayal of the collective, the rogue individual sends out dozens of tiny packets into the ether trying to convince the other individuals that they want to join - to ‘snatch’ their bodies for the cause! Soon, there are more and more infected individuals and the collective is starting to break down.
This seems a lot like the plot from Invasion of the Body Snatchers but it happens every day in our bodies. Cells can control each other from a distance by sending out packets, called exosomes, that invade other cells and can take control . This article will focus on the many ways exosomes work in our bodies.
WHAT ARE EXOSOMES?
Exosomes are small pieces of the cell’s outer coating (plasma membrane) that pinch off to form spheres (vesicles). These little packages, because they are made out of the same material as the outside of a cell, can fuse with a different recipient cell. Exosomes have been isolated from many bodily fluids and recent studies have supported the hypothesis that exosomes have an important role in communication between cells. They can carry a wide range of cargo - including lipids, DNA, RNA, and protein - that can affect the receiving cell. Once the exosomes are sent out by a cell, they can follow two different paths, either: a) they can be taken up by neighboring cells; or b) they can be released into the bloodstream and be delivered to far away cells in other organs. This allows them to be a versatile carrier of both long-range and short-range messages inside the body.
RECEIVING A PACKAGE FROM THE CELLULAR FEDEX
How do these cellular packages know where in the body they should go? Although this question has not been fully answered, a recent study provided some clues. Researchers found that small, sticky proteins on the outside surface of exosomes (called integrins) allow the exosomes to attach to only particular types of cells. This integrin system acts as a address directing the exosome packets, which are only delivered to cells containing a particular molecular address.
Once the exosome delivery is taken up by the cell, it can begin to affect the cell. An important discovery in exosome biology was that the RNA molecules that were delivered by an exosome could be used by the recipient cell, in a novel form of information exchange between the two cells. How did scientists show this? Remember the fundamental way that information flows between biological molecules in a cell (Figure 1). DNA is converted to RNA that is then made into protein, the final ‘machine’ that does work in the cell.
Figure 1: Information transfer between biological molecules in the cell.
To understand how a cell was affected by receiving an exosome, researchers performed an experiment where they gave a mouse cell human exosomes containing human RNAs. The mouse cells were able to take up these exosomes and use the RNAs inside them to make proteins that are only found in humans! This is similar to buying a new book - now you can read a text that you never had before. The ability to send RNA messages is a powerful way for healthy cells to communicate with each other and coordinate the many complicated actions of your multicellular body.
AN EXOSOME IS WORTH A THOUSAND WORDS
The normal function of exosomes is to communicate messages between cells as a part of their healthy function. One of the first exosome functions in healthy cells was shown for the immune system. In this context, the exosome packages and their contents are used to coordinate the attacks of the immune cells against foreign invaders (like viruses) to your body. However, like all parts of a cell’s function, incorrect usage can lead to disease. Exosomes have been found to carry proteins from neurons suffering from degenerative diseases. For example, the gradual loss of neurons in Parkinson’s disease are caused by the accumulation of proteins in disorganized clumps. This is toxic to the cell because it prevents many normal processes (imagine that no one was taking out the garbage on your street block). A study from a group in the Mayo Clinic showed that neurons with a lot of these clumps of protein will release some of these clumps in exosomes, potentially as a way to decrease the toxicity for themselves. Unfortunately, other healthy cells are able to take up these exosomes packet and now receive the toxic clumps.
THE ‘SEED AND SOIL’ HYPOTHESIS OF CANCER
In 1889, Stephen Paget suggested a hypothesis for why cancer cells from the primary tumor (where the cancer first arises) only metastasize to specific areas of the body. He suggested that certain organs or areas of the body have the correct ‘soil’ to help the cancer ‘seed’ survive and grow, allowing these secondary tumors to arise. This is now known as the ‘seed and soil’ hypothesis of cancer. Although there was a lot of circumstantial evidence to support this idea, how this might actually be happening in the body is still not well understood. Exosomes, and the messages they carry, give one possible explanation for this phenomenon. In a recent study, scientists from Memorial Sloan Kettering Cancer Center found a role for exosomes in the metastasis of pancreatic cancer. By looking at exosomes from patients with aggressive cancer progression, compared to those with less aggressive disease, they were able to notice subtle differences between the exosome cargoes. For example, exosomes from patients with aggressive cancers carry molecules (such as RNA) that ‘reprogram’ certain cell types in the liver, where the metastasis will eventually occur. The cells in the liver that receive the signals from the tumor now begin to change and make the tissue around them more ‘welcoming’ for the tumor cells to grow in. This includes making the tissue of the liver easier for the cells to attach to as well as changing the immune system’s ability to survey the liver. This is akin to the way that a farmer would weed and till the soil before planting seeds in the pancreas to other types of cells. Other studies have also backed up this idea, giving cancer biologists a better understanding of how metastasis occurs. This understanding of exosomes is critical for cancer care, as most patients will die from the metastasis of the original (primary) tumor.
EXOSOMES AS A MEDICAL TOOL
As the examples above illustrate, exosomes have the ability to dramatically change a cell’s behavior, both for good and bad! Inspired by this idea, medical researchers are working on using exosomes to direct a diseased cell on the right course. These exosomes could either be isolated from healthy cells and given to the patient or could be manufactured and packed with the appropriate cargo. Some trials for this type of therapy are underway. For example, exosomes from mesenchymal stem cells (a cell type that makes many of the cells in your musculoskeletal system) were given to patients suffering from severe graft versus host disease (a condition where a patient getting a transplanted organ has a very aggressive immune reaction against the organ). These exosomes had been shown to have anti-inflammatory effects, and were able to calm many of the symptoms that the patients had. Exosomes can also be used as ‘nano-carriers’ of drugs. Because they are able to very specifically target a certain cell type or tissue, they can carry the drug to area that need to while avoiding side effects to other cells. For example, exosomes have been loaded with various anticancer drugs and used to treat mice with tumors. In the future, as we understand more about these little cellular packages and how they are made, we may be better able to use them to treat complicated diseases.
IN SICKNESS AND IN HEALTH
As cell biologists discover more ways that cells behave and communicate inside our bodies, we begin to shed light on the many fascinating behaviors that they exhibit. Although exosomes in healthy cells carry good messages, sick cells can send messages that turn cells into messy neighbors causing the disease to spread. Although our understanding of how exosomes allow cells to control each other from a distance remains far from complete, the information we’ve gained has already allowed us to engineer new therapeutic devices using exosome as nano-sized package delivery trucks.
