Obesity is known to affect both the risk of developing cancer and the prognosis when diagnosed, but the mechanisms are still unclear. This study discovered how surrounding fat cells can reprogram cancer cells to become more aggressive, and why the effect is reinforced by obesity. This opens the door for the creation of molecules targeting the involved mechanisms.
Until now, the communication between tumor cells and fat cells was mostly attributed to small proteins excreted by the cells. Growing evidence also suggests the involvement of exosomes. These are small vesicles that are formed from part of the cell membrane and can contain a mix of molecules from the cell of origin. This way they are transported from one cell to another. It is unclear how this affects the cancer cells, resulting in worse outcomes.
The nuts and bolts
Exosomes were isolated from fat cells and used to investigate their effect on melanoma and prostate cancer cell lines, in vitro and in mice. The content of the exosomes was determined to investigate how they exert this effect.
The results confirm that mature fat cells secrete a lot of exosomes. These are taken up by the melanoma cells, which leads to an increased migration. For example, in mice, lung colonization of melanoma cells incubated with these exosomes was much higher than with control cells. This effect was also present in a prostate cancer model, indicating that the increase in aggressiveness induced by exosomes from fat cells could be more general in nature.
So what is the mechanism behind this effect? The exosomes from fat cells were found to be rich in proteins involved in the process of fatty acid oxidation (FAO), which is important in lipid metabolism. The transfer of functional enzymes has the ability to reprogram the tumor cells’ metabolism. The effect could be countered by the administration of molecules inhibiting these enzymes.
The worse outcomes of obese patients thus has a number of related causes. First, there is a clear correlation between the BMI and the number of exosomes. Second, the individual effect of each exosome is also greater in obese individuals. They increased migration more than the exosomes from lean individuals. These effects work in synergy, favoring tumor cell migration even more.
An alternative hypothesis that remains to be tested is the involvement of free fatty acids. These are also known to regulate FAO. As fat cells contain more lipids in obesity, their exosomes also contain more fatty acids, which could explain the increase in tumor cell migration.
How will this help me?
This study shows that exosomes from surrounding fat cells can transport molecules that reprogram the FAO process in the cancer cells. These new insights open the door for the investigation of FAO inhibitors in the treatment of cancer, especially in obese individuals. Such molecules are already used clinically for the treatment of other diseases such as angina pectoris. However, this requires more study and clinical trials before customized treatments for obese patients become a reality.
Adipocyte exosomes promote melanoma aggressiveness through fatty acid oxidation: a novel mechanism linking obesity and cancer – Cancer Research (2016)