Senescent cells released fructose after cisplatin treatment and helped ovarian cancer spread in mouse models

Senescent cells released fructose after cisplatin treatment and helped ovarian cancer spread in mouse models

In a Nature Aging paper published on July 30, the authors traced this sequence in high-grade serous ovarian cancer cells and in mice. Fructose from the medium in which post-chemotherapy cells had been cultured altered the metabolism of neighboring tumor cells and made it easier for them to detach.

Cisplatin damages DNA in tumor cells. After this damage, some cells stop dividing but remain alive and release molecules into their surroundings. This state is called senescence. The substances released by these cells are collectively known as the SASP, or senescence-associated secretory phenotype.

In the Nature Aging paper, the researchers studied high-grade serous ovarian cancer, a common and aggressive subtype of ovarian cancer. They collected the medium in which cisplatin-treated senescent cells had been cultured and added it to dividing cells from the same cancer. Within tumor cell clusters, the cells detached from one another more often. When the researchers administered this medium to mice three times a week, more tumor nodules developed in the abdominal cavity.

The authors searched for the active component among small molecules. Heating the medium did not eliminate the effect, nor did passing it through a filter that retained proteins and large vesicles. Mass spectrometry showed that the medium contained more fructose and less glucose. Adding fructose alone caused the cells to detach. Blocking its uptake into cells or its breakdown eliminated the effect.

In the authors' model, fructose acted as a signal from one tumor cell to another. Through the AMPK protein, it activated mitochondrial complex I, after which the cell produced less cholesterol. Cholesterol in the cell membrane helps cells remain attached to one another. As cholesterol levels fell, these connections weakened, making it easier for cells to enter the abdominal cavity. Disabling part of complex I or the enzyme that breaks down fructose reduced tumor spread in mice.

The SASP is often described in terms of inflammatory proteins. This study adds a sugar to that profile: chemotherapy leaves some cells in a senescent state, fructose released by these cells alters the behavior of neighboring tumor cells, and those cells detach from the tumor more readily.