Blocking ovarian cancer's energy supply helps curb spread

It is often the case that an ovarian cancer diagnosis reveals that the tumor has already spread to nearby tissue. Now, scientists have discovered a potential way to cut off the energy supply fueling this invasive stage of ovarian cancer.

A new study, led by the University of Chicago in Illinois, has unraveled the role of glycogen in fueling ovarian cancer spread.

It is the first to reveal how tumor cells interact with support cells called cancer-associated fibroblasts to make this happen.

"No systematic study," says senior study author Ernst Lengyel, who is a professor of obstetrics and gynecology at the university, "of the signaling pathways initiated by human cancer cells and cancer-associated fibroblasts has been performed."

He and his colleagues report their recent findings in a paper that now features in the journal Cell Metabolism.

"We think this could have significant clinical implications," claims Prof. Lengyel.

Ovarian cancer and metastasis

The ovaries are female hormone-producing glands that make eggs. Each woman has two ovaries; one on either side of the uterus. About once per month, a mature egg carrying the biological mother's genes travels through a fallopian tube to the uterus.

There, it is made ready for fertilization by sperm, which carries the biological father's genes. A fertilized egg then becomes a fetus that has genes from both parents.

Ovarian cancer starts when cells in the ovaries or fallopian tubes grow out of control and form a tumor.

The American Cancer Society (ACS) estimate that around "22,240 women" in the United States will find that they have ovarian cancer and around 14,070 will die of the disease in 2018.

In nearly 4 out of 5 cases of ovarian cancer, the tumor has already invaded the omentum, a curtain of fatty tissue that hangs over the intestines, at the time of diagnosis.

Once the cancer has penetrated this "energy-dense fat pad," it speeds up. The process of spread, which begins with tissue invasion, is called metastasis and is complex and multistaged.

The next stage is when tumor cells travel through the bloodstream and lymph system to set up new tumors in other parts of the body.

Metastatic cancer is much harder to treat than cancer that is confined to the primary tumor, and it is the main reason for cancer deaths.

Mobilizing energy supplies

In the case of ovarian cancer, as the tumor invades the omentum, it depletes its fat cells and then recruits cells called cancer-associated fibroblasts to help it take the next step.

The fibroblasts speed up metastasis by helping cancer cells get the resources they need to grow and proliferate, such as increasing blood supply to the tumor and mobilizing energy supplies.

Prof. Lengyel and his colleagues investigated the signals that go back and forth between human ovarian cancer cells and cancer-associated fibroblasts.

They did this by growing ovarian cancer cells and fibroblasts together in the laboratory and then using a method called "quantitative phosphoproteomics" to monitor their "cellular crosstalk."

The investigators found that chemical signals from the fibroblasts trigger the cancer cells to metabolize their own stored glycogen into glucose.

This ready supply of glucose fuels the invasion of other tissues, which, in turn, leads to a more aggressive tumor and rapid metastasis.

Blocking energy supply

The researchers suggest that there could be a way to halt or slow the invasion process. They found that a signaling pathway called p38α MAPK activated glycogen mobilization in the cancer-associated fibroblasts.

They also revealed that disrupting the enzymes involved in this pathway, or blocking the signaling pathways that trigger glycogen metabolism in the cancer cells, "reduced metastasis."

They suggest that this could be a "therapeutic strategy" for reducing "abdominally metastasizing" tumors following surgery.

"This is the first time that the role of glycogen in cancer metastasis has been thoroughly investigated."

Prof. Ernst Lengyel