Quiescent ovarian cancer cells secrete follistatin to induce resistance in neighboring cells

Researchers have discovered a mechanism by which chemotherapy-resistant ovarian cancer cells signal neighboring cells to enter a similarly resistant state. A team from the University of Pittsburgh observed a so-called quiescent state. ovarian cancer Characterized by very slow growth, the cells overexpress a normal ovarian protein called follistatin. This protein acts as a signal to local cancer cells to grow more slowly and avoid killing by chemotherapy. This research clinical cancer research.

“We found that follistatin reduced the growth of ovarian cancer cells,” said the first author. Dr. Santiago Paneso, M.D.Working in the lab of Ronald Buccanovich, M.D., Ph.D., he is a professor of medicine at Pitt University and co-director of the Center for Women’s Cancer Research, which studies mechanisms of chemoresistance. While this may seem desirable, slow-growing cells can develop resistance to standard chemotherapy. This is part of the reason why nearly 70% of ovarian cancers recur and actively recur.

The team’s efforts have mainly focused on cells that rely on quiescence as they enter reversible cell cycle arrest. During quiescence, cancer cells acquire new mutations that allow them to survive and then regrow. It is also the time when cells become chemoresistant and shun immune cells.

In a previous study, the team found that follistatin was one of the proteins upregulated in another type of quiescent cell in hair follicles. From there, the team wanted to see if follistatin had a role in quiescent ovarian cancer cells.

In this new study, the researchers found that in both laboratory-expanded human ovarian cancer cells and mice xenografted with human quiescent ovarian cancer cells, quiescent cells expressed follistatin in response to chemotherapy drugs. found to increase production.

Next, we showed that quiescent cells arrest the growth of adjacent, actively dividing cancer cells and confer resistance to chemotherapeutic drugs. First, they added medium from quiescent cells and showed that the cells grew more slowly. The same effect was observed when quiescent cells were co-cultured with normal proliferating cells. They grew more slowly and were more chemoresistant.

“Dormant cells appear to have the ability to communicate with other cells to slow down to avoid being killed if they are susceptible to chemotherapy during division, and how follistatin does that. “By telling neighboring cells to slow down, we create a loop of resistance.”

When the team blocked follistatin with a research-specific antibody, this effect was lost, demonstrating that follistatin promotes chemotherapy resistance.

To further confirm the role of follistatin in promoting chemoresistance, the research team genetically deleted the gene encoding follistatin in tumor cells. This gene causes an aggressive and incurable form of ovarian cancer in mice. The results were dramatic. After chemotherapy, 30% of mice with tumors lacking follistatin were cured, whereas all mice with normal tumors died.

The team then analyzed Cancer Genome Atlas data from hundreds of ovarian cancer patients. They showed that higher levels of follistatin were associated with lower survival rates, indicating that follistatin also affects the ovaries in humans.

Finally, we compared samples from ovarian cancer patients before and after chemotherapy. Follistatin levels doubled or tripled in just 24 hours after treatment. On the other hand, follistatin levels dropped to baseline levels in patients not receiving chemotherapy, with no evidence of disease.

The team hopes to develop new antibody therapies that target follistatin, possibly by blocking its receptor or the follistatin gene.

20,000 women are diagnosed with ovarian cancer each year, and 13,000 to 14,000 die each year. “If our model is correct and we can cure 20 to 30 percent of these, great,” he says Panesso. “We hope that this will prove to be an effective method to help patients respond better to chemotherapy and reduce relapses.”