Illustration of female reproductive system including uterus and ovaries to represent ovarian cancer
Credit: freshidea/Fotolia

Researchers have discovered a mechanism by which chemoresistant ovarian cancer cells signal neighboring cells to fall into a similar resistant state. A team from the University of Pittsburgh observed that so-called quiescent ovarian cancer cells, which are characterized by very slow growth, overexpress a normal ovarian protein called follistatin. That protein acts as a signal to local cancer cells to grow more slowly and evade killing by chemotherapies. The research is published in a paper in Clinical Cancer Research.

“We found that follistatin drives ovarian cancer cells to proliferate less,” said first author Santiago Panesso, MD, who works in the laboratory of Ronald Buckanovich, MD, PhD, professor of medicine at Pitt and co-director of the Women’s Cancer Research Center studying mechanisms of chemoresistance. While this might appear to be desirable, those slowly growing cells are able to develop resistance to standard chemotherapies. This is part of the reason why almost 70% of ovarian cancers recur and do so aggressively.

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

In earlier research, the team discovered that follistatin was one of the top upregulated proteins in another type of quiescent cell in the hair follicle. From there, the team wanted to probe if follistatin had a role in quiescent ovarian cancer cells.

In this new study, the team found that quiescent cells ramp up production of follistatin in response to chemotherapy drugs in both lab-grown human ovarian cancer cells and mice xenografted with human quiescent ovarian cancer cells.

Next, they showed that quiescent cells halt the growth of neighboring actively dividing cancer cells, making them resistant to chemotherapy drugs. First, they added media from quiescent cells and showed that the cells grew slower. The same effect was observed when quiescent cells were co-cultured with normal proliferating cells: they grew more slowly and were more chemoresistant.

“It seems that the quiescent cells have the capability of communicating to other cells to slow down to avoid being killed when they are vulnerable to chemotherapy during division and we think follistatin is how they do that,” said Panesso. “By telling neighboring cells to slow down, it creates a loop of resistance.”

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

To further confirm the role of follistatin in driving chemoresistance, the team genetically deleted the gene encoding follistatin in tumor cells that initiate 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, while all mice with normal tumors died.

Next, the team analyzed Cancer Genome Atlas data from hundreds of ovarian cancer patients. They showed that higher follistatin levels were associated with worse survival rates, indicating that follistatin also affects human ovarian.

Finally, they 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 no longer receiving chemotherapy with no evidence of disease.

The team hopes to develop new antibody therapies targeting follistatin, perhaps by blocking its receptor or the gene for follistatin.

Twenty thousand women are diagnosed with ovarian cancer every year and 13,000-14,000 are dying yearly. “So if our models are correct,  and we can cure 20-30% of these, what would be amazing,” said Panesso. “We are hoping this will prove to be a successful way of helping patients respond better to chemotherapy and reduce recurrence.”

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