Ovarian cancer is the fifth biggest cause of cancer death in women, and part of its frustrating stubbornness to treat and high level of recurrence may be down to some surprisingly cellular cooperation.
A new study has shed light on the way chemotherapy-resistant quiescent cells behave during and after treatment and how they directly impact the cancer cells around them.
Chemotherapy largely targets rapidly dividing cancer cells, which makes the slow-dividing quiescent cells difficult to treat. Researchers from the University of Pittsburgh and the University of Pittsburgh Medical Center hospital have observed that not only do quiescent cells withstand aggressive drug intervention, they secrete a protein known as follistatin that slows the dividing speed of neighboring cells, making those more resistant too.
“I think about quiescent cancer cells like the yellow center of a daisy and neighboring cells as the surrounding white petals,” said Dr Ronald Buckanovich, professor of medicine at Pitt, co-director of the Women’s Cancer Research Center and co-author of the study. “In response to chemotherapy, quiescent cells secrete follistatin that acts like a signal to protect the whole flower.
“When chemotherapy stops, follistatin levels drop and cells start proliferating again, almost like a barometer that says, ‘Conditions are good to grow,’” he added. “This might explain why ovarian cancers often come back so quickly.”
The team found that quiescent cells boosted their production of follistatin in response to chemotherapy drugs in both mice and lab-grown human cells. They then observed follistatin halted the growth of surrounding dividing cells, to help them survive treatment. When researchers blocked this protein secretion, the shielding effect on surrounding cells was lost and they were again vulnerable to chemotherapy.
“We thought that quiescent cells would produce factors to make themselves resistant to chemotherapy, but the fact they also protect their neighbors and amplify chemoresistance was surprising,” said Dr Buckanovich. “If some of these neighbors learn to be quiescent themselves, which in turn protect their own neighbors, more and more resistant cells will persist and lead to cancer recurrence.”
The American Cancer Society estimates nearly 20,000 women will receive an ovarian cancer diagnosis in 2023. While surgery and chemotherapy is effective, particularly in early stages, more than 70% of patients treated for the disease will see their cancer return and at this point it’s rarely curable.
“If we’re able to reverse chemoresistance and fewer patients relapse, we might be able to increase cure rates,” said Dr Buckanovich. “Even if this approach works for 20% of patients, that would be huge because approximately 14,000 patients each year are dying from ovarian cancer.”
The team also compared samples from ovarian cancer patients before and after chemotherapy and found that follistatin levels doubled or tripled immediately after treatment. The researchers are confident that human trials may lead to follistatin-suppressing treatments to make chemotherapy more effective.
Follistatin has earlier been linked to improving outcomes for lung cancer patients undergoing chemotherapy.
“To me, the most exciting thing about this study was the fact that we saw this incredible response to chemotherapy in patients within 24 hours,” said Buckanovich. “These data reinforce our findings in mice and suggest that follistatin is a new target to improve ovarian cancer response to chemotherapy.”
The study was published in the journal Clinical Cancer Research.
Source: University of Pittsburgh
